Difference between revisions of "Exercise - Types, Lengths, and Benefits"

From ApoE4.Info Wiki
Jump to navigation Jump to search
m (added paper to exercise and brain)
(→‎Exercise and the Brain: added paper: Exercise restores brain insulin sensitivity in sedentary adults who are overweight and obese (Stephanie Kullmann 22 Sep 2022))
 
(47 intermediate revisions by the same user not shown)
Line 4: Line 4:
== Why ApoE4s should Exercise ==
== Why ApoE4s should Exercise ==
Exercise is good for many reasons, but especially APOE4s.
Exercise is good for many reasons, but especially APOE4s.
 
* This study [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583203/ '''Exercise engagement as a moderator of APOE effects on amyloid deposition'''] (Denise Head et al, 27 Feb 2013)  found that exercise may be particularly beneficial for cognitively normal ε4+ individuals in reducing risk of brain amyloid deposition.
* It can reduce, even reverse, '''hippocampal atrophy''' in the brain.  The hippocampus is part of the brain that is the center for emotion, memory, and the autonomic nervous system. See [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005962/ Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease (2014)].
* Exercise can reduce, even reverse, '''hippocampal atrophy''' in the brain.  The hippocampus is part of the brain that is the center for emotion, memory, and the autonomic nervous system. See [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005962/ Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease (2014)].
* Exercise increases '''BDNF''' – Brain Derived Neurotrophic Factor.  BDNF is the most active neurotrophin.  Neurotrophins induce survival, development, and function of neurons. See [https://www.ncbi.nlm.nih.gov/pubmed/27716670 BDNF Responses in Healthy Older Persons to 35 Minutes of Physical Exercise, Cognitive Training, and Mindfulness: Associations with Working Memory Function. (2017)] also [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772595/ The Effects of Aerobic Exercise Intensity and Duration on Levels of Brain-Derived Neurotrophic Factor in Healthy Men (2013)].
* Exercise increases '''BDNF''' – Brain Derived Neurotrophic Factor.  BDNF is the most active neurotrophin.  Neurotrophins induce survival, development, and function of neurons. See [https://www.ncbi.nlm.nih.gov/pubmed/27716670 BDNF Responses in Healthy Older Persons to 35 Minutes of Physical Exercise, Cognitive Training, and Mindfulness: Associations with Working Memory Function. (2017)] also [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772595/ The Effects of Aerobic Exercise Intensity and Duration on Levels of Brain-Derived Neurotrophic Factor in Healthy Men (2013)].
* Increases '''insulin sensitivity''', which benefits the body all over, but is particularly critical in the brain.  The brain needs insulin, so insulin sensitivity is imperative for healthy cognition.  It has been concluded that basically everyone who has Alzheimer’s has brain insulin resistance, whether or not they have insulin resistance elsewhere in the body. See [[Insulin Resistance]]
* Increases '''insulin sensitivity''', which benefits the body all over, but is particularly critical in the brain.  The brain needs insulin, so insulin sensitivity is imperative for healthy cognition.  It has been concluded that basically everyone who has Alzheimer’s has brain insulin resistance, whether or not they have insulin resistance elsewhere in the body. See [[Insulin Resistance]] also [[Insulin Resistance in the brain]]
* When done regularly while incorporating allowances for recovery, exercise lowers '''inflammation'''.  Low levels of inflammation correspond with maintaining cognitive function and longevity.   
* When done regularly while incorporating allowances for recovery, exercise lowers '''inflammation'''.  Low levels of inflammation correspond with maintaining cognitive function and longevity.   
* Aids mitochondrial health.  '''Mitochondria''' are the powerhouses of the cell. The brain is highly dependent on mitochondrial activity for energy production from glucose.  ApoE4 has been found to have detrimental effects on mitochondria, but exercise boosts mitochondria.
* Aids mitochondrial health.  '''Mitochondria''' are the powerhouses of the cell. The brain is highly dependent on mitochondrial activity for energy production from glucose.  ApoE4 has been found to have detrimental effects on mitochondria, but exercise boosts mitochondria.
Line 15: Line 15:
* Exercise helps keep your fat cells fit. Fat cells aren’t merely storage units, and fat isn’t merely a reserve source of body energy.  Fat is a necessary part of our body, called '''adipose tissue,''' and this tissue is comparable to an organ that serves important body functions.    Exercise aids with the blood flow and oxygen delivery to fat cells.  This helps hold inflammation at bay which occurs in the fat cells with insulin resistance.  And as discussed above and in [[Insulin Resistance]] there is a strong link between insulin resistance and Alzheimer’s Disease.
* Exercise helps keep your fat cells fit. Fat cells aren’t merely storage units, and fat isn’t merely a reserve source of body energy.  Fat is a necessary part of our body, called '''adipose tissue,''' and this tissue is comparable to an organ that serves important body functions.    Exercise aids with the blood flow and oxygen delivery to fat cells.  This helps hold inflammation at bay which occurs in the fat cells with insulin resistance.  And as discussed above and in [[Insulin Resistance]] there is a strong link between insulin resistance and Alzheimer’s Disease.
* Exercise is often accompanied by sweating and '''sweat''' can help release '''toxins/metals''' in the body.
* Exercise is often accompanied by sweating and '''sweat''' can help release '''toxins/metals''' in the body.
* Exercise increases '''endocannabinoids''' and according to this article[https://www.salk.edu/news-release/cannabinoids-remove-plaque-forming-alzheimers-proteins-from-brain-cells/ Cannabinoids Remove Plaque Forming Alzheimers Proteins from Brain Cells] "It was the study of J147 [Alzheimer’s drug candidate] that led the scientists to discover that endocannabinoids are involved in the removal of amyloid beta and the reduction of inflammation.
* Exercise increases '''endocannabinoids''' and according to this article [https://www.salk.edu/news-release/cannabinoids-remove-plaque-forming-alzheimers-proteins-from-brain-cells/ Cannabinoids Remove Plaque Forming Alzheimers Proteins from Brain Cells] "It was the study of J147 [Alzheimer’s drug candidate] that led the scientists to discover that endocannabinoids are involved in the removal of amyloid beta and the reduction of inflammation.


== Types of Exercise ==
== Types of Exercise ==
Line 29: Line 29:
::A large body of research in humans has demonstrated that consistent aerobic exercise (e.g., 30 minutes every day) induces persistent improvements in certain cognitive functions, healthy alterations in gene expression in the brain, and beneficial forms of neuroplasticity and behavioral plasticity; some of these long-term effects include: increased neuron growth, increased neurological activity (e.g., c-Fos and BDNF signaling), improved stress coping, enhanced cognitive control of behavior, improved declarative, spatial, and working memory, and structural and functional improvements in brain structures and pathways associated with cognitive control and memory.[1][2][3][4][5][6][7][8][9][10] The effects of exercise on cognition have important implications for improving academic performance in children and college students, improving adult productivity, preserving cognitive function in old age, preventing or treating certain neurological disorders, and improving overall quality of life.[1][11][12]
::A large body of research in humans has demonstrated that consistent aerobic exercise (e.g., 30 minutes every day) induces persistent improvements in certain cognitive functions, healthy alterations in gene expression in the brain, and beneficial forms of neuroplasticity and behavioral plasticity; some of these long-term effects include: increased neuron growth, increased neurological activity (e.g., c-Fos and BDNF signaling), improved stress coping, enhanced cognitive control of behavior, improved declarative, spatial, and working memory, and structural and functional improvements in brain structures and pathways associated with cognitive control and memory.[1][2][3][4][5][6][7][8][9][10] The effects of exercise on cognition have important implications for improving academic performance in children and college students, improving adult productivity, preserving cognitive function in old age, preventing or treating certain neurological disorders, and improving overall quality of life.[1][11][12]


=== High Intensity Interval Training (HIIT or HIT) – Sprint Interval Training, Tabatas, Nitric Oxide Dump ===


High Intensity Interval Training or HIIT is where one performs a short burst of high-intensity exercise followed by a period of low-intensity activity, then repeating this cycle by going back to a burst of high intensity.  There is no universal amount of time to do HIIT, but a routine typically lasts no more than 30 minutes, and for a non-athlete just working on general fitness, often far less, just a few minutes.   
=== High Intensity Interval Training (HIIT or HIT) – Sprint Interval Training, Tabata training, Nitric Oxide Dump ===
 
'''High Intensity Interval Training or HIIT''' is where one performs a short burst of high-intensity exercise followed by a period of low-intensity activity, then repeating this cycle by going back to a burst of high intensity.  There is no universal amount of time to do HIIT, but a routine typically lasts no more than 30 minutes, and for a non-athlete just working on general fitness, often far less, just a few minutes.   
 
This type of exercise has been gaining in general popularity largely because it’s not a major time commitment and it shouldn’t be done more than three times a week. 


This type of exercise has been gaining in general popularity largely because it’s not a major time commitment and it shouldn’t be done more than three times a week.  Plus, it is more effective than longer, slower cardio workouts for certain benefits.
Dr Michael Mosely suggests that HIIT (which he refers to as HIT) practiced for just three minutes can reap benefits, particularly with insulin sensitivity.  Results do vary, however, based on genetics (not ApoE4), so while 15% of people made huge strides, 20% showed no real improvement.  This link tells more:  [http://www.bbc.com/news/health-17177251 '''Can three minutes of exercise a week help make you fit?''']


Dr Michael Mosely suggests that HIIT (which he refers to as HIT) practiced for just three minutes can reap benefits, particularly with insulin sensitivity.   Results do vary, however, based on genetics (not ApoE4), so while 15% of people made huge strides, 20% showed no real improvement.  This link tells more:  [http://www.bbc.com/news/health-17177251 Can three minutes of exercise a week help make you fit?]
'''Sprint Intensity Training''' is similar to HIIT in that it involves short periods of high intensity. Sprint intensity training typically involves bursts at 100% exertion. In contrast, HIIT uses high intensity, but not necessarily full exertion, for the high intensity intervals.


According to this study, [http://www.cell.com/cell-metabolism/fulltext/S1550-4131(17)30099-2 Enhanced Protein Translation Underlies Improved Metabolic and Physical Adaptations to Different Exercise Training Modes in Young and Old Humans] published in Cell Metabolism in March 2017, “High-intensity interval training improved age-related decline in muscle mitochondria” and “HIIT revealed a more robust increase in gene transcripts than other exercise modalities, particularly in older adults,…”
'''Tabata training''' is a variation on HIIT.  Tabata training breaks a workout down into clearly defined intervals – typically, 20 seconds of a push-it-to-the-limit exercise followed by 10 seconds of rest. Eight consecutive work-and-relax cycles go into a 4-minute round in Tabata. Four rounds go into a full 20-minute training circuit. This is intended to be an intense aerobic (cardio) and anaerobic (strength) experience. Tabata pushes the boundary of VO2 max, the technical term for oxygen used during exercise.


Dr Joe Mercola, an osteopathic physician who through his website http://fitness.mercola.com/ discusses alternative medicine approaches, advocates a particular type of HIIT called the Nitric Oxide DumpHe says it is easier than other HIIT practices, requires no equipment, can be done by anyone regardless of fitness level, and only takes three minutes two or three times a day. He says controlling Nitric Oxide formation has a number of influences on one’s health, including stimulating the brain.  You can read more about this at [https://www.healthnutnews.com/new-exercise-dumps-nitric-oxide-relaxes-blood-vessels-in-3-minutes/ New exercise dumps nitric oxide, relaxes blood vessels in 3 minutes]
'''Nitric Oxide Dump''' The Nitric Oxide Dump exercise involves just four movements — squats, alternating arm raises, arm circles, and shoulder presses — which are done in repetitions of 10, with four sets each. In total, it takes just three to four minutes. By incorporating all of these exercises, you maximize the amount of blood flow throughout your body, rather than limiting it to just one portion of your bodyIt is easier than other HIIT practices, requires no equipment, can be done by nearly anyone regardless of fitness level, plus only takes three minutes two or three times a day. Controlling Nitric Oxide formation has a number of influences on one’s health, including stimulating the brain and lowering high blood pressureIn this almost 8 minute long video [https://www.youtube.com/watch?v=we_YV83RDsQ '''The 4 Minute Workout | Nitric Oxide Boost at Any Age'''] Jan Howell (note she is not a buff athlete, but a gray-haired, ordinary woman) illustrates and discusses this 4 minute (or less) workout created by Dr. Zach Bush.


=== Strength training - Weight lifting, resistance training (flex bands, body weight), cross-fit ===
=== Zone 2 Exercise ===
 
When you say the word “exercise” to some people they respond negatively, but it doesn’t have to be a “butt-kicking” exhausting drudgery. When it comes to cardiovascular exertion, there are 5 “zones” representing a rating of perceived exertion from very light exertion (zone 1) to very hard (zone 5).
 
Zone 2 aka “Light” is '''prolonged low-intensity aerobic training'''. It is of particular interest to those wishing boost their mitochondria, important for ApoE4s, as it stimulates the mitochondria to create ATP (cellular energy) and improves mitochondrial efficiency. See  [[Mitochondria]].  Zone 2 exercise offers many other health benefits also: increased cardiovascular health, helpful if trying to lose weight, improves mood, and prevents injury.
 
Zone 2 cardio is an exercise performed within a heart rate zone that represents 60% to 70% of the maximum heart rate (MHR). To determine whether you're in zone 2, you can go off perceived exertion or calculate your maximum heart rate and calculate a target range from there.
 
Most will tell you that your maximum heart rate is found using the equation: 220 - your age = MHR. (So if 60 years old: 220 – 60 = 160 maximum heart rate (MHR). Then 60% to 70% of that MHR is a Zone 2 heart rate target of 96 to 112.
 
However, a newer formula used among trainers is 208 - (0.7 x your age) = MHR. (So if 60 years old: 208 – (0.7x60 which is 42) = 166. Then 60 to 70% of 166 is a Zone 2 heart rate target of 99.6 to 116.2.)
 
There is no clear consensus on the amount of time zone 2 training, however, at least 30 minutes to it two to three times per week is a good recommendation.
 
 
=== Resistance training - Weight lifting, strength training, bands, body weight, cross-fit, pilates ===


Being strong is a part of general health and well-being.  Exercising for strength has many benefits, but those of particular interest to ApoE4s:
Being strong is a part of general health and well-being.  Exercising for strength has many benefits, but those of particular interest to ApoE4s:
Line 52: Line 70:
==== Resistance training and Cognition ====
==== Resistance training and Cognition ====


There aren’t many studies correlating strength exercise specifically to cognitive health, but here are two:  
A complete ApoE4 exercise program should include resistance training.  Resistance training also known as strength training involves the performance of exercises that are designed to improve strength and endurance. This training is performed by contracting muscles against a ''resisting'' force.  It is often associated with the lifting of weights, but it can also incorporate a variety of training techniques such as bodyweight exercises, resistance bands, isometrics, and plyometrics (plyometrics is a type of exercise training that uses speed and force). 
 
Resistance training can increase muscle, tendon, and ligament strength as well as bone density, metabolism, and the lactate threshold; improve joint and cardiac function; and reduce the risk of injury.  But of greatest interest to ApoE4s, resistance training improves '''muscle and bone health'''.
 
===== Muscles and brain health =====
'''Sarcopenia''' is the gradual loss of muscle mass and strength.  Studies indicate that loss of muscle mass is correlated with loss of cognition.  Risk factors for sarcopenia include age, malnutrition, and level of physical activity.  Some studies on sarcopenia with their findings:
 
[https://www.mdpi.com/1422-0067/24/9/7809 '''APP in the Neuromuscular Junction for the Development of Sarcopenia and Alzheimer’s Disease'''] (Min-Yi Wu et al, 25 Apr 2023)
::We summarize key findings from the burgeoning literature, which may open new avenues to investigate the link between muscle cells and brain cells in the development and progression of AD and sarcopenia.
 
[https://journals.physiology.org/doi/abs/10.1152/japplphysiol.00659.2022 '''Early-stage Alzheimer’s disease: are skeletal muscle and exercise the key?'''] (Matthew H. Brisendine and Joshua C. Drake, 21 Feb 2023)  This paper is behind a paywall, but from the abstract:
::Evidence from animal models of AD suggests a close link among skeletal muscle mass, mitochondria function, and cognition. Exercise is a powerful stimulus for improving mitochondria function and muscle health, and its benefits to cognition have been suggested as a possible therapeutic strategy for AD.
 
[https://onlinelibrary.wiley.com/doi/full/10.1002/jcsm.12830 '''Skeletal muscle atrophy-induced hemopexin accelerates onset of cognitive impairment in Alzheimer's disease'''] (Tsukasa Nagase & Chihiro Tohda, 17 Oct 2021) From conclusions:
::These findings provide new evidence indicating that skeletal muscle atrophy has an unbeneficial impact on the occurrence of memory impairment in young 5XFAD mice, which is mediated by the muscle secreted hemopexin.
 
[https://www.sciencedirect.com/science/article/abs/pii/S016749432030265X '''Sarcopenia and frailty in individuals with dementia: A systematic review'''] (Samantha J. Waite et al,  January–February 2021).  The full paper is behind a paywall, but from the abstract:
::An increased prevalence of frailty and sarcopenia was noted in dementia patients.
 
[https://www.frontiersin.org/articles/10.3389/fneur.2018.00710/full '''Sarcopenia and Muscle Functions at Various Stages of Alzheimer Disease'''] (Yusuke Ogawa et al, 28 Aug 2018)
This study aimed to investigate the prevalence of sarcopenia, factors associated with sarcopenia in elderly subjects with AD, and differences in muscle functions of the upper and lower extremities and gait speed at various stages of AD. ...The '''prevalence rate of sarcopenia was significantly higher in early AD, mild AD, and moderate AD''' than in NC [normal cognition]. (bold font added for emphasis)
 
 
'''SOLEUS MUSCLE'''
[[File:Soleus muscle2.jpeg|thumb|The soleus muscle is a wide flat muscle of the lower leg that lies under the gastronemius muscle]]
The soleus muscle appears to be one muscle that shouldn’t be ignored when it comes to brain health.  The soleus is a wide flat muscle of the lower leg that lies under the gastronemius muscle.  These two muscles are known as the calf muscles. The soleus muscles are responsible for pumping blood back up to the heart.  This is measured by resting diastolic blood pressure.  Diastolic blood pressure is the second number of a blood pressure reading, it measures the pressure in the arteries between heartbeats. Low diastolic pressure can arise as a result of medication use, heart failure or other health complications. But, in most people, it is simply a matter of the heart not pumping out enough blood with each stroke; in other words, when not enough blood is being returned to the heart from the lower body. 
 
From this article  [https://neurosciencenews.com/calf-muscles-dementia-19069/?fbclid=IwAR0Cq54YurdXCdLozMOU1P2BSgWdjH8Pnlc7H8xJlz3z_IdSUa1UPPQ2IfU '''Calf Muscles and Blood Pressure Can Predict Dementia Risk'''] published by ''NeuroscienceNews'' on August 5, 2021:
::Low blood pressure is associated with decreased blood flow to the brain when an individual is sitting or standing. Many researchers have come to believe that insufficient brain blood flow plays a critical role in the development of dementia, Alzheimer’s and perhaps even Parkinson’s disease. Some believe that it may even play the primary role.
::The soleus muscles, specialized muscles in the middle of your lower legs, are responsible for pumping blood back up to the heart.
::An effective strategy for maintaining normal blood pressure, and brain blood flow, is to “re-train” your soleus muscles. These deep postural muscles are most active during activities such as sustained squatting or toe standing.
 
There's also this paper [https://www.dovepress.com/reversal-of-cognitive-impairment-in-a-hypotensive-elderly-population-u-peer-reviewed-fulltext-article-CIA '''Reversal of cognitive impairment in a hypotensive elderly population using a passive exercise intervention'''] (KJ McLeod and A Stromhaug, 7 Nov 2017) where the researchers Used a “passive” exercise regimen (noninvasive calf muscle pump stimulation) on elderly (82.5±7.5 years) participants to improve diastolic blood pressure (DBP) and from this paper:
::Here, we investigate a passive form of exercise, micromechanical stimulation of the plantar surface, a technology which activates the calf muscle pump in the lower legs, thereby enhancing cardiac return, normalizing blood pressure, and improving cerebral blood flow. Men and women residing in a senior living center were segregated into normal blood pressure (control) group and low blood pressure (intervention) group. The intervention group undertook passive exercise for 1 hour/day. While at the start of the study the intervention group’s performance was significantly worse in executive function tests compared to the control group, by the 14th week of the study, those in the intervention group had improved to the point of matching the performance of the control group.
 
===== Bones and brain health =====
Bones are generally thought of as static structural support for the body, but bones are becoming increasingly recognized for its endocrine function of secreting several hormones, thereby controlling various physiological pathways.  Osteocalcin is one of those bone derived hormones and one of the physiological functions it influences is brain function.
 
''Medscape'' reported on a study that was published online on March 22, 2023 in Neurology in this article, [https://www.medscape.com/viewarticle/990048?fbclid=IwAR3tX7yw7bBnlLOqj0ZTTvEDNR-A-klN36tYUw28bIn5JAj_N4Lvjb5voBU&form=fpf '''Poor Bone Health a 'Robust' Dementia Risk Factor'''].  The article reported:
::Now a long-running Rotterdam study has recently found that low bone mineral density (BMD), particularly at the femoral neck, emerged as a "robust" risk factor for dementia in older adults.
 
This 2020 article [https://www.theguardian.com/science/2020/jul/04/does-the-key-to-anti-ageing-lie-in-our-bones?fbclid=IwAR0aEMY297PQ-IL6rEfrMDEWdVE7zGmxYCXcVMy-jD_MrNKR6RUN7cNvikw '''Does the key to anti-ageing lie in our bones?'''] addresses osteocalcin specifically:
::Osteocalcin, a hormone produced in the bones, could one day provide treatments for age-related issues such as muscle and memory loss.
 
 
===== Papers on resistance training and cognition =====
Some studies that have found cognitive improvements through resistance training:
 
[https://link.springer.com/article/10.1186/s11556-019-0217-2?fbclid=IwAR0thvhgKQG-dfpF4oyCnhtMEwg4K5df40f9ksl_JE25YojiJ9PYCZLwNRg '''Functional and/or structural brain changes in response to resistance exercises and resistance training lead to cognitive improvements – a systematic review'''] (Fabian Herold et al, 10 Jul 2019)
::Based on our analyses, resistance exercises and resistance training evoked substantial functional brain changes, especially in the frontal lobe, which were accompanied by improvements in executive functions. Furthermore, resistance training led to lower white matter atrophy and smaller white matter lesion volumes.


In Australia, a University of Sydney study, [http://onlinelibrary.wiley.com/doi/10.1111/jgs.14542/full Mediation of Cognitive Function Improvements by Strength Gains After Resistance Training in Older Adults with Mild Cognitive Impairment: Outcomes of the Study of Mental and Resistance Training] linked stronger muscles with improved cognitive function.  Published in the Journal of American Geriatrics in October 2016, the trial was done on a group of 100 patients age 55 to 68, suffering MCI (mild cognitive impairment).  The participants were divided into four groups, and each assigned a particular activity:  
In Australia, a University of Sydney study, [http://onlinelibrary.wiley.com/doi/10.1111/jgs.14542/full Mediation of Cognitive Function Improvements by Strength Gains After Resistance Training in Older Adults with Mild Cognitive Impairment: Outcomes of the Study of Mental and Resistance Training] linked stronger muscles with improved cognitive function.  Published in the Journal of American Geriatrics in October 2016, the trial was done on a group of 100 patients age 55 to 68, suffering MCI (mild cognitive impairment).  The participants were divided into four groups, and each assigned a particular activity:  
Line 64: Line 131:
Another study, [http://www.nature.com/mp/journal/v21/n11/full/mp201619a.html?foxtrotcallback=true Therapeutically relevant structural and functional mechanisms triggered by physical and cognitive exercise ] published March 2016 found that PRT [progressive resistance training] improved global cognition.  From the study:  
Another study, [http://www.nature.com/mp/journal/v21/n11/full/mp201619a.html?foxtrotcallback=true Therapeutically relevant structural and functional mechanisms triggered by physical and cognitive exercise ] published March 2016 found that PRT [progressive resistance training] improved global cognition.  From the study:  


::Here we report for the first time that resistance training can conserve and even increase cortical thickness in the posterior cingulate. This mechanism may be salient to long-term protection from further cognitive decline and impairment because loss of PC gray matter is a biomarker of AD,71, 72 most likely because of neuronal loss in specific cortical laminae.73, 74  
::Here we report for the first time that resistance training can conserve and even increase cortical thickness in the posterior cingulate. This mechanism may be salient to long-term protection from further cognitive decline and impairment because loss of PC gray matter is a biomarker of AD,71, 72 most likely because of neuronal loss in specific cortical laminae.73, 74


==== Aim for Healthy muscles, not Big muscles ====
==== Aim for Healthy muscles, not Big muscles ====
Line 74: Line 141:
Body builders who want large, pronounced muscles eat a high protein diet to aid in achieving this.  Protein raises Insulin Like Growth Factor 1 or IGF-1.  As the name suggests, IGF-1 stimulates cells, like muscle cells, to grow.  But IGF-1 doesn’t discriminate. In addition to muscle cells, it can also stimulate cancer cell growth and affect other factors that affect longevity.  A lower IGF-1 is connected with longer, more healthful aging.  It should be noted plant protein doesn’t have the same effect on IGF-1.  Excess animal protein is especially more likely to raise IGF-1. Some studies:
Body builders who want large, pronounced muscles eat a high protein diet to aid in achieving this.  Protein raises Insulin Like Growth Factor 1 or IGF-1.  As the name suggests, IGF-1 stimulates cells, like muscle cells, to grow.  But IGF-1 doesn’t discriminate. In addition to muscle cells, it can also stimulate cancer cell growth and affect other factors that affect longevity.  A lower IGF-1 is connected with longer, more healthful aging.  It should be noted plant protein doesn’t have the same effect on IGF-1.  Excess animal protein is especially more likely to raise IGF-1. Some studies:


[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988204/ Low Protein Intake is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population] published March 2014:  
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988204/ '''Low Protein Intake is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population'''] published March 2014:  
::Respondents (n=6,381) aged 50–65 reporting high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer and diabetes mortality during an 18 year follow up period. These associations were either abolished or attenuated if the source of proteins was plant-based.
::Respondents (n=6,381) aged 50–65 reporting high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer and diabetes mortality during an 18 year follow up period. These associations were either abolished or attenuated if the source of proteins was plant-based.


[https://www.ncbi.nlm.nih.gov/pubmed/26268661 Growth hormone modulates hypothalamic inflammation in long-lived pituitary dwarf mice]
[https://www.ncbi.nlm.nih.gov/pubmed/26268661 '''Growth hormone modulates hypothalamic inflammation in long-lived pituitary dwarf mice''']
Published Dec 2015:
Published Dec 2015:
::Mice in which the genes for growth hormone (GH) or GH receptor (GHR(-/-) ) are disrupted from conception are dwarfs, possess low levels of IGF-1 and insulin, have low rates of cancer and diabetes, and are extremely long-lived.
::Mice in which the genes for growth hormone (GH) or GH receptor (GHR(-/-) ) are disrupted from conception are dwarfs, possess low levels of IGF-1 and insulin, have low rates of cancer and diabetes, and are extremely long-lived.


[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673798/ Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans ] Published Oct 2008:
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673798/ '''Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans'''] Published Oct 2008:
::Reduced function mutations in the insulin/IGF-I signaling pathway increase maximal lifespan and health span in many species…. These findings demonstrate that, unlike in rodents, long-term severe CR does not reduce serum IGF-1 concentration and IGF-1 : IGFBP-3 ratio in humans.  In addition, our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans, and suggest that reduced protein intake may become an important component of anticancer and anti-aging dietary interventions.
::Reduced function mutations in the insulin/IGF-I signaling pathway increase maximal lifespan and health span in many species…. These findings demonstrate that, unlike in rodents, long-term severe CR does not reduce serum IGF-1 concentration and IGF-1 : IGFBP-3 ratio in humans.  In addition, our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans, and suggest that reduced protein intake may become an important component of anticancer and anti-aging dietary interventions.
===== Oxidative Stress from too much exercise =====
Excess exercise can increase radical production and oxidative stress which negatively impacts the body.
[https://www.frontiersin.org/articles/10.3389/fphys.2021.712372/full?fbclid=IwAR0tZLUugFj2vs96lrCLqvk0617cXRWW_gYOcri3_t7YEBKE3Uj91hCLE_o '''Management of Oxidative Stress: Crosstalk Between Brown/Beige Adipose Tissues and Skeletal Muscles''']
::In this review, we summarize the integrated effects of exercise on oxidative metabolism, and especially focus on the role of brown and beige adipose tissues in this process, providing more evidence and knowledge for a better management of exercise-induced oxidative stress.


===== Exercise Intensity can lead to cardiovascular damage =====
===== Exercise Intensity can lead to cardiovascular damage =====
Line 88: Line 164:
In his presentation at the Ancestral Health Symposium in August 2016, [https://www.youtube.com/watch?v=Bfr9RPq0HFg AHS16 - Steven Gundry - Dietary Management of the Apo E 4] at 26:10, Dr Steven Gundry said, “that the last thing ApoE4s should be doing is Cross Fit.”  CrossFit is a program of aerobic exercise, calisthenics and Olympic weightlifting.  It is typically very intense, emphasizing competition as well as exercise.  When later asked to elaborate on his statement, Dr Gundry indicated that that the indictment was not just on cross-fit but all intense, stressful workouts.  He cautioned that ApoE4s have to be mindful of their greater potential to develop small vessel disease.  Small blood vessels exist in the brain and heart as well as elsewhere in the body. He stated that almost every one of his patients who are intense cross-fitters, or marathoners, or other high-intensity participants have elevated Cardiac Troponin-I markers.  Cardiac Troponin-I is a test that is a hundred more times sensitive than the test in the emergency room looking for heart attacks.  But he also stated that when his patients back off from the intensity, this marker goes back to normal.   
In his presentation at the Ancestral Health Symposium in August 2016, [https://www.youtube.com/watch?v=Bfr9RPq0HFg AHS16 - Steven Gundry - Dietary Management of the Apo E 4] at 26:10, Dr Steven Gundry said, “that the last thing ApoE4s should be doing is Cross Fit.”  CrossFit is a program of aerobic exercise, calisthenics and Olympic weightlifting.  It is typically very intense, emphasizing competition as well as exercise.  When later asked to elaborate on his statement, Dr Gundry indicated that that the indictment was not just on cross-fit but all intense, stressful workouts.  He cautioned that ApoE4s have to be mindful of their greater potential to develop small vessel disease.  Small blood vessels exist in the brain and heart as well as elsewhere in the body. He stated that almost every one of his patients who are intense cross-fitters, or marathoners, or other high-intensity participants have elevated Cardiac Troponin-I markers.  Cardiac Troponin-I is a test that is a hundred more times sensitive than the test in the emergency room looking for heart attacks.  But he also stated that when his patients back off from the intensity, this marker goes back to normal.   


Another potential result of excess intense exercise is Atrial fibrillation (AFib).  AFib is an abnormal or rapid heart rate, a common but serious arrhythmia.  Two groups are at high risk for AFib: Obese, sedentary people, and thin, active people who '''over exercise'''.  From this article, [http://www.drjohnm.org/2011/09/an-iron-response/ An "Iron" response] by Dr. John Mandrola, a cardiac electrophysiologist:  “There are hundreds of citations documenting the risk of atrial fibrillation in long-term endurance athletes.” He then went on to cite six specific references.
Another potential result of excess intense exercise is '''Atrial fibrillation''' (AFib).  AFib is an abnormal or rapid heart rate, a common but serious arrhythmia.  Two groups are at high risk for AFib: Obese, sedentary people, and thin, active people who '''over exercise'''.  From this article, [http://www.drjohnm.org/2011/09/an-iron-response/ An "Iron" response] by Dr. John Mandrola, a cardiac electrophysiologist:  “There are hundreds of citations documenting the risk of atrial fibrillation in long-term endurance athletes.” He then went on to cite six specific references.
 
=== Blood Flow Restriction (BFR) Bands (KAATSU, B Strong, etc.) ===
 
Blood flow Restriction bands trick the body into thinking it’s working harder than it really is.  They help with building/maintaining muscle, muscle warm up before exercise, muscle recovery after exercise, pain relief, and therapeutically for injury or surgery recovery. 
 
KAATSU bands are unique blood flow restriction bands as they come with a compressor that inflates and deflates the bands to cycle the restriction.  In cycle mode, they can provide benefit while just sitting or doing mild activity around the house.
 
'''How blood flow restriction provides benefit''':
::*Increase muscle strength with lower weight thereby protecting the load on tendons and joints and without actually breaking down muscle fiber. This is especially beneficial for those who are middle-aged and older.
::*Upregulate healing growth hormones, like BDNF and plasmalogens.  This is accomplished by creating a mildly hypoxic state in your muscles. 
::*Engorges the blood in your capillaries and veins enabling circulation to improve and for your vascular system to become more elastic — upregulating nitric oxide — protecting against cardiovascular disease.
 
But be safe when using BFR bands.  This isn’t hard, but it is important to know how to position the bands appropriately and how to test for capillary refill time to assure you’re not occluding blood flow too harshly which can be damaging.
 
For more info: 
[https://www.apollohealthco.com/kaatsu-for-strength-training-and-much-more/?fbclid=IwAR1nvRBua5GBYRBfVu4TwcyZU2ZpWMFj4N7NUea-WQSL68BkSzkVxS-j3Gw KAATSU for Strength Training and Much More] 
 
[https://health.clevelandclinic.org/blood-flow-restriction-training/ What Is Blood Flow Restriction (BFR) Training?]
 
[https://www.ihmc.us/stemtalk/episode-34/ EPISODE 34: JIM STRAY-GUNDERSEN EXPLAINS HOW BLOOD FLOW RESTRICTION TRAINING BUILDS MUSCLE AND IMPROVES PERFORMANCE] Includes show notes and references
 
=== Vibration plate therapy ===
 
Vibration plates or vibration platforms are machines that vibrate at high frequencies.  As it vibrates, it transmits energy to the body, forcing the muscles to contract and relax dozens of times each second.
 
Vibration therapy was first used to reduce the severity of muscle mass and bone density decline in cosmonauts.  It was later used in improving muscle strength.  For years now, professional athletes have been training with vibration plates to prepare for competition and recover quicker.
 
Reported vibration plate benefits include:
::*improved muscle strength
::*reduced back pain
::*improved strength and balance in older adults
::*improved circulation
::*boost to lymphatic drainage
::*improved bone density
::*pain reduction
 
Just standing on the device is said to activate and build muscle, but using the vibration plate with exercise amplifies the benefits.
 
Using a vibration plate may also benefit the brain.  This study, [https://www.nature.com/articles/s41598-022-13178-1?fbclid=IwAR1lMKUo3d8U5u7hNrtR4r10aqbrNeLst8b3wGd3OH0z-lCE5ZbVC92lgFI '''Chronic whole body vibration ameliorates hippocampal neuroinflammation, anxiety-like behavior, memory functions and motor performance in aged male rats dose dependently'''](Tamás Oroszi et al, 30 May 22) was conducted on aged rats over five weeks: 
::Our results indicate, that WBV [Whole Body Vibration] seems to be a comparable strategy on age-related anxiety, cognitive and motor decline, as well as alleviating age-related (neuro)inflammation.
 
But vibration plate therapy is not a substitute for exercise and it is also is not for everyone.  In certain cases it may lead to joint pain, muscle damage and back pain.  There are a number of conditions that are contraindicated for vibration plate usage, so some investigation and/or health care practioner consultation may be prudent before hopping on.


=== Just moving - strolling in the park, tai chi, dancing, gardening, etc. ===
=== Just moving - strolling in the park, tai chi, dancing, gardening, etc. ===


There’s a lot to be said for just moving.  As a society, we sit a lot:  working on the computer, video games, desk work, driving, watching television. Our ancestors didn’t do that, but they did keep very active.   
There’s a lot to be said for just moving.  As a society, we sit a lot:  working on the computer, video games, desk work, driving, watching television. Our DNA still thinks it's living in the past and our ancestors weren't sedentary.  They didn't run marathons, but they kept very active.   


According to this study, [https://www.ncbi.nlm.nih.gov/pubmed/24690272 Exercise, APOE genotype, and the evolution of the human lifespan  ]
According to this study, [https://www.ncbi.nlm.nih.gov/pubmed/24690272 '''Exercise, APOE genotype, and the evolution of the human lifespan''' ]
::Our hypothesis suggests that increased selection for exercise and physical activity served to ameliorate the effects of APOE ε4, supporting the evolution of longer human lifespans and achieving the potential for successful advanced aging. Thus, changes induced by modern-day environmental constraints and human behavior may have led to greater vulnerability to the effects of APOE ε4 in subgroups of elderly in which high levels of physical activity throughout life are no longer required.
::Our hypothesis suggests that increased selection for exercise and physical activity served to ameliorate the effects of APOE ε4, supporting the evolution of longer human lifespans and achieving the potential for successful advanced aging. Thus, changes induced by modern-day environmental constraints and human behavior may have led to greater vulnerability to the effects of APOE ε4 in subgroups of elderly in which high levels of physical activity throughout life are no longer required.
In other words, physical activity helped man extend its overall lifespan, but now, modern day lifestyle has far less demand for physical activity and this is exposing the ApoE4 gene’s health vulnerabilities.   
In other words, physical activity helped man extend its overall lifespan, but now, modern day lifestyle has far less demand for physical activity and this is exposing the ApoE4 gene’s health vulnerabilities.   
Line 132: Line 250:
<big><big>Not a complete compilation of studies, just a sampling.
<big><big>Not a complete compilation of studies, just a sampling.
</big></big>
</big></big>
=== Exercise and ApoE4 ===
[https://www.frontiersin.org/articles/10.3389/fnagi.2023.1184609/full '''Association between physical activity and episodic memory and the moderating effects of the apolipoprotein E ε4 allele and age'''] (Boung Chul Lee et al, 11 Jul 2023)
::Our findings suggest that physical activity has beneficial effects on episodic memory, as an AD-related cognitive domain, in individuals aged > 70 years and in APOE4-positive individuals. Physicians should take age and APOE4 status account into when recommending physical activity to prevent AD-related cognitive decline.
[https://www.bmj.com/content/380/bmj-2022-072691 '''Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study'''] (Jianping Jia et al, 25 Jan 2023)
::Conclusion A healthy lifestyle is associated with slower memory decline, even in the presence of the APOE ε4 allele. This study might offer important information to protect older adults against memory decline.
[https://n.neurology.org/content/99/8/e789 '''Effects of Sex, APOE4, and Lifestyle Activities on Cognitive Reserve in Older Adults'''](Judy Pa et al, 23 Aug 2022)
::Discussion. The associations of self-reported physical and cognitive activities with cognitive reserve are more pronounced in women, although APOE4 attenuates these associations. Future studies are needed to understand the causal relationship among sex, lifestyle activities, and genetic factors on cognitive reserve in older adults to best understand which lifestyle activities may be most beneficial and for whom.
[https://www.sciencedirect.com/science/article/abs/pii/S0197458022000355?via%3Dihub '''Cerebrovascular response to exercise interacts with individual genotype and amyloid-beta deposition to influence response inhibition with aging'''](Jacqueline A. Palmer et al, June 2022)
::• Neurobiological interactions between CVR [cerebrovascular response], APOE genotype, and Aβ [Amyloid beta ]are behaviorally significant.
::• Blunted CVR to exercise is associated with impaired response inhibition specifically in APOE4 carriers.
::• APOE4 carriers with more robust CVR have higher response inhibition performance, despite having greater Aβ deposition.
::• Assessment of multifactorial neurobiological variables offers an early and sensitive biomarker of cognitive behavioral dysfunction with aging.
[https://www.frontiersin.org/articles/10.3389/fnagi.2021.697528/full '''Influence of Physical Activity Levels and Functional Capacity on Brain β-Amyloid Deposition in Older Women'''] (Raquel Pedrero-Chamizo1 et al, 8 July 2021)
::The aim of this study was to determine if PA [Physical Activity] levels and/or functional capacity (FC) are associated with Aβ plaque deposition, and whether these associations differed according to APOE-ε4 genotype. … In conclusion, low performance in TUGt [Timed Up and Go test] is associated with a negative effect on brain pathology with increasing cerebral Aβ depositions in older women who are APOE-ε4+. In physically active older women (> 600 METs·min/week), higher PA levels are not associated with reduction in Aβ depositions.
[https://www.mdpi.com/1660-4601/18/14/7238 '''Can Physical Activity Reduce the Risk of Cognitive Decline in Apolipoprotein e4 Carriers? A Systematic Review'''] (Jose Luis Perez-Lasierra et al, 6 Jul 2021)
The link will take to you the abstract but within this link you can download the entire PDF paper.  From the conclusions section of the paper: 
::The results of the studies included in this systematic review support the idea that PA [Physical Activity]is a protective factor against CD [Cognitive Decline] in individuals of high genetic risk, specifically APOE e4 carriers. These findings have high clinical and public health significance. Moreover, the results suggest that in this population, a higher dose of PA (amount and/or intensity) might have greater benefits, but it would be necessary to carry out further studies that would allow these findings to be contrasted, since the existing evidence is limited. Further studies should try to establish the optimal dose of PA to effectively and efficiently prevent CD in APOE e4 carriers.
[https://link.springer.com/article/10.1007/s40119-020-00209-z '''Exercise as Potential Therapeutic Target to Modulate Alzheimer’s Disease Pathology in APOE ε4 Carriers: A Systematic Review'''] (Sevilay Tokgöz and Jurgen A. H. R. Claassen 5 Jan 2021)
::This review focuses on the effect of exercise on cognitive function, dementia risk, amyloid-β (Aβ) metabolism, lipid metabolism, neuroinflammation, neurotrophic factors and vascularization in APOE ε4 carriers. We searched the literature in the PubMed electronic database using the following search terms: physical activity, exercise, aerobic fitness, training, sport, APOE4, Alzheimer’s disease, AD and dementia. … From these studies, we conclude that exercise is a non-pharmacological treatment option for high-risk APOE ε4 carriers to ameliorate the AD pathological processes including reducing Aβ load, protecting against hippocampal atrophy, improving cognitive function, stabilizing cholesterol levels and lowering pro-inflammatory signals.
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093017/ '''Midlife Lifestyle Activities Moderate APOE ε4 Effect on in vivo Alzheimer’s Disease Pathologies'''] (So Yeon Jeon et al, 27 Feb 2020)
::The findings suggest that high midlife cognitive activity may accelerate hippocampal atrophy induced by APOE4, whereas high midlife physical activity may delay AD-related cerebral hypometabolism by weakening the influence of APOE4-associated Aβ retention.
=== Exercise and the Brain ===
=== Exercise and the Brain ===
Not a complete list.
[https://www.cell.com/neuron/fulltext/S0896-6273(23)00623-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627323006232%3Fshowall%3Dtrue '''Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling'''] (Eunhee Kim et al, 8 Sep 2023)  The findings of this paper reveal a cellular and molecular mechanism by which exercise-induced irisin attenuates Amyloid beta pathology. 
::In summary, we present the experimental data showing that irisin reduces Aβ pathology by increasing NEP activity/level secreted from astrocytes. Furthermore, we have delineated the involved molecular mechanism from identifying the astrocyte receptor, integrin αV/β5, to demonstrating the inhibition of IL-6/ERK and NF-κB-STAT3 signaling, resulting in increased secretion of NEP and reduction of Aβ levels. Thus, our findings offer strong support for developing irisin as a therapeutic target to reduce Aβ burden for AD treatment and prevention.
[https://journals.physiology.org/doi/full/10.1152/japplphysiol.00611.2022?fbclid=IwAR2bvzVwaOghGZZTmALtydgr8cbitkWXQIg20ULzhpfoXoRGEMaUlu0JbvQ '''Exercise and mitochondrial remodeling to prevent age-related neurodegeneration'''](Colleen L. O’Reilly et al 09 JAN 2023)
::This mini-review describes the role of mitochondria in neurodegeneration and brain health, current practices for assessing both aspects of mitochondrial remodeling, and how exercise mitigates the adverse effects of aging in the brain. Exercise training elicits functional adaptations to improve brain health, and current literature strongly suggests that mitochondrial remodeling plays a vital role in these positive adaptations. Despite substantial implications that the two aspects of mitochondrial remodeling are interdependent, very few investigations have simultaneously measured mitochondrial dynamics and protein synthesis. An improved understanding of the partnership between mitochondrial protein turnover and mitochondrial dynamics will provide a better understanding of their role in both brain health and disease, as well as how they induce protection following exercise.
[https://journals.physiology.org/doi/full/10.1152/japplphysiol.00375.2022 '''Brain Insulin Resistance and Cognitive Function: influence of exercise'''] (Steven K. Malin et al, 8 Dec 2022) Brain insulin resistance has been associated with age-related declines in memory and executive function as well as Alzheimer’s disease pathology.
::Herein, we provide an overview of brain insulin sensitivity in relation to cognitive function from animal and human studies, with particular emphasis placed on the impact exercise may have on brain insulin sensitivity. Mechanisms discussed include mitochondrial function, brain growth factors, and neurogenesis, which collectively help combat obesity-related metabolic disease and Alzheimer’s dementia.
[https://www.mdpi.com/1422-0067/23/6/3245/htm '''Physical Exercise, a Potential Non-Pharmacological Intervention for Attenuating Neuroinflammation and Cognitive Decline in Alzheimer’s Disease Patients'''](Samo Ribarič 17 March 2022)
::This narrative review summarises the evidence for considering physical exercise (PE) as a non-pharmacological intervention for delaying cognitive decline in patients with Alzheimer’s disease (AD) not only by improving cardiovascular fitness but also by attenuating neuroinflammation. ... Further studies in human are necessary to develop optimal, personalised protocols, adapted to the progression of AD and the individual’s mental and physical limitations, to take full advantage of the beneficial effects of PE that include improved cardiovascular fitness, attenuated systemic inflammation and neuroinflammation, stimulated brain Aβ peptides brain catabolism and brain clearance.
[https://neurosciencenews.com/exercise-inflammation-alzheimers-19712/ '''Exercise May Reduce Brain Inflammation, Reducing the Risk of Alzheimer’s''' ](NeuroscienceNews 28 Nov 2021)
::Physical activity is very important for a number of reasons – including that it helps to protect the structure and function of our brain as we age. This may be key in reducing the risk of developing certain neurodegenerative conditions, such as Alzheimer’s disease.
[https://www.frontiersin.org/articles/10.3389/fendo.2021.660181/full '''Effects of Aerobic Exercise Training on Systemic Biomarkers and Cognition in Late Middle-Aged Adults at Risk for Alzheimer’s Disease'''] (Julian M. Gaitán et al, 20 May 2021)
Until this study, systemic biomarkers to measure exercise effects on brain function and the link to relevant metabolic responses were lacking. This study shows that a memory biomarker, myokine Cathepsin B (CTSB), increased in older adults following a 26-week structured aerobic exercise training. The positive association between CTSB and cognition, and the substantial modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function and brain health in asymptomatic individuals at risk for Alzheimer's.
::Overall, our analyses indicate metabolic regulation of exercise-induced plasma BDNF changes and provide evidence that CTSB is a marker of cognitive changes in late middle-aged adults at risk for dementia.
[https://www.nature.com/articles/s42255-021-00438-z '''Exercise hormone irisin is a critical regulator of cognitive function'''](Mohammad R. Islam et al, 20 August 2021)
Full paper is behind paywall, but the abstract:
::Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.


[https://www.frontiersin.org/articles/10.3389/fnbeh.2020.626769/full '''The Contribution of Physical Exercise to Brain Resilience'''](Ricardo Mario Arida and Lavinia Teixeira-Machado, 20 Jan 2021)
[https://www.frontiersin.org/articles/10.3389/fnbeh.2020.626769/full '''The Contribution of Physical Exercise to Brain Resilience'''](Ricardo Mario Arida and Lavinia Teixeira-Machado, 20 Jan 2021)
::Exercise is known to induce many positive effects on the brain. … Among many beneficial effects, exercise intervention has been associated with cognitive improvement and stress resilience in humans and animal models. Thus, a growing number of studies have demonstrated that exercise not only recovers or minimizes cognitive deficits by inducing better neuroplasticity and cognitive reserve but also counteracts brain pathology…. Overall, the literature indicates that brain/cognitive reserve built up by regular exercise in several stages of life, prepares the brain to be more resilient to cognitive impairment and consequently to brain pathology.
::Exercise is known to induce many positive effects on the brain. … Among many beneficial effects, exercise intervention has been associated with cognitive improvement and stress resilience in humans and animal models. Thus, a growing number of studies have demonstrated that exercise not only recovers or minimizes cognitive deficits by inducing better neuroplasticity and cognitive reserve but also counteracts brain pathology…. Overall, the literature indicates that brain/cognitive reserve built up by regular exercise in several stages of life, prepares the brain to be more resilient to cognitive impairment and consequently to brain pathology.
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9675563/ '''Exercise restores brain insulin sensitivity in sedentary adults who are overweight and obese'''](Stephanie Kullmann 22 Sep 2022)
::Our study demonstrates that an 8-week exercise intervention in sedentary individuals can restore insulin action in the brain. Hence, the ameliorating benefits of exercise toward brain insulin resistance may provide an objective therapeutic target in humans in the challenge to reduce diabetes risk factors.




Line 174: Line 367:


[https://content.iospress.com/articles/brain-plasticity/bpl190081?fbclid=IwAR3QTJb9y6ly3XcH2Fn0rBHX3Fq_ynXmPp7jcbirDp7KvoRayb7Ldd0ypjM '''Modulation of Distinct Intrinsic Resting State Brain Networks by Acute Exercise Bouts of Differing Intensity'''] (Angelika Schmitt, et al, 26 Dec 2019) Researchers discovered that low-intensity exercise triggers brain networks involved in cognition control and attention processing, while high-intensity exercise primarily activates networks involved in affective/emotion processing.
[https://content.iospress.com/articles/brain-plasticity/bpl190081?fbclid=IwAR3QTJb9y6ly3XcH2Fn0rBHX3Fq_ynXmPp7jcbirDp7KvoRayb7Ldd0ypjM '''Modulation of Distinct Intrinsic Resting State Brain Networks by Acute Exercise Bouts of Differing Intensity'''] (Angelika Schmitt, et al, 26 Dec 2019) Researchers discovered that low-intensity exercise triggers brain networks involved in cognition control and attention processing, while high-intensity exercise primarily activates networks involved in affective/emotion processing.
[https://jamanetwork.com/journals/jamaneurology/fullarticle/2738357?guestAccessKey=e956534b-dc6c-47b7-ae67-1d0b6dd4f3c4&utm_source=silverchair&utm_campaign=altmetric&utm_content=2019_year-end&cmp=1&utm_medium=email '''Associations of Physical Activity and β-Amyloid With Longitudinal Cognition and Neurodegeneration in Clinically Normal Older Adults'''] (Jennifer S. Rabin et al, 16 Jul 2019)
::Greater physical activity and lower vascular risk independently attenuated the negative association of Aβ burden with cognitive decline and neurodegeneration in asymptomatic individuals. These findings suggest that engaging in physical activity and lowering vascular risk may have additive protective effects on delaying the progression of Alzheimer disease.




Line 185: Line 382:


[https://link.springer.com/article/10.1007/s10433-019-00513-1?fbclid=IwAR3RkIbj9gDYDh9oXOi0dOmStEHyloKn989loKZwxcfRAzVG5xcagt-j770 '''Association of non-exercise physical activity in mid- and late-life with cognitive trajectories and the impact of APOE ε4 genotype status: the Mayo Clinic Study of Aging''' ] (Janina Krell-Roesch et al, 12 Apr 2019) This paper found that midlife physical activity was significantly associated with less decline in memory function among ApoE4 carriers. Physical activity included laundry, vacuuming, making beds, dusting, scrubbing floors, washing windows, gardening, raking leaves, carrying heavy objects, heavy digging, pushing a lawn mower or hard manual labor. This benefit was found regardless of intensity level.
[https://link.springer.com/article/10.1007/s10433-019-00513-1?fbclid=IwAR3RkIbj9gDYDh9oXOi0dOmStEHyloKn989loKZwxcfRAzVG5xcagt-j770 '''Association of non-exercise physical activity in mid- and late-life with cognitive trajectories and the impact of APOE ε4 genotype status: the Mayo Clinic Study of Aging''' ] (Janina Krell-Roesch et al, 12 Apr 2019) This paper found that midlife physical activity was significantly associated with less decline in memory function among ApoE4 carriers. Physical activity included laundry, vacuuming, making beds, dusting, scrubbing floors, washing windows, gardening, raking leaves, carrying heavy objects, heavy digging, pushing a lawn mower or hard manual labor. This benefit was found regardless of intensity level.
[https://cp.neurology.org/content/8/3/257 '''Exercise for cognitive brain health in aging'''] (Joyce Gomes-Osman et al, 30 May 2018)  This research examined nearly 100 previously published studies on exercise and cognition, with a total of more than 11,000 participants whose average age was 73. The common denominator across all these studies was that various forms of exercise all led to sharper thinking if the participants achieved this minimum 52-hour target over roughly six months. Studies with fewer hours of exercise or shorter time scales did not yield positive results.




Line 190: Line 390:
::In sum, the present results indicate that both dance and fitness training can induce hippocampal plasticity in the elderly, but only dance training improved balance capabilities.
::In sum, the present results indicate that both dance and fitness training can induce hippocampal plasticity in the elderly, but only dance training improved balance capabilities.


=== Exercise and Overall Better Health/Longevity ===
[https://medicalxpress.com/news/2023-03-metabolic-benefits.html '''Understanding how exercise induces systemic metabolic benefits'''] (Olivia Dimmer, ''MedicalXpress'', 16 Mar 2023) This article addresses research that explores how during exercise, autophagy, the body's cellular recycling system that allows old or damaged cellular structures to be broken down, is activated in both contracting muscles and various non-contracting organs, such as the liver.
[https://neurosciencenews.com/walking-longevity-20133/ '''How Many Daily Walking Steps Needed for Longevity Benefit?'''](UMass, NeuroScienceNews.com, March 3, 2022)  The oft-repeated 10,000-steps-a-day mantra grew out of a decades-old marketing campaign for a Japanese pedometer, with no science to back up the impact on health.  A meta-analysis of 15 studies involving nearly 50,000 people from four continents offers new insights into identifying the amount of daily walking steps that will optimally improve adults’ health and longevity – and whether the number of steps is different for people of different ages.


[https://cp.neurology.org/content/8/3/257 '''Exercise for cognitive brain health in aging'''] (Joyce Gomes-Osman et al, 30 May 2018)  This research examined nearly 100 previously published studies on exercise and cognition, with a total of more than 11,000 participants whose average age was 73. The common denominator across all these studies was that various forms of exercise all led to sharper thinking if the participants achieved this minimum 52-hour target over roughly six months. Studies with fewer hours of exercise or shorter time scales did not yield positive results.


=== Exercise and Overall Better Health/Longevity ===
[https://www.sciencedaily.com/releases/2022/03/220303215826.htm '''Resistance exercise may be superior to aerobic exercise for getting better ZZZs'''](American Heart Association, Science Daily, March 3, 2022)  A new study found that resistance exercise may be superior to aerobic exercise as a way to get better sleep. A year-long resistance exercise program improved sleep quality, duration and other indicators of a good night's sleep more so than aerobic exercise, combined aerobic and resistance exercise, and no exercise. Researchers say interventions focused on resistance exercises may be a way to improve sleep and, in turn, cardiovascular health.
 
   
   
[https://advances.sciencemag.org/content/7/4/eabd9502 '''Exercise mimetics and JAK inhibition attenuate IFN-γ–induced wasting in engineered human skeletal muscle'''] (Zhaowei Chen et al, 22 Jan 2021) Biomedical engineers at Duke University have demonstrated that human muscle has an innate ability to ward off the damaging effects of chronic inflammation when exercised.  
[https://advances.sciencemag.org/content/7/4/eabd9502 '''Exercise mimetics and JAK inhibition attenuate IFN-γ–induced wasting in engineered human skeletal muscle'''] (Zhaowei Chen et al, 22 Jan 2021) Biomedical engineers at Duke University have demonstrated that human muscle has an innate ability to ward off the damaging effects of chronic inflammation when exercised.  
Line 205: Line 411:


[https://www.cell.com/molecular-cell/fulltext/S1097-2765(19)30894-9?_returnURL=https://linkinghub.elsevier.com/retrieve/pii/S1097276519308949?showall=true&fbclid=IwAR12GQXknzap5qPPC_Y28X8DC41n_6HKWdYowTmG0V14A8OzFu_s_WSEJPM '''Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1''']  (Charles P. Najt et al, 13 Dec 2019)  Research by the University of Minnesota Medical School found that the fat in olive oil appears to activate pathways in cells that are linked to longer life. The researchers said olive-oil fats were stored in the body and when the fat is broken down during exercising or fasting is when the signalling and beneficial effects are realized
[https://www.cell.com/molecular-cell/fulltext/S1097-2765(19)30894-9?_returnURL=https://linkinghub.elsevier.com/retrieve/pii/S1097276519308949?showall=true&fbclid=IwAR12GQXknzap5qPPC_Y28X8DC41n_6HKWdYowTmG0V14A8OzFu_s_WSEJPM '''Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1''']  (Charles P. Najt et al, 13 Dec 2019)  Research by the University of Minnesota Medical School found that the fat in olive oil appears to activate pathways in cells that are linked to longer life. The researchers said olive-oil fats were stored in the body and when the fat is broken down during exercising or fasting is when the signalling and beneficial effects are realized
[https://www.hindawi.com/journals/omcl/2019/7058350/?utm_source=google&utm_medium=cpc&utm_campaign=HDW_MRKT_GBL_SUB_ADWO_PAI_DYNA_JOUR_X_PJ&gclid=CjwKCAiAmJGgBhAZEiwA1JZolsXHt8UERepgo6F_uVUuYAmwi1LOYJxmZw35Ys3saISwbBCjQXmx-BoCBegQAvD_BwE '''Stay Fit, Stay Young: Mitochondria in Movement: The Role of Exercise in the New Mitochondrial Paradigm'''](Jesus R. Huertas et al, 19 Jun 2019)
::Skeletal muscles require the proper production and distribution of energy to sustain their work. To ensure this requirement is met, mitochondria form large networks within skeletal muscle cells, and during exercise, they can enhance their functions. In the present review, we discuss recent findings on exercise-induced mitochondrial adaptations. We emphasize the importance of mitochondrial biogenesis, morphological changes, and increases in respiratory supercomplex formation as mechanisms triggered by exercise that may increase the function of skeletal muscles. Finally, we highlight the possible effects of nutraceutical compounds on mitochondrial performance during exercise and outline the use of exercise as a therapeutic tool in noncommunicable disease prevention. The resulting picture shows that the modulation of mitochondrial activity by exercise is not only fundamental for physical performance but also a key point for whole-organism well-being.19)





Latest revision as of 14:34, 26 February 2024

There is no researched-based consensus as to the best type(s) of exercise or its length of practice for cognitive health. (See Physical Activity and Alzheimer's Disease: A Systematic Review (2017).) However, it is known that exercise is good for the brain as well as the body. This page attempts to broadly address the different types of exercise with their benefits to assist an individual in determining a regimen that best meets their needs.

Why ApoE4s should Exercise

Exercise is good for many reasons, but especially APOE4s.

  • This study Exercise engagement as a moderator of APOE effects on amyloid deposition (Denise Head et al, 27 Feb 2013) found that exercise may be particularly beneficial for cognitively normal ε4+ individuals in reducing risk of brain amyloid deposition.
  • Exercise can reduce, even reverse, hippocampal atrophy in the brain. The hippocampus is part of the brain that is the center for emotion, memory, and the autonomic nervous system. See Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease (2014).
  • Exercise increases BDNF – Brain Derived Neurotrophic Factor. BDNF is the most active neurotrophin. Neurotrophins induce survival, development, and function of neurons. See BDNF Responses in Healthy Older Persons to 35 Minutes of Physical Exercise, Cognitive Training, and Mindfulness: Associations with Working Memory Function. (2017) also The Effects of Aerobic Exercise Intensity and Duration on Levels of Brain-Derived Neurotrophic Factor in Healthy Men (2013).
  • Increases insulin sensitivity, which benefits the body all over, but is particularly critical in the brain. The brain needs insulin, so insulin sensitivity is imperative for healthy cognition. It has been concluded that basically everyone who has Alzheimer’s has brain insulin resistance, whether or not they have insulin resistance elsewhere in the body. See Insulin Resistance also Insulin Resistance in the brain
  • When done regularly while incorporating allowances for recovery, exercise lowers inflammation. Low levels of inflammation correspond with maintaining cognitive function and longevity.
  • Aids mitochondrial health. Mitochondria are the powerhouses of the cell. The brain is highly dependent on mitochondrial activity for energy production from glucose. ApoE4 has been found to have detrimental effects on mitochondria, but exercise boosts mitochondria.
  • Exercise works hand in hand with diet to encourage ketosis, providing an alternative source of energy (ketones) for the brain. The brain prefers to use glucose for energy, but in Alzheimer’s this energy source is impaired, and this impairment begins decades before symptoms manifest. Ketosis enables a brain to easily switch between energy sources thus staving off cognitive impairment. See Ketosis and Ketogenic Diet
  • Can enhance sleep. Good, quality sleep is very important for ApoE4s. According to this study, Sleep Drives Metabolite Clearance from the Adult Brain “The restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.” In other words, sleep takes out the brain’s trash.
  • Can reduce stress. Stress affects the brain with its many nerve connections. In this article, Exercise Fuels the Brain’s Stress Buffers The American Psychological Association says exercise gives the body a chance to practice dealing with stress, thereby enhancing its ability to respond to it. It forces the body's physiological systems: cardiovascular, renal, muscular, central and sympathetic nervous systems — all of which are involved in the stress response — to communicate much more closely than usual. This workout of the body's communication system enables our bodies to be more efficient in dealing with stress.
  • Exercise helps keep your fat cells fit. Fat cells aren’t merely storage units, and fat isn’t merely a reserve source of body energy. Fat is a necessary part of our body, called adipose tissue, and this tissue is comparable to an organ that serves important body functions. Exercise aids with the blood flow and oxygen delivery to fat cells. This helps hold inflammation at bay which occurs in the fat cells with insulin resistance. And as discussed above and in Insulin Resistance there is a strong link between insulin resistance and Alzheimer’s Disease.
  • Exercise is often accompanied by sweating and sweat can help release toxins/metals in the body.
  • Exercise increases endocannabinoids and according to this article Cannabinoids Remove Plaque Forming Alzheimers Proteins from Brain Cells "It was the study of J147 [Alzheimer’s drug candidate] that led the scientists to discover that endocannabinoids are involved in the removal of amyloid beta and the reduction of inflammation.

Types of Exercise

Aerobic or “Cardio” Exercise – Running, cycling, swimming, rowing, cross-country skiing, etc.

Aerobic refers to a level of exercise where oxygen use meets the energy demands of the body. Aerobic exercise is performed at a moderate level of intensity over a relatively long period of time. For example, running a long distance at a moderate pace is an aerobic exercise; however, sprinting hard for a short distance is not. Aerobic exercise can take many forms: running, walking, hiking, cycling, swimming, rowing, cross-country skiing, roller blading, kayaking, on and on.

Dr Bredesen recommends 150 minutes of moderate aerobic exercise in the form of brisk exercise or something more vigorous in his book The End of Alzheimer's. In this video https://www.youtube.com/watch?v=2HFs0GyIR2M from December 2013, he recommends starting slowly but to incorporate aerobic exercise of at least 30 minutes a day, 5 times a week, starting slowly to get your heart rate up without hurting yourself, to around the 70% max heart beat range. See Bredesen Protocol on Exercise.

The benefits of aerobic exercise are many. From a neurological standpoint, this quote was taken from the Wikipedia page Neurobiological effects of physical exercise accessed 16 August 2017

A large body of research in humans has demonstrated that consistent aerobic exercise (e.g., 30 minutes every day) induces persistent improvements in certain cognitive functions, healthy alterations in gene expression in the brain, and beneficial forms of neuroplasticity and behavioral plasticity; some of these long-term effects include: increased neuron growth, increased neurological activity (e.g., c-Fos and BDNF signaling), improved stress coping, enhanced cognitive control of behavior, improved declarative, spatial, and working memory, and structural and functional improvements in brain structures and pathways associated with cognitive control and memory.[1][2][3][4][5][6][7][8][9][10] The effects of exercise on cognition have important implications for improving academic performance in children and college students, improving adult productivity, preserving cognitive function in old age, preventing or treating certain neurological disorders, and improving overall quality of life.[1][11][12]


High Intensity Interval Training (HIIT or HIT) – Sprint Interval Training, Tabata training, Nitric Oxide Dump

High Intensity Interval Training or HIIT is where one performs a short burst of high-intensity exercise followed by a period of low-intensity activity, then repeating this cycle by going back to a burst of high intensity. There is no universal amount of time to do HIIT, but a routine typically lasts no more than 30 minutes, and for a non-athlete just working on general fitness, often far less, just a few minutes.

This type of exercise has been gaining in general popularity largely because it’s not a major time commitment and it shouldn’t be done more than three times a week.

Dr Michael Mosely suggests that HIIT (which he refers to as HIT) practiced for just three minutes can reap benefits, particularly with insulin sensitivity. Results do vary, however, based on genetics (not ApoE4), so while 15% of people made huge strides, 20% showed no real improvement. This link tells more: Can three minutes of exercise a week help make you fit?

Sprint Intensity Training is similar to HIIT in that it involves short periods of high intensity. Sprint intensity training typically involves bursts at 100% exertion. In contrast, HIIT uses high intensity, but not necessarily full exertion, for the high intensity intervals.

Tabata training is a variation on HIIT. Tabata training breaks a workout down into clearly defined intervals – typically, 20 seconds of a push-it-to-the-limit exercise followed by 10 seconds of rest. Eight consecutive work-and-relax cycles go into a 4-minute round in Tabata. Four rounds go into a full 20-minute training circuit. This is intended to be an intense aerobic (cardio) and anaerobic (strength) experience. Tabata pushes the boundary of VO2 max, the technical term for oxygen used during exercise.

Nitric Oxide Dump The Nitric Oxide Dump exercise involves just four movements — squats, alternating arm raises, arm circles, and shoulder presses — which are done in repetitions of 10, with four sets each. In total, it takes just three to four minutes. By incorporating all of these exercises, you maximize the amount of blood flow throughout your body, rather than limiting it to just one portion of your body. It is easier than other HIIT practices, requires no equipment, can be done by nearly anyone regardless of fitness level, plus only takes three minutes two or three times a day. Controlling Nitric Oxide formation has a number of influences on one’s health, including stimulating the brain and lowering high blood pressure. In this almost 8 minute long video The 4 Minute Workout | Nitric Oxide Boost at Any Age Jan Howell (note she is not a buff athlete, but a gray-haired, ordinary woman) illustrates and discusses this 4 minute (or less) workout created by Dr. Zach Bush.

Zone 2 Exercise

When you say the word “exercise” to some people they respond negatively, but it doesn’t have to be a “butt-kicking” exhausting drudgery. When it comes to cardiovascular exertion, there are 5 “zones” representing a rating of perceived exertion from very light exertion (zone 1) to very hard (zone 5).

Zone 2 aka “Light” is prolonged low-intensity aerobic training. It is of particular interest to those wishing boost their mitochondria, important for ApoE4s, as it stimulates the mitochondria to create ATP (cellular energy) and improves mitochondrial efficiency. See Mitochondria. Zone 2 exercise offers many other health benefits also: increased cardiovascular health, helpful if trying to lose weight, improves mood, and prevents injury.

Zone 2 cardio is an exercise performed within a heart rate zone that represents 60% to 70% of the maximum heart rate (MHR). To determine whether you're in zone 2, you can go off perceived exertion or calculate your maximum heart rate and calculate a target range from there.

Most will tell you that your maximum heart rate is found using the equation: 220 - your age = MHR. (So if 60 years old: 220 – 60 = 160 maximum heart rate (MHR). Then 60% to 70% of that MHR is a Zone 2 heart rate target of 96 to 112.

However, a newer formula used among trainers is 208 - (0.7 x your age) = MHR. (So if 60 years old: 208 – (0.7x60 which is 42) = 166. Then 60 to 70% of 166 is a Zone 2 heart rate target of 99.6 to 116.2.)

There is no clear consensus on the amount of time zone 2 training, however, at least 30 minutes to it two to three times per week is a good recommendation.


Resistance training - Weight lifting, strength training, bands, body weight, cross-fit, pilates

Being strong is a part of general health and well-being. Exercising for strength has many benefits, but those of particular interest to ApoE4s:

  • Improves insulin sensitivity. See An Introduction to ApoE4, biochemistry and possible prevention strategies and Insulin Resistance
  • Reduces inflammation. Muscles, when worked, help ameliorate the effects of fat and reduce inflammation. Fat tissue secretes the pro-inflammatory cytokine TNF- α (TNF stands for tumor necrosis factor, and immune cells secrete it in the presence of tumor cells). Muscle derived IL-6 is anti-inflammatory. IL-6 is interesting; it is a cytokine that causes inflammation, but it is also a myokine that according to wikipedia has many positive effects. Muscle contraction releases large amounts of IL-6, which sensitizes our cells to its effect, resulting in less inflammation causing IL-6 circulating to rest. So why not just do aerobic exercise to get muscles to secrete IL-6? Different muscle fiber types release different clusters of myokines, so different types of exercise offer different myokine benefits.
  • Resistance training can produce better sleep, see Optimize sleep as discussed in Bredesen’s protocol.
  • High-intensity workouts and exercises that involve muscle contraction activates AMPK (AMP-activated protein kinase). Per http://ampkactivator.net/ AMPK acts as the “master regulator” of the cellular energy homeostasis. It is activated in response to the stimuli and stresses that use up the ATP supplies (e.g. low glucose, ischemia, hypoxia, heat shock). Activating AMPK positively regulates the signaling pathways (such as autophagy, see Enhance autophagy, ketogenesis in Bredesen’s Protocol, and fatty acid oxidation) that replenish the cellular ATP supplies.
  • Feeling strong gives a person a sense of well being, and it can boost self-confidence and mood.

Resistance training and Cognition

A complete ApoE4 exercise program should include resistance training. Resistance training also known as strength training involves the performance of exercises that are designed to improve strength and endurance. This training is performed by contracting muscles against a resisting force. It is often associated with the lifting of weights, but it can also incorporate a variety of training techniques such as bodyweight exercises, resistance bands, isometrics, and plyometrics (plyometrics is a type of exercise training that uses speed and force).

Resistance training can increase muscle, tendon, and ligament strength as well as bone density, metabolism, and the lactate threshold; improve joint and cardiac function; and reduce the risk of injury. But of greatest interest to ApoE4s, resistance training improves muscle and bone health.

Muscles and brain health

Sarcopenia is the gradual loss of muscle mass and strength. Studies indicate that loss of muscle mass is correlated with loss of cognition. Risk factors for sarcopenia include age, malnutrition, and level of physical activity. Some studies on sarcopenia with their findings:

APP in the Neuromuscular Junction for the Development of Sarcopenia and Alzheimer’s Disease (Min-Yi Wu et al, 25 Apr 2023)

We summarize key findings from the burgeoning literature, which may open new avenues to investigate the link between muscle cells and brain cells in the development and progression of AD and sarcopenia.

Early-stage Alzheimer’s disease: are skeletal muscle and exercise the key? (Matthew H. Brisendine and Joshua C. Drake, 21 Feb 2023) This paper is behind a paywall, but from the abstract:

Evidence from animal models of AD suggests a close link among skeletal muscle mass, mitochondria function, and cognition. Exercise is a powerful stimulus for improving mitochondria function and muscle health, and its benefits to cognition have been suggested as a possible therapeutic strategy for AD.

Skeletal muscle atrophy-induced hemopexin accelerates onset of cognitive impairment in Alzheimer's disease (Tsukasa Nagase & Chihiro Tohda, 17 Oct 2021) From conclusions:

These findings provide new evidence indicating that skeletal muscle atrophy has an unbeneficial impact on the occurrence of memory impairment in young 5XFAD mice, which is mediated by the muscle secreted hemopexin.

Sarcopenia and frailty in individuals with dementia: A systematic review (Samantha J. Waite et al, January–February 2021). The full paper is behind a paywall, but from the abstract:

An increased prevalence of frailty and sarcopenia was noted in dementia patients.

Sarcopenia and Muscle Functions at Various Stages of Alzheimer Disease (Yusuke Ogawa et al, 28 Aug 2018) This study aimed to investigate the prevalence of sarcopenia, factors associated with sarcopenia in elderly subjects with AD, and differences in muscle functions of the upper and lower extremities and gait speed at various stages of AD. ...The prevalence rate of sarcopenia was significantly higher in early AD, mild AD, and moderate AD than in NC [normal cognition]. (bold font added for emphasis)


SOLEUS MUSCLE

The soleus muscle is a wide flat muscle of the lower leg that lies under the gastronemius muscle

The soleus muscle appears to be one muscle that shouldn’t be ignored when it comes to brain health. The soleus is a wide flat muscle of the lower leg that lies under the gastronemius muscle. These two muscles are known as the calf muscles. The soleus muscles are responsible for pumping blood back up to the heart. This is measured by resting diastolic blood pressure. Diastolic blood pressure is the second number of a blood pressure reading, it measures the pressure in the arteries between heartbeats. Low diastolic pressure can arise as a result of medication use, heart failure or other health complications. But, in most people, it is simply a matter of the heart not pumping out enough blood with each stroke; in other words, when not enough blood is being returned to the heart from the lower body.

From this article Calf Muscles and Blood Pressure Can Predict Dementia Risk published by NeuroscienceNews on August 5, 2021:

Low blood pressure is associated with decreased blood flow to the brain when an individual is sitting or standing. Many researchers have come to believe that insufficient brain blood flow plays a critical role in the development of dementia, Alzheimer’s and perhaps even Parkinson’s disease. Some believe that it may even play the primary role.
The soleus muscles, specialized muscles in the middle of your lower legs, are responsible for pumping blood back up to the heart.
An effective strategy for maintaining normal blood pressure, and brain blood flow, is to “re-train” your soleus muscles. These deep postural muscles are most active during activities such as sustained squatting or toe standing.

There's also this paper Reversal of cognitive impairment in a hypotensive elderly population using a passive exercise intervention (KJ McLeod and A Stromhaug, 7 Nov 2017) where the researchers Used a “passive” exercise regimen (noninvasive calf muscle pump stimulation) on elderly (82.5±7.5 years) participants to improve diastolic blood pressure (DBP) and from this paper:

Here, we investigate a passive form of exercise, micromechanical stimulation of the plantar surface, a technology which activates the calf muscle pump in the lower legs, thereby enhancing cardiac return, normalizing blood pressure, and improving cerebral blood flow. Men and women residing in a senior living center were segregated into normal blood pressure (control) group and low blood pressure (intervention) group. The intervention group undertook passive exercise for 1 hour/day. While at the start of the study the intervention group’s performance was significantly worse in executive function tests compared to the control group, by the 14th week of the study, those in the intervention group had improved to the point of matching the performance of the control group.
Bones and brain health

Bones are generally thought of as static structural support for the body, but bones are becoming increasingly recognized for its endocrine function of secreting several hormones, thereby controlling various physiological pathways. Osteocalcin is one of those bone derived hormones and one of the physiological functions it influences is brain function.

Medscape reported on a study that was published online on March 22, 2023 in Neurology in this article, Poor Bone Health a 'Robust' Dementia Risk Factor. The article reported:

Now a long-running Rotterdam study has recently found that low bone mineral density (BMD), particularly at the femoral neck, emerged as a "robust" risk factor for dementia in older adults.

This 2020 article Does the key to anti-ageing lie in our bones? addresses osteocalcin specifically:

Osteocalcin, a hormone produced in the bones, could one day provide treatments for age-related issues such as muscle and memory loss.


Papers on resistance training and cognition

Some studies that have found cognitive improvements through resistance training:

Functional and/or structural brain changes in response to resistance exercises and resistance training lead to cognitive improvements – a systematic review (Fabian Herold et al, 10 Jul 2019)

Based on our analyses, resistance exercises and resistance training evoked substantial functional brain changes, especially in the frontal lobe, which were accompanied by improvements in executive functions. Furthermore, resistance training led to lower white matter atrophy and smaller white matter lesion volumes.

In Australia, a University of Sydney study, Mediation of Cognitive Function Improvements by Strength Gains After Resistance Training in Older Adults with Mild Cognitive Impairment: Outcomes of the Study of Mental and Resistance Training linked stronger muscles with improved cognitive function. Published in the Journal of American Geriatrics in October 2016, the trial was done on a group of 100 patients age 55 to 68, suffering MCI (mild cognitive impairment). The participants were divided into four groups, and each assigned a particular activity:

  1. weightlifting exercises
  2. seated stretching exercises
  3. real cognitive training on a computer
  4. placebo training on a computer

Only the weight training activity demonstrated a measured improvement in brain function. From the conclusion of the study:

High-intensity PRT [Progressive Resistance Training] results in significant improvements in cognitive function, muscle strength, and aerobic capacity in older adults with MCI. Strength gains, but not aerobic capacity changes, mediate the cognitive benefits of PRT. Future investigations are warranted to determine the physiological mechanisms linking strength gains and cognitive benefits.

Another study, Therapeutically relevant structural and functional mechanisms triggered by physical and cognitive exercise published March 2016 found that PRT [progressive resistance training] improved global cognition. From the study:

Here we report for the first time that resistance training can conserve and even increase cortical thickness in the posterior cingulate. This mechanism may be salient to long-term protection from further cognitive decline and impairment because loss of PC gray matter is a biomarker of AD,71, 72 most likely because of neuronal loss in specific cortical laminae.73, 74

Aim for Healthy muscles, not Big muscles

After saying that maintaining strong muscles can be of great benefit, now some cautions. The key to success is likely to work the muscles without overdoing it.

Protein, IGF-1, and longevity

Body builders who want large, pronounced muscles eat a high protein diet to aid in achieving this. Protein raises Insulin Like Growth Factor 1 or IGF-1. As the name suggests, IGF-1 stimulates cells, like muscle cells, to grow. But IGF-1 doesn’t discriminate. In addition to muscle cells, it can also stimulate cancer cell growth and affect other factors that affect longevity. A lower IGF-1 is connected with longer, more healthful aging. It should be noted plant protein doesn’t have the same effect on IGF-1. Excess animal protein is especially more likely to raise IGF-1. Some studies:

Low Protein Intake is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population published March 2014:

Respondents (n=6,381) aged 50–65 reporting high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer and diabetes mortality during an 18 year follow up period. These associations were either abolished or attenuated if the source of proteins was plant-based.

Growth hormone modulates hypothalamic inflammation in long-lived pituitary dwarf mice Published Dec 2015:

Mice in which the genes for growth hormone (GH) or GH receptor (GHR(-/-) ) are disrupted from conception are dwarfs, possess low levels of IGF-1 and insulin, have low rates of cancer and diabetes, and are extremely long-lived.

Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans Published Oct 2008:

Reduced function mutations in the insulin/IGF-I signaling pathway increase maximal lifespan and health span in many species…. These findings demonstrate that, unlike in rodents, long-term severe CR does not reduce serum IGF-1 concentration and IGF-1 : IGFBP-3 ratio in humans. In addition, our data provide evidence that protein intake is a key determinant of circulating IGF-1 levels in humans, and suggest that reduced protein intake may become an important component of anticancer and anti-aging dietary interventions.


Oxidative Stress from too much exercise

Excess exercise can increase radical production and oxidative stress which negatively impacts the body.

Management of Oxidative Stress: Crosstalk Between Brown/Beige Adipose Tissues and Skeletal Muscles

In this review, we summarize the integrated effects of exercise on oxidative metabolism, and especially focus on the role of brown and beige adipose tissues in this process, providing more evidence and knowledge for a better management of exercise-induced oxidative stress.


Exercise Intensity can lead to cardiovascular damage

In his presentation at the Ancestral Health Symposium in August 2016, AHS16 - Steven Gundry - Dietary Management of the Apo E 4 at 26:10, Dr Steven Gundry said, “that the last thing ApoE4s should be doing is Cross Fit.” CrossFit is a program of aerobic exercise, calisthenics and Olympic weightlifting. It is typically very intense, emphasizing competition as well as exercise. When later asked to elaborate on his statement, Dr Gundry indicated that that the indictment was not just on cross-fit but all intense, stressful workouts. He cautioned that ApoE4s have to be mindful of their greater potential to develop small vessel disease. Small blood vessels exist in the brain and heart as well as elsewhere in the body. He stated that almost every one of his patients who are intense cross-fitters, or marathoners, or other high-intensity participants have elevated Cardiac Troponin-I markers. Cardiac Troponin-I is a test that is a hundred more times sensitive than the test in the emergency room looking for heart attacks. But he also stated that when his patients back off from the intensity, this marker goes back to normal.

Another potential result of excess intense exercise is Atrial fibrillation (AFib). AFib is an abnormal or rapid heart rate, a common but serious arrhythmia. Two groups are at high risk for AFib: Obese, sedentary people, and thin, active people who over exercise. From this article, An "Iron" response by Dr. John Mandrola, a cardiac electrophysiologist: “There are hundreds of citations documenting the risk of atrial fibrillation in long-term endurance athletes.” He then went on to cite six specific references.

Blood Flow Restriction (BFR) Bands (KAATSU, B Strong, etc.)

Blood flow Restriction bands trick the body into thinking it’s working harder than it really is. They help with building/maintaining muscle, muscle warm up before exercise, muscle recovery after exercise, pain relief, and therapeutically for injury or surgery recovery.

KAATSU bands are unique blood flow restriction bands as they come with a compressor that inflates and deflates the bands to cycle the restriction. In cycle mode, they can provide benefit while just sitting or doing mild activity around the house.

How blood flow restriction provides benefit:

  • Increase muscle strength with lower weight thereby protecting the load on tendons and joints and without actually breaking down muscle fiber. This is especially beneficial for those who are middle-aged and older.
  • Upregulate healing growth hormones, like BDNF and plasmalogens. This is accomplished by creating a mildly hypoxic state in your muscles.
  • Engorges the blood in your capillaries and veins enabling circulation to improve and for your vascular system to become more elastic — upregulating nitric oxide — protecting against cardiovascular disease.

But be safe when using BFR bands. This isn’t hard, but it is important to know how to position the bands appropriately and how to test for capillary refill time to assure you’re not occluding blood flow too harshly which can be damaging.

For more info: KAATSU for Strength Training and Much More

What Is Blood Flow Restriction (BFR) Training?

EPISODE 34: JIM STRAY-GUNDERSEN EXPLAINS HOW BLOOD FLOW RESTRICTION TRAINING BUILDS MUSCLE AND IMPROVES PERFORMANCE Includes show notes and references

Vibration plate therapy

Vibration plates or vibration platforms are machines that vibrate at high frequencies. As it vibrates, it transmits energy to the body, forcing the muscles to contract and relax dozens of times each second.

Vibration therapy was first used to reduce the severity of muscle mass and bone density decline in cosmonauts. It was later used in improving muscle strength. For years now, professional athletes have been training with vibration plates to prepare for competition and recover quicker.

Reported vibration plate benefits include:

  • improved muscle strength
  • reduced back pain
  • improved strength and balance in older adults
  • improved circulation
  • boost to lymphatic drainage
  • improved bone density
  • pain reduction

Just standing on the device is said to activate and build muscle, but using the vibration plate with exercise amplifies the benefits.

Using a vibration plate may also benefit the brain. This study, Chronic whole body vibration ameliorates hippocampal neuroinflammation, anxiety-like behavior, memory functions and motor performance in aged male rats dose dependently(Tamás Oroszi et al, 30 May 22) was conducted on aged rats over five weeks:

Our results indicate, that WBV [Whole Body Vibration] seems to be a comparable strategy on age-related anxiety, cognitive and motor decline, as well as alleviating age-related (neuro)inflammation.

But vibration plate therapy is not a substitute for exercise and it is also is not for everyone. In certain cases it may lead to joint pain, muscle damage and back pain. There are a number of conditions that are contraindicated for vibration plate usage, so some investigation and/or health care practioner consultation may be prudent before hopping on.

Just moving - strolling in the park, tai chi, dancing, gardening, etc.

There’s a lot to be said for just moving. As a society, we sit a lot: working on the computer, video games, desk work, driving, watching television. Our DNA still thinks it's living in the past and our ancestors weren't sedentary. They didn't run marathons, but they kept very active.

According to this study, Exercise, APOE genotype, and the evolution of the human lifespan

Our hypothesis suggests that increased selection for exercise and physical activity served to ameliorate the effects of APOE ε4, supporting the evolution of longer human lifespans and achieving the potential for successful advanced aging. Thus, changes induced by modern-day environmental constraints and human behavior may have led to greater vulnerability to the effects of APOE ε4 in subgroups of elderly in which high levels of physical activity throughout life are no longer required.

In other words, physical activity helped man extend its overall lifespan, but now, modern day lifestyle has far less demand for physical activity and this is exposing the ApoE4 gene’s health vulnerabilities.

There's also this paper, Dancing or Fitness Sport? The Effects of Two Training Programs on Hippocampal Plasticity and Balance Abilities in Healthy Seniors (Kathrin Rehfeld et al, 15 Jun 2017)

In sum, the present results indicate that both dance and fitness training can induce hippocampal plasticity in the elderly, but only dance training improved balance capabilities.

According to Dr Joe Mercola in his post Two Key Strategies to Help Your Fitness Soar in 2017

The scientific literature also clearly shows that sitting for extended periods is a major, independent risk factor for chronic disease, even if you exercise regularly, so daily non-exercise movement is likely one of the most important fitness strategies for many — especially if you’re currently not exercising on a regular basis.
The reason for this is because sitting blocks a number of insulin-mediated systems, including muscular and cellular pathways that process blood sugar, triglycerides and cholesterol. Standing up — bearing your own body weight on your legs — activates all of these systems at the molecular level.

So move often. Better yet, do it outside, walk around the park or do some gardening. The sunshine will provide a nice dose of Vitamin D, see 25OH-D3 = 50-80ng/ml in the Bredesen Protocol discussion. Among its many benefits, Vitamin D supports the health of the immune system, brain and nervous system.

Also, being outside will likely expose a person to M. vaccae, a bacteria that lives naturally in the soil. According to this article Dirt has a microbiome, and it may double as an antidepressant

In a 2007 paper published in the journal Neuroscience, Lowry and his team wrote that the bacteria activated groups of neurons in the mouse brains responsible for producing serotonin—a neurotransmitter that, when impaired, can cause depression.

The article also said:

Papers published since (2007) have described feeding mice M. vaccae-laced peanut butter sandwiches, and watching them race through challenging mazes far faster than their counterparts, suggesting the bacteria gave them a significant brain boost, in addition to apparently elevating their mood.

So get moving and do it outside as much as possible for some beneficial fresh air, sunshine, and bacteria.

Yoga

Yoga may be lower on the benefit scale for ApoEs when compared to other exercises, but shouldn’t be discounted entirely. There are many types of yoga, from “Power Yoga” which is a high-intensity practice designed to build muscle to “Yoga Nidra” or yogic sleep where the yogi (a person who practices yoga) typically just lies on the floor and is guided verbally into a relaxed state.

Yoga helps promote vagal tone. From 6 ways to Stimulate your Vagus Nerve to reduce Inflammation, Depression, Migranes, and More:

High vagal tone improves the function of many body systems, causing better blood sugar regulation, reduced risk of stroke and cardiovascular disease, lower blood pressure, improved digestion via better production of stomach basic and digestive enzymes, and reduced migraines. The higher vagal tone is also associated with better mood, less anxiety, and more stress resilience.

For more information, see Vagus Nerve. Yoga classes often open and close with a chant of “om” this stimulates the vagus nerve. Yoga can also be meditative and meditation also improves vagal tone.

Yoga can be a good stress reducer. Stress increases risk factors for cognitive decline and cardiovascular disease, but yoga lowers cortisol which results from stress, protects the hippocampus from atrophy, and increases the thickness of the cerebral cortex.

If new to exercise, a very gentle program of yoga, coupled with a light aerobic activity like walking or swimming may be the best way to start. Even if suffering from arthritis, yoga helps with staying flexible and strong. All good yoga instructors are sensitive to the fact that every person’s body is different and insist that a pose only be performed to the ability of that person. Many community recreation centers, “active adult” centers, and yoga studios offer yoga classes for novices or those with physical issues.

Deeper Dive into the Science

Not a complete compilation of studies, just a sampling.

Exercise and ApoE4

Association between physical activity and episodic memory and the moderating effects of the apolipoprotein E ε4 allele and age (Boung Chul Lee et al, 11 Jul 2023)

Our findings suggest that physical activity has beneficial effects on episodic memory, as an AD-related cognitive domain, in individuals aged > 70 years and in APOE4-positive individuals. Physicians should take age and APOE4 status account into when recommending physical activity to prevent AD-related cognitive decline.


Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study (Jianping Jia et al, 25 Jan 2023)

Conclusion A healthy lifestyle is associated with slower memory decline, even in the presence of the APOE ε4 allele. This study might offer important information to protect older adults against memory decline.


Effects of Sex, APOE4, and Lifestyle Activities on Cognitive Reserve in Older Adults(Judy Pa et al, 23 Aug 2022)

Discussion. The associations of self-reported physical and cognitive activities with cognitive reserve are more pronounced in women, although APOE4 attenuates these associations. Future studies are needed to understand the causal relationship among sex, lifestyle activities, and genetic factors on cognitive reserve in older adults to best understand which lifestyle activities may be most beneficial and for whom.


Cerebrovascular response to exercise interacts with individual genotype and amyloid-beta deposition to influence response inhibition with aging(Jacqueline A. Palmer et al, June 2022)

• Neurobiological interactions between CVR [cerebrovascular response], APOE genotype, and Aβ [Amyloid beta ]are behaviorally significant.
• Blunted CVR to exercise is associated with impaired response inhibition specifically in APOE4 carriers.
• APOE4 carriers with more robust CVR have higher response inhibition performance, despite having greater Aβ deposition.
• Assessment of multifactorial neurobiological variables offers an early and sensitive biomarker of cognitive behavioral dysfunction with aging.


Influence of Physical Activity Levels and Functional Capacity on Brain β-Amyloid Deposition in Older Women (Raquel Pedrero-Chamizo1 et al, 8 July 2021)

The aim of this study was to determine if PA [Physical Activity] levels and/or functional capacity (FC) are associated with Aβ plaque deposition, and whether these associations differed according to APOE-ε4 genotype. … In conclusion, low performance in TUGt [Timed Up and Go test] is associated with a negative effect on brain pathology with increasing cerebral Aβ depositions in older women who are APOE-ε4+. In physically active older women (> 600 METs·min/week), higher PA levels are not associated with reduction in Aβ depositions.


Can Physical Activity Reduce the Risk of Cognitive Decline in Apolipoprotein e4 Carriers? A Systematic Review (Jose Luis Perez-Lasierra et al, 6 Jul 2021) The link will take to you the abstract but within this link you can download the entire PDF paper. From the conclusions section of the paper:

The results of the studies included in this systematic review support the idea that PA [Physical Activity]is a protective factor against CD [Cognitive Decline] in individuals of high genetic risk, specifically APOE e4 carriers. These findings have high clinical and public health significance. Moreover, the results suggest that in this population, a higher dose of PA (amount and/or intensity) might have greater benefits, but it would be necessary to carry out further studies that would allow these findings to be contrasted, since the existing evidence is limited. Further studies should try to establish the optimal dose of PA to effectively and efficiently prevent CD in APOE e4 carriers.


Exercise as Potential Therapeutic Target to Modulate Alzheimer’s Disease Pathology in APOE ε4 Carriers: A Systematic Review (Sevilay Tokgöz and Jurgen A. H. R. Claassen 5 Jan 2021)

This review focuses on the effect of exercise on cognitive function, dementia risk, amyloid-β (Aβ) metabolism, lipid metabolism, neuroinflammation, neurotrophic factors and vascularization in APOE ε4 carriers. We searched the literature in the PubMed electronic database using the following search terms: physical activity, exercise, aerobic fitness, training, sport, APOE4, Alzheimer’s disease, AD and dementia. … From these studies, we conclude that exercise is a non-pharmacological treatment option for high-risk APOE ε4 carriers to ameliorate the AD pathological processes including reducing Aβ load, protecting against hippocampal atrophy, improving cognitive function, stabilizing cholesterol levels and lowering pro-inflammatory signals.


Midlife Lifestyle Activities Moderate APOE ε4 Effect on in vivo Alzheimer’s Disease Pathologies (So Yeon Jeon et al, 27 Feb 2020)

The findings suggest that high midlife cognitive activity may accelerate hippocampal atrophy induced by APOE4, whereas high midlife physical activity may delay AD-related cerebral hypometabolism by weakening the influence of APOE4-associated Aβ retention.

Exercise and the Brain

Not a complete list.


Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling (Eunhee Kim et al, 8 Sep 2023) The findings of this paper reveal a cellular and molecular mechanism by which exercise-induced irisin attenuates Amyloid beta pathology.

In summary, we present the experimental data showing that irisin reduces Aβ pathology by increasing NEP activity/level secreted from astrocytes. Furthermore, we have delineated the involved molecular mechanism from identifying the astrocyte receptor, integrin αV/β5, to demonstrating the inhibition of IL-6/ERK and NF-κB-STAT3 signaling, resulting in increased secretion of NEP and reduction of Aβ levels. Thus, our findings offer strong support for developing irisin as a therapeutic target to reduce Aβ burden for AD treatment and prevention.


Exercise and mitochondrial remodeling to prevent age-related neurodegeneration(Colleen L. O’Reilly et al 09 JAN 2023)

This mini-review describes the role of mitochondria in neurodegeneration and brain health, current practices for assessing both aspects of mitochondrial remodeling, and how exercise mitigates the adverse effects of aging in the brain. Exercise training elicits functional adaptations to improve brain health, and current literature strongly suggests that mitochondrial remodeling plays a vital role in these positive adaptations. Despite substantial implications that the two aspects of mitochondrial remodeling are interdependent, very few investigations have simultaneously measured mitochondrial dynamics and protein synthesis. An improved understanding of the partnership between mitochondrial protein turnover and mitochondrial dynamics will provide a better understanding of their role in both brain health and disease, as well as how they induce protection following exercise.


Brain Insulin Resistance and Cognitive Function: influence of exercise (Steven K. Malin et al, 8 Dec 2022) Brain insulin resistance has been associated with age-related declines in memory and executive function as well as Alzheimer’s disease pathology.

Herein, we provide an overview of brain insulin sensitivity in relation to cognitive function from animal and human studies, with particular emphasis placed on the impact exercise may have on brain insulin sensitivity. Mechanisms discussed include mitochondrial function, brain growth factors, and neurogenesis, which collectively help combat obesity-related metabolic disease and Alzheimer’s dementia.


Physical Exercise, a Potential Non-Pharmacological Intervention for Attenuating Neuroinflammation and Cognitive Decline in Alzheimer’s Disease Patients(Samo Ribarič 17 March 2022)

This narrative review summarises the evidence for considering physical exercise (PE) as a non-pharmacological intervention for delaying cognitive decline in patients with Alzheimer’s disease (AD) not only by improving cardiovascular fitness but also by attenuating neuroinflammation. ... Further studies in human are necessary to develop optimal, personalised protocols, adapted to the progression of AD and the individual’s mental and physical limitations, to take full advantage of the beneficial effects of PE that include improved cardiovascular fitness, attenuated systemic inflammation and neuroinflammation, stimulated brain Aβ peptides brain catabolism and brain clearance.


Exercise May Reduce Brain Inflammation, Reducing the Risk of Alzheimer’s (NeuroscienceNews 28 Nov 2021)

Physical activity is very important for a number of reasons – including that it helps to protect the structure and function of our brain as we age. This may be key in reducing the risk of developing certain neurodegenerative conditions, such as Alzheimer’s disease.


Effects of Aerobic Exercise Training on Systemic Biomarkers and Cognition in Late Middle-Aged Adults at Risk for Alzheimer’s Disease (Julian M. Gaitán et al, 20 May 2021) Until this study, systemic biomarkers to measure exercise effects on brain function and the link to relevant metabolic responses were lacking. This study shows that a memory biomarker, myokine Cathepsin B (CTSB), increased in older adults following a 26-week structured aerobic exercise training. The positive association between CTSB and cognition, and the substantial modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function and brain health in asymptomatic individuals at risk for Alzheimer's.

Overall, our analyses indicate metabolic regulation of exercise-induced plasma BDNF changes and provide evidence that CTSB is a marker of cognitive changes in late middle-aged adults at risk for dementia.


Exercise hormone irisin is a critical regulator of cognitive function(Mohammad R. Islam et al, 20 August 2021) Full paper is behind paywall, but the abstract:

Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.


The Contribution of Physical Exercise to Brain Resilience(Ricardo Mario Arida and Lavinia Teixeira-Machado, 20 Jan 2021)

Exercise is known to induce many positive effects on the brain. … Among many beneficial effects, exercise intervention has been associated with cognitive improvement and stress resilience in humans and animal models. Thus, a growing number of studies have demonstrated that exercise not only recovers or minimizes cognitive deficits by inducing better neuroplasticity and cognitive reserve but also counteracts brain pathology…. Overall, the literature indicates that brain/cognitive reserve built up by regular exercise in several stages of life, prepares the brain to be more resilient to cognitive impairment and consequently to brain pathology.


Exercise restores brain insulin sensitivity in sedentary adults who are overweight and obese(Stephanie Kullmann 22 Sep 2022)

Our study demonstrates that an 8-week exercise intervention in sedentary individuals can restore insulin action in the brain. Hence, the ameliorating benefits of exercise toward brain insulin resistance may provide an objective therapeutic target in humans in the challenge to reduce diabetes risk factors.


A prospective analysis of leisure-time physical activity in mid-life and beyond and brain damage on MRI in older adults(Priya Palta et al, 6 Jan 2021) This paper suggests that higher levels of leisure-time physical activity in midlife are associated with a lower risk for brain blood vessel problems in later life.


Cortical, corticospinal and reticulospinal contributions to strength training (Isabel S. Glover and Stuart N. Baker, 22 Jul 2020) According to this paper weight training strengthens the nervous system and remember the brain is part of the nervous system


The effects of aerobic exercise intensity on memory in older adults (Ana Kovacevic et al, 6 June 2020) Seniors who exercised using short, bursts of activity saw an improvement of up to 30 percent in memory performance while participants who worked out moderately saw no improvement, on average.


Aerobic exercise improves cognition and cerebrovascular regulation in older adults (Veronica Guadagni et al, 13 May 2020) This study suggests older adults, even couch potatoes, may perform better on certain thinking and memory tests after just six months of aerobic exercise.


Brain Perfusion Change in Patients with Mild Cognitive Impairment After 12 Months of Aerobic Exercise Training (Thomas, Binu P et al, 8 Mar 2020) The results from this paper suggest that the beneficial effects of aerobic exercise is brought about by redistribution of blood flow (perfusion) and neural activity in sensitive regions of the brain.


Relationship Between Exercise and Alzheimer’s Disease: A Narrative Literature Review (Qing Meng et al, 26 Mar 2020)

Patients with AD who presented with long-term exercise interventions appeared to have improved blood flow, increased hippocampal volume, and improved neurogenesis. Most prospective studies have proven that physical inactivity is one of the most common preventable risk factors for developing AD and that higher physical activity levels are associated with a reduced risk of AD development. Physical exercise seems to be effective in improving several neuropsychiatric symptoms of AD, notably cognitive function. Compared with medications, exercise has been shown to have fewer side effects and better adherence.


One-Week High-Intensity Interval Training Increases Hippocampal Plasticity and Mitochondrial Content without Changes in Redox State (Jonathas Rodrigo dos Santos et al, 28 Feb 2020)

In conclusion, our one-week HIIT protocol increased neuroplasticity and mitochondrial content regardless of changes in redox status, adding new insights into the neuronal modulation induced by new training models.

Cardiorespiratory Fitness and Gray Matter Volume in the Temporal, Frontal, and Cerebellar Regions in the General Population (Katharina Wittfeld et al, 1 Jan 2020) This study provides new evidence of an association between cardiorespiratory fitness and brain health, particularly in gray matter and total brain volume -- regions of the brain involved with cognitive decline and aging.


Brain Glucose Metabolism, Cognition, and Cardiorespiratory Fitness Following Exercise Training in Adults at Risk for Alzheimer’s Disease (Julian M. Gaitán et al, 26 Dec 2019) Researchers studied 23 late middle-aged adults with genetic predispositions for AD, including ApoE4. They found increased brain glucose metabolism and executive function following 26 weeks of aerobic exercise training associated with cardiorespiratory fitness improvement.


Modulation of Distinct Intrinsic Resting State Brain Networks by Acute Exercise Bouts of Differing Intensity (Angelika Schmitt, et al, 26 Dec 2019) Researchers discovered that low-intensity exercise triggers brain networks involved in cognition control and attention processing, while high-intensity exercise primarily activates networks involved in affective/emotion processing.


Associations of Physical Activity and β-Amyloid With Longitudinal Cognition and Neurodegeneration in Clinically Normal Older Adults (Jennifer S. Rabin et al, 16 Jul 2019)

Greater physical activity and lower vascular risk independently attenuated the negative association of Aβ burden with cognitive decline and neurodegeneration in asymptomatic individuals. These findings suggest that engaging in physical activity and lowering vascular risk may have additive protective effects on delaying the progression of Alzheimer disease.


Exercise for Brain Health: An Investigation into the Underlying Mechanisms Guided by Dose (Danylo F. Cabral et al, 13 Jun 2019)

The purpose of this review is to summarize the evidence on the effects of exercise interventions on various mechanisms believed to support cognitive improvements: cerebral perfusion, synaptic neuroplasticity, brain volume and connectivity, neurogenesis, and regulation of trophic factors. We synthesized the findings according to exposure to exercise (short- [1 day-16 weeks], medium- [24-40 weeks], and long-term exercise [52 weeks and beyond]) and have limited our discussion of dose effects to studies in aging adults and aged animals (when human data was not available)


Distinctive Effects of Aerobic and Resistance Exercise Modes on Neurocognitive and Biochemical Changes in Individuals with Mild Cognitive Impairment (Tsai Chia-Liang et al, 24 Apr 2019) The full paper is behind a paywall, but from the abstract, “Conclusion: These findings suggested that in older adults with aMCI [amnestic Mild Cognitive Impairment] not only aerobic but also resistance exercise is effective with regard to increasing neurotrophins [neurotrophins are a family of proteins that promote the survival, development, and function of neurons], reducing some inflammatory cytokines, and facilitating neurocognitive performance.”


Association of non-exercise physical activity in mid- and late-life with cognitive trajectories and the impact of APOE ε4 genotype status: the Mayo Clinic Study of Aging (Janina Krell-Roesch et al, 12 Apr 2019) This paper found that midlife physical activity was significantly associated with less decline in memory function among ApoE4 carriers. Physical activity included laundry, vacuuming, making beds, dusting, scrubbing floors, washing windows, gardening, raking leaves, carrying heavy objects, heavy digging, pushing a lawn mower or hard manual labor. This benefit was found regardless of intensity level.


Exercise for cognitive brain health in aging (Joyce Gomes-Osman et al, 30 May 2018) This research examined nearly 100 previously published studies on exercise and cognition, with a total of more than 11,000 participants whose average age was 73. The common denominator across all these studies was that various forms of exercise all led to sharper thinking if the participants achieved this minimum 52-hour target over roughly six months. Studies with fewer hours of exercise or shorter time scales did not yield positive results.


Dancing or Fitness Sport? The Effects of Two Training Programs on Hippocampal Plasticity and Balance Abilities in Healthy Seniors (Kathrin Rehfeld et al, 15 Jun 2017)

In sum, the present results indicate that both dance and fitness training can induce hippocampal plasticity in the elderly, but only dance training improved balance capabilities.

Exercise and Overall Better Health/Longevity

Understanding how exercise induces systemic metabolic benefits (Olivia Dimmer, MedicalXpress, 16 Mar 2023) This article addresses research that explores how during exercise, autophagy, the body's cellular recycling system that allows old or damaged cellular structures to be broken down, is activated in both contracting muscles and various non-contracting organs, such as the liver.


How Many Daily Walking Steps Needed for Longevity Benefit?(UMass, NeuroScienceNews.com, March 3, 2022) The oft-repeated 10,000-steps-a-day mantra grew out of a decades-old marketing campaign for a Japanese pedometer, with no science to back up the impact on health. A meta-analysis of 15 studies involving nearly 50,000 people from four continents offers new insights into identifying the amount of daily walking steps that will optimally improve adults’ health and longevity – and whether the number of steps is different for people of different ages.


Resistance exercise may be superior to aerobic exercise for getting better ZZZs(American Heart Association, Science Daily, March 3, 2022) A new study found that resistance exercise may be superior to aerobic exercise as a way to get better sleep. A year-long resistance exercise program improved sleep quality, duration and other indicators of a good night's sleep more so than aerobic exercise, combined aerobic and resistance exercise, and no exercise. Researchers say interventions focused on resistance exercises may be a way to improve sleep and, in turn, cardiovascular health.


Exercise mimetics and JAK inhibition attenuate IFN-γ–induced wasting in engineered human skeletal muscle (Zhaowei Chen et al, 22 Jan 2021) Biomedical engineers at Duke University have demonstrated that human muscle has an innate ability to ward off the damaging effects of chronic inflammation when exercised.


Association of Daily Step Count and Step Intensity With Mortality Among US Adults (Pedro F. Saint-Maurice et al, 24/31 Mar 2020) In this study, higher daily step counts were associated with lower mortality risk from all causes.


Metabolic Architecture of Acute Exercise Response in Middle-Aged Adults in the Community (Matthew Nayor et al, 15 Sep 2020) This study demonstrates that short bursts of vigorous exercise can produce “striking” effects on the metabolites circulating through the body and, by extension, lead to improvements in a wide range of bodily functions.


Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1 (Charles P. Najt et al, 13 Dec 2019) Research by the University of Minnesota Medical School found that the fat in olive oil appears to activate pathways in cells that are linked to longer life. The researchers said olive-oil fats were stored in the body and when the fat is broken down during exercising or fasting is when the signalling and beneficial effects are realized


Stay Fit, Stay Young: Mitochondria in Movement: The Role of Exercise in the New Mitochondrial Paradigm(Jesus R. Huertas et al, 19 Jun 2019)

Skeletal muscles require the proper production and distribution of energy to sustain their work. To ensure this requirement is met, mitochondria form large networks within skeletal muscle cells, and during exercise, they can enhance their functions. In the present review, we discuss recent findings on exercise-induced mitochondrial adaptations. We emphasize the importance of mitochondrial biogenesis, morphological changes, and increases in respiratory supercomplex formation as mechanisms triggered by exercise that may increase the function of skeletal muscles. Finally, we highlight the possible effects of nutraceutical compounds on mitochondrial performance during exercise and outline the use of exercise as a therapeutic tool in noncommunicable disease prevention. The resulting picture shows that the modulation of mitochondrial activity by exercise is not only fundamental for physical performance but also a key point for whole-organism well-being.19)


Study: Even a Little Walking May Help You Live Longer (American Cancer Society, 19 Oct 2017) This article references a study of almost 140,000 people participating in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Researchers has found that even low levels of walking are linked with lower mortality. From the article:

Older Americans in the study who did even a little walking at a moderate pace had a decreased risk of death compared with those who did little or no activity. Those who walked at or above recommended levels decreased their risk even more.


Does Strength-Promoting Exercise Confer Unique Health Benefits? A Pooled Analysis of Data on 11 Population Cohorts With All-Cause, Cancer, and Cardiovascular Mortality Endpoints (Emmanuel Stamatakis et al, 31 Oct 2017) Summary of key findings:

  • participation in any strength-promoting exercise was associated with a 23 percent reduction in all-cause mortality and a 31 percent reduction in cancer mortality
  • own bodyweight exercises that can be performed in any setting without equipment yielded comparable results to gym-based activities
  • adherence to WHO's strength-promoting exercise guideline alone was associated with reduced risk of cancer-related death, but adherence to the WHO's aerobic physical activity guideline alone was not
  • adherence to WHO's strength-promoting exercise and aerobic guidelines combined was associated with a greater risk reduction in mortality than aerobic physical activity alone
  • there was no evidence of an association between strength-promoting exercise and cardiovascular disease mortality.


Enhanced Protein Translation Underlies Improved Metabolic and Physical Adaptations to Different Exercise Training Modes in Young and Old Humans (Matthew M. Robinson et al, 7 Mar 2017) This study found that exercise -- and in particular high-intensity interval training in aerobic exercises such as biking and walking -- caused cells to make more proteins for their energy-producing mitochondria and their protein-building ribosomes, effectively stopping aging at the cellular level.


The importance of non-exercise physical activity for cardiovascular health and longevity (Elin Ekblom-Bak et al, 28 Oct 2013) Conclusions: A generally active daily life was, regardless of exercising regularly or not, associated with cardiovascular health and longevity in older adults.


The Effects of Tai Chi Chuan Relaxation and Exercise on Stress Responses and Well-Being: An Overview of Research (Erica S. Sandlund & Torsten Norlander, Apr 2000)

Studies reviewed in this article characterize Tai Chi as a form of moderate exercise. Although Tai Chi may not be suitable for achieving aerobic fitness, it may enhance flexibility and overall psychological well-being. Cognitively, there are indications that Tai Chi exercise may lead to improvements in mood. However, it is not clear whether the positive effects of Tai Chi are due solely to its relaxation and meditation component, or whether they are the consequence of various peripheral factors, since it is known that stress reduction often occurs when we indulge in activities we find pleasurable and satisfying. An important finding is that all studies on the benefits of Tai Chi for senior adults have revealed positive results. (bold font added to quote for emphasis)