Non-white or non-European descent

Minorities are underrepresented in health studies, most research on APOE-ε4 and Alzheimer’s has been conducted on white subjects of European descent. Further compounding this situation is that much of the research conducted on health conditions that affect ApoE4s: Alzheimer’s, Cardiovascular disease, shortened longevity, etc. often do not stratify by APOE status much less racial/ethnic status. One would think genes are color blind, and yet there are differences in non-European ApoE4s. So what to believe? This wiki is dedicated to sharing what research is available.

Black/African descent

According to this article Researchers Explain Why Black Americans Are At Higher Risk For Alzheimer's (Meghan Rabbitt, 24 Jun 2020) less than 5 percent of participants in U.S. health studies are black yet older African Americans are about twice as likely than non-Hispanic white people to develop Alzheimer’s or other dementias.

So is the key to this statistic that they are black, ApoE4, living in the United States, something else, or some combination of these? While the answer is not clear, in 2005 this paper APOE ε4 is not associated with Alzheimer's disease in elderly Nigerians (Oye Gureje et al, 22 Dec 2005) was published that found Nigerian APOEε4/4 carriers held a very low incidence of Alzheimer’s, contrary to what is generally considered a very high genetic risk. From the abstract of this paper:

Since 1992, research teams from Indiana University and the University of Ibadan have been collecting and comparing data from two diverse, elderly populations to identify risk factors for dementia and Alzheimer's disease. Apolipoprotein E (APOE) was genotyped in 2,245 Nigerian samples. Of these, 830 had a diagnosis: 459 were normal, and 140 had dementia including 123 diagnosed with Alzheimer's disease. In contrast with other populations, the APOE ε4 allele was not significantly associated with Alzheimer's disease or dementia. This lack of association in the Yoruba might reflect genetic variation, environmental factors, as well as genetic/environmental interactions.

In the video contained in this link, African Ancestry Reduces Risk From APOE Gene in Alzheimer's(Greg Laub April 18, 2022) Farid Rajabli, PhD, from the University of Miami Miller School of Medicine in Florida, explains the protective effect of the APOE ε4 allele in patients with an African ancestral from the results of a study of which was the lead author. Dr Rajabli's paper can be found here: A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer’s Disease in African Ancestry(Farid Rajabli et al, 5 July 2022).

From this Key Alzheimer’s gene acts differently in non-Europeans(LA Bline, 15 Nov 2019):

In this study, individuals with African-derived ancestry in their APOE gene had 39 percent lower odds of Alzheimer’s than did individuals with European-derived APOE.

and from the same study, this article, Research Provides More Clues into APOE Gene’s Protective Factors (Phil Gutis, 13 Nov 2019)

Caribbean Hispanic individuals who inherited their APOE E4 from European ancestors had greater risk of Alzheimer’s disease compared to individuals who inherited APOE E4 from African ancestors, after adjusting for other known risk factors

From this research article Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds (Anthony J. Griswold et al, 1 Feb 2021)

Apolipoprotein E (APOE) ε4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE ε4 carriers with European local ancestry (ELA).

And further investigating connection of lower AD in those with African ancestry, this study, Global and local ancestry modulate APOE association with Alzheimer’s neuropathology and cognitive outcomes in an admixed sample (Michel Satya Naslavsky et al, 7 Sept 2022)

A study from a large UK cohort also suggests that older Blacks have a higher prevalence of dementia than Whites [3]. Paradoxically, several studies suggest that apolipoprotein E ε4 allele (APOE4), considered the strongest genetic risk factor for late-onset AD, has a weaker effect in Blacks than in Whites [4, 5] or that the effect of APOE4 on AD risk is attenuated in African ancestry (AFR), especially when the APOE gene is on a local African ancestry [6,7,8]....In conclusion, our work corroborates the need to increase the number of admixed populations in AD research. It suggests that neuropathology, clinical outcomes, and APOE genotyping differ with different ancestry backgrounds. The association between increased AFR proportion and worse functional cognitive scores was lost in APOE4 + , supporting the hypothesis that APOE4 risk in AD is attenuated in individuals with AFR ancestry compared to EUR ancestry.

But in some 3/4s, risk can be elevated. A variant found just in people of African descent, called R145C, pops up only on the E3 allele of ApoE. When the other allele is of the E4 variety, it appears to increase Alzheimer’s risk. The full paper that discovered this, Association of African Ancestry–Specific APOE Missense Variant R145C With Risk of Alzheimer Disease(Yann Le Guen et al, 21 Feb 2023) published in JAMA, is behind a paywall, but this article, Scientists find genetic Alzheimer’s risk factor tied to African ancestry applies. From the article:

At the molecular level, the R145C variant is a tiny shift in the ApoE gene’s coding sequence, resulting in the replacement of a single protein building block, the amino acid arginine, with another one, cysteine, in the ApoE protein’s sequence. This switch shifts the shape and, consequently, function of ApoE in a way that, somehow, puts an R145C carrier at increased Alzheimer’s risk — but apparently only under certain conditions.”

Le Guen and Greicius gained access to several databases containing the ApoE genotypes of 31,929 individuals of African descent (about 3% Nigerian, the rest African American) along with health information about those individuals. The researchers compared the genotypes of individuals diagnosed with Alzheimer’s disease with those whose medical records indicated that they were free of Alzheimer’s or any other form of dementia.

R145C’s presence in individuals with E2/E3 and E3/E3 genotypes conveyed no detectable added risk, the study showed. But carrying R145C substantially increased Alzheimer’s risk among those with an E3/E4 genotype.

About 30% of the individuals in the study were E3/E4. And of those E3/E4 individuals, 3% (about 1% of the entire study sample) had the R145C variant riding shotgun on their E3 allele. The R145C variant’s presence in E3/E4 individuals nearly tripled carriers’ risk of acquiring Alzheimer’s, compared with that of R145C-free E3/E4 carriers.

In addition, the R145C variant’s presence in combination with the E3/E4 genotype lowered the average age of onset of the disorder by more than five years, the study indicated.

In these E3/E4 R145C carriers, Le Guen said, “The average Alzheimer’s risk was so high, they might as well have had a E4/E4 genotype.”

While harmful, an E4/E4 genotype increases Alzheimer’s risk in an African-ancestry individual by 5 to 10 times versus the E3/E3 “reference” genotype, less than the 10- to 16-fold increased risk seen among E4/E4 individuals with a European heritage. The reasons for this are not yet known.

“R145C doesn’t increase risk in the absence of E4,” said Le Guen, “hinting that perhaps R145C wipes out some beneficial property of ApoE3 that would normally mitigate the increased Alzheimer’s risk conveyed by ApoE4.”

Furthermore, according to The Relationship of APOE ε4, Race, and Sex on the Age of Onset and Risk of Dementia(Danielle S. Powell et al, 20 Oct 2021) lower cerebrospinal fluid concentrations of tau biomarkers were found in Black APOE ε4 carriers thus adding to the need for race-adjusted diagnostics.

According to the Alzheimer’s Association Alzheimer’s Disease Facts and Figures report, older African Americans are about twice as likely to have Alzheimer’s or other dementias as older whites. Yet according to the research from this article, Lower Amyloid Levels Observed in Black People Despite Higher Alzheimer Disease Risk(Victoria Johnson Neurology Live 19 Feb 2021) black individuals had lower rates of amyloid-positivity and lower continuous amyloid levels compared to white individuals.

From this article, Alzheimer's risk factors may be measurable in adolescents and young adults (Science News, 30 Jul 2020) the risk factors that are disproportionately apparent in African Americans include heart health factors -- such as high blood pressure, high cholesterol and diabetes -- and social factors like education quality. But this is largely conjecture, as cited above, black Americans are sorely underrepresented in health studies.

Fortunately, there is more all-inclusive research is being conducted. This press release addresses four studies NIH expands nation’s Alzheimer’s and related dementias research capacity (National Institutes of Health, 10 Sep 2020):

To further incentivize innovative ideas and opportunities in Alzheimer's disease and related dementias research, the National Institute on Aging (NIA), part of the National Institutes of Health, has funded four exploratory Alzheimer’s Disease Research Centers (ADRCs). These new centers will broaden current ADRC research initiatives with underrepresented populations such as African Americans, Native Americans, and those in rural communities — all of which have different risk factors for developing these devastating diseases.

Whether these studies will separate APOE genetic status is unknown.

For further exploration:

From Insight: Promising new Alzheimer's drugs may benefit whites more than Blacks (Julie Steenhuysen, Reuters, 31 Jul 2023) With respect to two drugs: Leqembi by Eisai & Biogen and donanemab by Eli Lilly:

Although older Black Americans have twice the rate of dementia as whites, they were screened out of clinical trials of these drugs at a higher rate, according to interviews with 10 researchers as well as 4 Eisai and Lilly executives.

Prospective Black volunteers with early disease symptoms did not have enough amyloid in their brain to qualify for the trials, the 10 researchers explained.

From Amyloid PET imaging in self-identified non-Hispanic Blacks from the Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) Study (Kacie Deters et al, 10 Feb 2021)

Results: NHB [Non-Hispanic Blacks] had lower rates of amyloid-positivity and lower continuous amyloid levels compared to NHW [Non-Hispanic Whites]. This race effect on amyloid was strongest in the APOE ε4 group. Within NHB, those with a lower percentage of African ancestry had higher amyloid. A greater proportion of NHB did not pass initial screening compared to NHW, suggesting potential sources of bias related to race in the A4 PET data.

From Racial Differences in Dietary Relations to Cognitive Decline and Alzheimer’s Disease Risk: Do We Know Enough? (Puja Agarwal et al, 3 Sep 2020):

In the past few decades, diet has been identified as an important modifiable risk factor for cognitive decline and Alzheimer’s disease. Some studies report poor diet quality among African American and Hispanic older adult populations compared to their white counterparts. We have a limited understanding of how diet affects brain health in different racial-ethnic groups. One primary reason for our lack of knowledge is that most cohort studies are of majority non-Hispanic white participants. Moreover, those that do include minority participants do not publish their findings stratified by racial-ethnic groups, and likely have a less accurate measurement of dietary intake among minority groups. In this review, we summarize the current, albeit limited, literature on racial/ethnic differences in dietary relations to dementia outcomes. We will also discuss methodological issues in conducting nutrition studies in diverse cultures, and suggestions for future research directions. Overcoming the gaps will make it possible to make dietary recommendations for Alzheimer’s prevention that are more relevant for different racial/ethnic groups and set us on a faster track to reduce health disparities.” (Bold font added to quote for emphasis).

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel (Brian W. Kunkle et al, 19 Oct 2020):

Findings: In this genome-wide association meta-analysis of 2748 individuals with Alzheimer disease and 5222 controls, several novel genetic loci and pathways associated with Alzheimer disease in African American individuals were identified.

Meaning: While the major pathways involved in Alzheimer disease etiology in African American individuals are largely similar to those in non-Hispanic White individuals, many of the disease-associated loci within these pathways differ.

Assessment of Racial Disparities in Biomarkers for Alzheimer Disease (John C. Morris et al, 7 Jan 2019)

Conclusions and Relevance: The results of this study suggest that analyses of molecular biomarkers of Alzheimer disease should adjust for race. The lower CSF concentrations of total tau and phosphorylated tau181 in African American individuals appear to reflect a significant race by APOE ε4 interaction, suggesting a differential effect of this Alzheimer risk variant in African American individuals compared with white individuals.

Association of Apolipoprotein E Genotype and Alzheimer Disease in African Americans (Jill R. Murrell et al, Mar 2006)

These findings are in marked contrast to the lack of association between APOE and AD in the Ibadan, Nigeria, sample of this project. These results suggest that other genetic factors and different environmental influences may play a role in the risk for AD in individuals of African ancestry.

Some insight may also be gained by reviewing the below section on the Hispanics as some population have more African ancestry and differences were found in those Hispanics with African ancestry vs European ancestry.

Hispanic, Latino, etc.

Hispanics experience dementia at one and a half times the rate of whites yet the exact reasons for this are not completely clear as they are less likely to participate in health studies and experience amyloid at lower levels than white people.

Studies on the effects of APOE on cognition are inconsistent. Some studies suggest strong associations between ApoE4 and rate of cognitive decline in Hispanics. Sources: APOE and Alzheimer Disease Meta Analysis Consortium. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis(LA Farrer et al, 22 Oct 1997); Apolipoprotein E ε4 and age at onset of sporadic and familial Alzheimer disease in Caribbean Hispanics(L Olarte et al, Nov 2006); and Familial Alzheimer disease in Latinos Interaction between APOE, stroke, and estrogen replacement(GA Rippon et al, 9 Jan 2006). Whereas other studies report no significant associations between ApoE4 and cognition. Source: APOE ε4 allele predicts faster cognitive decline in mild Alzheimer disease(S. Cosentino et al, 6 May 2008).

Additionally, according to the research from this article, Insight: Promising new Alzheimer's drugs may benefit whites more than Blacks(Victoria Johnson Neurology Live 19 Feb 2021) Hispanics were excluded from clinical trials of recent proposed Alzheimer's drugs due to low amyloid, although the issue was not as pronounced as for Black people. Nevertheless, Eisai, the manufacturer of the drug Leqembi, told Reuters that 55% of the Hispanic clinical trial volunteers were excluded due to low amyloid.

So why the higher rate of dementia and what is the role of ApoE4 in Hispanics?

The Link between APOE4 Presence and Neuropsychological Test Performance among Mexican Americans and Non-Hispanic Whites of the Multiethnic Health & Aging Brain Study – Health Disparities Cohort(S.E. O’Bryant, et al, 2022) The full paper is behind a paywall, but the abstract is available through the link and presents more research on the variable impact of the APOEε4 allele when considering racial differences. From the conclusion:

The APOEε4 allele was associated with poorer cognition across multiple domains among NHWs [non-hispanic Whites]; however, allele presence was specifically associated with poorer memory performance among MAs [Mexican Americans]. When combined with prior work, the current findings demonstrate that the risk factors associated with cognitive dysfunction differ among MAs as compared to NHWs and require additional investigation.

Apolipoprotein E ε4 Allele-Based Differences in Brain Volumes Are Largely Uniform Across Late Middle Aged and Older Hispanic/Latino- and Non-Hispanic/Latino Whites Without Dementia (Ariana M. Stickel et al, 26 Feb 2021)

Hispanics/Latinos are at an equal or a greater risk for Alzheimer's disease (AD), yet risk factors remain more poorly characterized as compared to non-Hispanic/Latino Whites. Among non-Hispanic/Latino White cohorts, the apolipoprotein E (APOE) ε4 allele is one of the strongest risk factors for AD with subtle declines in episodic memory and brain volumes detectable in the preclinical stages. We examined whether the APOE ε4 status had a differential impact on cognition and brain volumes among cognitively healthy and mild cognitively impaired Hispanics/Latinos (n = 86; ε4 n = 23) compared to a well-matched group of non-Hispanic/Latino Whites (n = 92; ε4 n = 29). Neither the APOE ε4 status nor the interaction between the ε4 status and ethnicity was associated with cognitive performance. The APOE ε4 status was associated with white matter and not with gray matter volumes. APOE ε4 carriers had a significantly smaller total brain white matter volumes, as well as smaller right middle temporal and left superior temporal volumes. The Hispanics/Latinos had significantly smaller left middle frontal gray matter volumes, yet marginally larger overall white matter volumes, than the non-Hispanic/Latino Whites. Exploratory analysis within the Hispanic/Latino sample found that those people whose primary language was Spanish had larger total brain white matter volumes compared primarily to the English speakers. Importantly, primary language differences only held for Hispanic/Latino ε4 carriers and did not differentiate Hispanic/Latino non-carriers, underscoring the need for further investigation into the impacts of language and acculturation on cognitive aging among the fastest growing ethnic minority group in the United States.

Association between ApoE ε4 Carrier Status and Cardiovascular Risk Factors on Mild Cognitive Impairment among Mexican Older Adults (Sara G. Aguilar-Navarro et al, 14 Nov 2020)

-Cardiovascular risk factors (CVRF), such as hypertension, diabetes, or dyslipidemia, and the presence of the Apolipoprotein E ε4 (ApoE ε4) polymorphism have been associated with an increased risk of developing Alzheimer’s disease (AD) and other dementias but the relationship is inconsistent worldwide. We aimed to establish the association between the ApoE ε4 carrier status and CVRF on MCI [Mild Cognitive Impairment] subtypes (amnestic and non-amnestic) in Mexican older adults.Bulleted list item

-ApoE ε4 carrier status was present in 28.8% participants. The models showed that ApoE ε4 carrier status was not associated neither aMCI [amnesic Mild Cognitive Impairment] nor naMCI [non-amnesic Mild Cognitive Impairment] condition. The interaction term ApoE ε4 × CVRF was not statistically significant for both types of MCI. However, CVRF were associated with both types of MCI and the association remained statistically significant after adjustment by sex, age, and education level. The carrier status of the ApoE genotype does not contribute to this risk.

APOE alleles’ association with cognitive function differs across Hispanic/Latino groups and genetic ancestry in the study of Latinos‐investigation of neurocognitive aging (HCHS/SOL) (Einat Granot‐Hershkovitz et al, 6 Nov 2020) This research took on six Latino subgroups as they differ based on what proportion of their genes trace back to African, European, and Amerindian (indigenous American) ancestries. Cuban individuals have the lowest proportion of Amerindian ancestry of the six groups and a relatively higher proportion of European ancestry.

Results: APOE ε4 was associated with an increased risk of significant cognitive decline (odds ratio [OR] = 1.15, P‐value = 0.03), with the strongest association in Cubans (OR = 1.46, P‐value = 0.007). APOE‐ε2 was associated with decreased risk of MCI (OR = 0.37, P‐value = 0.04) in Puerto Ricans. Amerindian genetic ancestry was found to protect from the risk conferred by APOE ε4 on significant cognitive decline.

Discussion: Results suggest that APOE alleles' effects on cognitive outcomes differ across six Latino backgrounds and are modified by continental genetic ancestry.

Local ancestry at APOE modifies Alzheimer's disease risk in Caribbean Hispanics (Elizabeth E. Blue, et al. 9 Oct 2019) The study looked at the relationship between APOE and Alzheimer's between 3,067 Caribbean Hispanics and 3,028 individuals of European descent. They found that individuals with African-derived ancestry in their APOE gene had 39 percent lower odds of Alzheimer's than individuals with European-derived APOE.

Results: Among the Caribbean Hispanics, individuals with African‐derived ancestry at APOE had 39% lower odds of AD than individuals with European‐derived APOE, after adjusting for APOE genotype, age, and genome‐wide ancestry. While APOE E2 and E4 effects on AD risk and age at onset were significant in the Caribbean Hispanics, they were substantially attenuated compared with those in European ancestry individuals.

Discussion: These results suggest that additional genetic variation in the APOE region influences AD risk beyond APOE E2/E3/E4.

Genetics of cognitive trajectory in Brazilians: 15 years of follow-up from the Bambuí-Epigen Cohort Study of Aging (Mateus H. Gouveia et al, 2 Dec 2019) Latin American populations have some of the highest prevalence rates of dementia in the world, but are under-studied. Recognizing that most genetic risk factors for Age-related Cognitive Decline (ACD) come from European populations, this research focused on Latin American population, examining genetic factors of 1,407 older Brazilians over 15 years.

Abstract: Age-related cognitive decline (ACD) is the gradual process of decreasing of cognitive function over age. Most genetic risk factors for ACD have been identified in European populations and there are no reports in admixed Latin American individuals. We performed admixture mapping, genome-wide association analysis (GWAS), and fine-mapping to examine genetic factors associated with 15-year cognitive trajectory in 1,407 Brazilian older adults, comprising 14,956 Mini-Mental State Examination measures. Participants were enrolled as part of the Bambuí-Epigen Cohort Study of Aging. Our admixture mapping analysis identified a genomic region (3p24.2) in which increased Native American ancestry was significantly associated with faster ACD. Fine-mapping of this region identified a single nucleotide polymorphism (SNP) rs142380904 (β = −0.044, SE = 0.01, p = 7.5 × 10−5) associated with ACD. In addition, our GWAS identified 24 associated SNPs, most in genes previously reported to influence cognitive function. The top six associated SNPs accounted for 18.5% of the ACD variance in our data. Furthermore, our longitudinal study replicated previous GWAS hits for cognitive decline and Alzheimer’s disease. Our 15-year longitudinal study identified both ancestry-specific and cosmopolitan genetic variants associated with ACD in Brazilians, highlighting the need for more trans-ancestry genomic studies, especially in underrepresented ethnic groups.

Native American

Given that some Hispanic populations hold a considerable percentage of Native American ancestry, review of the above discussion may be of interest.

There doesn't appear to be much research in this area, however, according to this article highlighting research APOE ε4 is not associated with increased risk for Alzheimer’s disease and dementia in American Indians(National Institute on Aging, 3 Mar 2022)

The apolipoprotein E gene APOE ε4 (APOE4) is known to be a significant genetic risk factor for Alzheimer’s disease; however, several studies have indicated that the association between APOE4 and Alzheimer’s risk differs between various racial and ethnic groups. Researchers studied this association in a group of American Indians who are part of the Strong Heart Study, an NIH-funded longitudinal cohort study.

The referenced study APOE genotype, hippocampus, and cognitive markers of Alzheimer’s disease in American Indians: Data from the Strong Heart Study (Suchy-Dicey A, et al., 2022) is behind a paywall.

Asian

Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk (Daichi Shigemizu et al, 3 Mar 2021)

Abstract: Alzheimer’s disease (AD) has no cure, but early detection and risk prediction could allow earlier intervention. Genetic risk factors may differ between ethnic populations. To discover novel susceptibility loci of AD in the Japanese population, we conducted a genome-wide association study (GWAS) with 3962 AD cases and 4074 controls. Out of 4,852,957 genetic markers that passed stringent quality control filters, 134 in nine loci, including APOE and SORL1, were convincingly associated with AD. Lead SNPs located in seven novel loci were genotyped in an independent Japanese AD case–control cohort. The novel locus FAM47E reached genome-wide significance in a meta-analysis of association results. This is the first report associating the FAM47E locus with AD in the Japanese population. A trans-ethnic meta-analysis combining the results of the Japanese data sets with summary statistics from stage 1 data of the International Genomics of Alzheimer’s Project identified an additional novel susceptibility locus in OR2B2. Our data highlight the importance of performing GWAS in non-European populations. (bold font added for emphasis)

APOE ε4 and the Influence of Sex, Age, Vascular Risk Factors, and Ethnicity on Cognitive Decline (Steve R Makkar et al, Oct 2020) Participants included 19,225 individuals aged 54–103 years from 15 longitudinal cohort studies with a mean follow-up duration ranging between 1.2 and 10.7 years.

APOE*4 is related to cognitive decline in men and women, although these effects are enhanced by age and carriage of two APOE*4 alleles in men, a higher numbers of vascular risk factors during the early stages of late adulthood in women, and Asian ethnicity.

APOE gene polymorphism in long-lived individuals from a central China population (Guodong Liu et al, 12 Jun 2017) Holding the ApoEε4 allele is typically negatively correlated with longevity, however this paper has found that carriage of ε4 in central China is associated with longevity. In southern and eastern China, this correlation does not hold up.

Arab

Epidemiology of Alzheimer’s Disease and Dementia in Arab Countries: A Systematic Review (Ashraf El-Metwally et al, 2019) Researchers looked at many studies and factors that influence dementia, including ApoE geneotypes. The researchers found that there was a greater prevalence of Alzheimer’s in ε4 carriers, but “The major risk factor that exacerbates dementia among the Arab countries is age and illiteracy.

Southern Italian

Although technically European, initial results indicate a possible separation from other European ApoE4 populations. According to the conclusions section of this paper, Cognitive Health of Nonagenarians in Southern Italy: A Descriptive Analysis from a Cross-Sectional, Home-Based Pilot Study of Exceptional Longevity (Cilento Initiative on Aging Outcomes or CIAO)(Vincenzo Pizza et al, May 2020)

According to the results of this pilot study on a limited sample of NCs [Nonagenarians (90-99 years old) and Centenarians (100+ years old)] from the Cilento region in Southern Italy, NCs seem to have a good cognitive status without significant differences in the oxidative stress and the APOE genotype when compared to younger cohabitants aging 50–65 years. These results might be associated with optimal adherence to Mediterranean diet by the NC subjects, although the possible impact of other lifestyle factors as well as positive personality traits like resilience and wisdom on health and longevity should also be considered. Further studies on a larger population looking at more complex evaluations should be performed to confirm the results from this pilot study.