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Physical activity (PA) is a modifiable factor in mitigating/preventing Alzheimer's disease (AD). It is crucial to identify the conditions under which PA's effects on AD risk would be beneficial. This study aims to gain insights into pleiotropic predisposition to AD and PA within and across sexes and environmental effects. We performed a genome-wide association study (GWAS) of pleiotropic AD-PA associations in individuals (65 years and older) of European ancestry in a US sample (14,628 individuals), for men and women separately and combined, and contrasted them with the UK biobank (204,789 individuals) to elucidate the effects of the environment. Fisher's method and Wald's test were used for estimating the significance of pleiotropic associations and differences between the samples. We identified genetic markers in 60 loci with significant pleiotropic associations. Of them, 91.7% of loci exhibited antagonistic relationships characterized by a misalignment of the signs of the associations of the same alleles with AD and PA and a correlation between these phenotypes. Only 16.7% of associations were replicated in the UKB. Phosphorylation and the regulation of transcription were identified as more pronounced biological mechanisms of AD-PA pleiotropy in females and males, respectively. Our results demonstrate the intrinsic heterogeneity of AD-PA pleiotropy and suggest that PA should be used as an intervention against AD with caution, after identifying groups of individuals and combinations of gene–environment interactions with beneficial effects. [ABSTRACT FROM AUTHOR] more...

INTRODUCTION: Neurofibrillary tangles (NFTs), a hallmark of tau pathology in Alzheimer's disease (AD), accumulate in the aging brain. However, some individuals remain cognitively intact despite high Braak (III–VI) stages, which characterize NFTs' accumulation. METHODS: We studied resistance and resilience to tau pathology by assessing Braak stages based on apolipoprotein E (APOE) alleles, sex, and age in a sample of 1932 cognitively intact individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP). RESULTS: Resistance, characterized by low (0–II) Braak stages, was observed in men and women younger than 85 years of age. Resilience, indicated by high (III–VI) Braak stages, increased significantly with age in both men and women for each APOE allele. It became more pronounced, with the proportion of high Braak stages exceeding 50% at 85 years and older in women, irrespective of the APOE allele. DISCUSSION: The identification of factors underlying resistance and resilience against AD‐related pathologies is essential for promoting cognitively healthy aging. Highlights: We investigated cognitive resistance and resilience to tau pathology in Alzheimer's disease (AD).This study included individuals who were not diagnosed with AD.Braak stages 0–II and III–VI were considered as a measure of resistance and resilience, respectively.Resistance was stronger at ages younger than 85 years in non‐carriers of the apolipoprotein E (APOE) ε4 allele.Resilience increased with age for each APOE allele independently of sex.At age 85 years and older, high resilience (>50%) was observed in women regardless of the APOE allele. [ABSTRACT FROM AUTHOR] more...

INTRODUCTION: The variability in apolipoprotein E (APOE) ε4‐attributed susceptibility to Alzheimer's disease (AD) across ancestries, sexes, and ages may stem from the modulating effects of other genetic variants. METHODS: We examined associations of compound genotypes (CompGs) comprising the ε4‐encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with AD in White (7181/16,356 AD‐affected/unaffected), Hispanic/Latino (2305/2921), and Black American (547/1753) participants across sexes and ages. RESULTS: The absence and presence of the rs2075650 and/or rs12721046 minor alleles in the ε4‐bearing CompGs define lower‐ and higher‐AD‐risk profiles, respectively, in White participants. They differentially impact AD risks in men and women of different ancestries, exhibiting an increasing, decreasing, flat, and nonlinear—with lower risks at ages younger than 65/70 years and older than 85 years compared to the ages in between—patterns across ages. DISCUSSION: The ε4‐bearing CompGs have a potential to differentiate biological mechanisms of sex‐, age‐, and ancestry‐specific AD risks and serve as AD biomarkers. Highlights: Younger White women carrying the lower‐risk (LR) CompG are at small risk of AD.Black carriers of the LR CompG are at negligible risk of AD at 85 years and older.The higher‐risk (HR) CompGs confer high AD risk in Whites and Blacks at 70 to 85 years.AD risk decreases with age for Hispanic/Lation women carrying the HR CompGs.Hispanic/Lation carriers of the LR CompG but not HR CompGs have higher AD risk than Blacks. [ABSTRACT FROM AUTHOR] more...

Background: The Alzheimer's Association reports that more than two‐thirds of the approximately 5 million Alzheimer's disease (AD) cases in the USA are women. With studies suggesting a high genetic heritability for AD, gaining a better understanding of the genetic architecture underlying sex disparities in AD and its risk factors could enhance the understanding of their mechanisms. Method: We conducted genome‐wide association studies (GWAS) and pleiotropic meta‐analysis of AD and its risk factor—hypertension—in men and women of European ancestry. The AD GWAS focused on 168,962 men (including 6,229 cases) and 199,668 women (including 7,628 cases) from 10 cohorts. The hypertension GWAS included 177,597 men (96,835 cases) and 205,482 women (88,861 cases) from eight of the 10 AD cohorts. Sex‐specific associations were characterized by the Wald chi‐square test and Fisher's method, and their significance was assessed at a false discovery rate q‐value of 5% or less. Result: GWAS of AD and hypertension identified 176 and 195 loci, respectively, on all chromosomes with the differences in the effects between sexes attaining q<0.05. Associations with AD were of the same directions in men and women only in one—the APOE gene—locus, with significantly larger adverse effect for the ε4‐encoding rs429358 polymorphism in women (β = 1.35, CI = 1.30‐1.41) than men (β = 1.16, CI = 1.10‐1.22). Associations with hypertension were of the same directions in each sex in 74 of 195 loci on all chromosomes, except chromosome 14. The ε4 allele showed no association with hypertension in either sex. No significant differences between sexes in the significant protective associations with AD and hypertension were identified for the ε2 allele. Our analyses revealed seven pleiotropic loci mapped to COL24A1, MGC4859‐PHF14, MFHAS1‐ERI1, SBF2, KICS2, BCL11B, and RPAP1 gene clusters characterized by the differences in the associations with AD and hypertension between sexes at q<0.05. In three underlined clusters, the associations with hypertension were of the same direction in men and women. Conclusion: Although the APOE ε4 allele partly underlies AD‐related sex disparities, the most substantial contribution comes from antagonistic relationships between genes and AD in men and women. Sex‐specific pleiotropic loci suggest contribution of hypertension to these AD‐related sex disparities. [ABSTRACT FROM AUTHOR] more...

Age‐related diseases characteristic of post‐reproductive life, aging, and life span are the examples of polygenic non‐Mendelian traits with intricate genetic architectures. Polygenicity of these traits implies that multiple variants can impact their risks independently or jointly as combinations of specific variants. Here, we examined chances to live to older ages, 85 years and older, for carriers of compound genotypes comprised of combinations of genotypes of rs429358 (APOE ɛ4 encoding polymorphism), rs2075650 (TOMM40), and rs12721046 (APOC1) polymorphisms using data from four human studies. The choice of these polymorphisms was motivated by our prior results showing that the ɛ4 carriers having minor alleles of the other two polymorphisms were at exceptionally high risk of Alzheimer's disease (AD), compared with non‐carriers of the minor alleles. Consistent with our prior findings for AD, we show here that the adverse effect of the ɛ4 allele on survival to older ages is significantly higher in carriers of minor alleles of rs2075650 and/or rs12721046 polymorphisms compared with their non‐carriers. The exclusion of AD cases made this effect stronger. Our results provide compelling evidence that AD does not mediate the associations of the same compound genotypes with chances to survive until older ages, indicating the existence of genetically heterogeneous mechanisms. The survival chances can be mainly associated with lipid‐ and immunity‐related mechanisms, whereas the AD risk, can be driven by the AD‐biomarker‐related mechanism, among others. Targeting heterogeneous polygenic profiles of individuals at high risks of complex traits is promising for the translation of genetic discoveries to health care. [ABSTRACT FROM AUTHOR] more...

Prevailing strategies in genome-wide association studies (GWAS) mostly rely on principles of medical genetics emphasizing one gene, one function, one phenotype concept. Here, we performed GWAS of blood lipids leveraging a new systemic concept emphasizing complexity of genetic predisposition to such phenotypes. We focused on total cholesterol, low- and high-density lipoprotein cholesterols, and triglycerides available for 29,902 individuals of European ancestry from seven independent studies, men and women combined. To implement the new concept, we leveraged the inherent heterogeneity in genetic predisposition to such complex phenotypes and emphasized a new counter intuitive phenomenon of antagonistic genetic heterogeneity, which is characterized by misalignment of the directions of genetic effects and the phenotype correlation. This analysis identified 37 loci associated with blood lipids but only one locus, FBXO33, was not reported in previous top GWAS. We, however, found strong effect of antagonistic heterogeneity that leaded to profound (quantitative and qualitative) changes in the associations with blood lipids in most, 25 of 37 or 68%, loci. These changes suggested new roles for some genes, which functions were considered as well established such as GCKR, SIK3 (APOA1 locus), LIPC, LIPG, among the others. The antagonistic heterogeneity highlighted a new class of genetic associations emphasizing beneficial and adverse trade-offs in predisposition to lipids. Our results argue that rigorous analyses dissecting heterogeneity in genetic predisposition to complex traits such as lipids beyond those implemented in current GWAS are required to facilitate translation of genetic discoveries into health care. [ABSTRACT FROM AUTHOR] more...

Introduction: Murine studies have shown that apolipoprotein E modulates pulmonary function during development, aging, and allergen-induced airway disease. It is not known whether the polymorphic human APOE gene influences pulmonary function. Objectives: We assessed whether an association exists between the polymorphic human APOE ε2, ε3, and ε4 alleles and pulmonary function among participants in the Long Life Family Study. Methods: Data from 4,468 Caucasian subjects who had genotyping performed for the APOE ε2, ε3, and ε4 alleles were analyzed, with and without stratification by sex. Statistical models were fitted considering the effects of the ε2 allele, defined as ε2/2 or ε2/3 genotypes, and the ε4 allele, defined as ε3/4 or ε4/4 genotypes, which were compared to the ε3/3 genotype. Results: The mean FEV1/FVC ratio (the forced expiratory volume in one second divided by the forced vital capacity) was lower among women with the ε4 allele as compared to women with the ε3/3 genotype or the ε2 allele. Carriage of the APOE ε4 allele was associated with FEV1/FVC, which implied lower values. Further analysis showed that the association primarily reflected women without lung disease who were older than 70 years. The association was not mediated by lipid levels, smoking status, body mass index, or cardiovascular disease. Conclusions: This study for the first time identifies that the APOE gene is associated with modified lung physiology in women. This suggests that a link may exist between the APOE ε4 allele, female sex, and a reduction in the FEV1/FVC ratio in older individuals. [ABSTRACT FROM AUTHOR] more...