Sex Differences in the Genetic Architecture of Alzheimer’s Disease

Dumitrescu, Logan; Mayeda, Elizabeth Rose; Sharman, Kavya; Moore, Annah M.; Hohman, Timothy J.

doi:10.1007/s40142-019-0157-1

Cited by 29 publications

(25 citation statements)

References 96 publications

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“…Similar associations at the phenotypic level have been reported previously, with an older age at menopause correlated with protection from cognitive decline (Robert N. McLay et al, 2003;Ryan et al, 2009;Ryan et al, 2014). Interestingly, we and others have published extensively on sex differences in the downstream consequences of neuropathology (Buckley et al, 2018;Deming et al, 2018;Hohman et al, 2018;Dumitrescu et al, 2019a;Dumitrescu et al, 2019b). The present results suggest that hormone changes in older adulthood may contribute to susceptibility to cognitive decline, but more work is needed to disentangle the potential contribution of educational attainment on these observed genetic correlations.…”

Section: Neuropsychiatric and Smoking Phenotypessupporting

confidence: 88%

Genetic Variants and Functional Pathways Associated with Resilience to Alzheimer’s Disease

Dumitrescu

Mahoney

Mukherjee

et al. 2020

Preprint

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Approximately 30% of older adults exhibit the neuropathologic features of Alzheimer's disease (AD) without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively normal in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modeling approach and representing betterthan-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5,108 participants from a clinical trial of AD and three longitudinal cohort studies of cognitive aging. All analyses were run across all participants and repeated restricting the sample to individuals with normal cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (p-values<2.5x10 -20 ), and we observed novel correlations with neuropsychiatric conditions

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Section: Neuropsychiatric and Smoking Phenotypessupporting

confidence: 88%

Genetic Variants and Functional Pathways Associated with Resilience to Alzheimer’s Disease

Dumitrescu

Mahoney

Mukherjee

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Similar associations at the phenotypic level have been reported previously, with an older age at menopause correlated with protection from cognitive decline ( McLay et al , 2003 ; Ryan et al , 2009 , 2014 ). Interestingly, we and others have published extensively on sex differences in the downstream consequences of neuropathology ( Buckley et al , 2018 ; Deming et al , 2018 ; Hohman et al , 2018 ; Dumitrescu et al , 2019 ; Mahoney et al , 2019 ). The present results suggest that hormone changes in older adulthood may contribute to susceptibility to cognitive decline, but more work is needed to disentangle the potential contribution of educational attainment on these observed genetic correlations.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants and functional pathways associated with resilience to Alzheimer’s disease

Dumitrescu

Mahoney

Mukherjee

et al. 2020

Brain

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Approximately 30% of older adults exhibit the neuropathological features of Alzheimer’s disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer’s disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10−20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10−4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer’s disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10−8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10−13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer’s disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.

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“…Genetic variation likely affects men and women differentially, pointing to mechanisms that contribute to known differences in AD pathology between the sexes (59). The set of proteins that were differentially affected by sex and PICALM genotype are primarily implicated in immune processes, cell adhesion, and regulatory processes, with widely overlapping functions (Figure S6).…”

Section: Discussionmentioning

confidence: 99%

Manifestations of Alzheimer’s Disease Genetic Risk in the Blood: A Cross-Sectional Multi-Omic Analysis in Healthy Adults Aged 18-90+

Heath¹,

Earls²,

Magis³

et al. 2021

Preprint

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Background: Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease.Methods: We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants, adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed.Results: We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable.Conclusions: Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

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Sex Differences in the Genetic Architecture of Alzheimer’s Disease

Cited by 29 publications

References 96 publications

Genetic Variants and Functional Pathways Associated with Resilience to Alzheimer’s Disease

Genetic Variants and Functional Pathways Associated with Resilience to Alzheimer’s Disease

Genetic variants and functional pathways associated with resilience to Alzheimer’s disease

Manifestations of Alzheimer’s Disease Genetic Risk in the Blood: A Cross-Sectional Multi-Omic Analysis in Healthy Adults Aged 18-90+

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