Alzheimer's Disease Polygenic Score Research Articles

Race, polygenic risk and their association with incident dementia among older US adults.

Dementia incidence increases steadily with age at rates that may vary across racial groups. This racial disparity may be attributable to polygenic risk, as well as lifestyle and behavioural factors. We examined whether Alzheimer's disease polygenic score and race predict Alzheimer's disease and other related dementia incidence differentially by sex and mediation through polygenic scores for other health and behavioural conditions. We used longitudinal data from the nationally representative Health and Retirement Study. We restricted participants to those with complete data on 31 polygenic scores, including Alzheimer's disease polygenic score (2006-2012). Among participants aged 55 years and older in 2008, we excluded those with any memory problems between 2006 and 2008 and included those with complete follow-up on incident Alzheimer's disease and all-cause dementia, between 2010 and 2018 (N = 9683), based on self- or proxy-diagnosis every 2 years (2010, 2012, 2014, 2016 and 2018). Cox proportional hazards and 4-way decomposition models were conducted. Analyses were also stratified by sex and by race. There were racial differences in all-cause dementia incidence (age and sex-adjusted model, per standard deviation: hazard ratio, HR = 1.34, 95% confidence interval, CI: 1.09-1.65, P = 0.007), partially driven by educational attainment and income. We also found independent associations of race (age and sex-adjusted model, African American versus White adults: HR = 2.07, 95% CI: 1.52-2.83, P < 0.001) and Alzheimer's disease polygenic score (age and sex-adjusted model, per SD: HR = 1.37, 95% CI: 1.00-1.87, P < 0.001) with Alzheimer's disease incidence, including sex differences whereby women had a stronger effect of Alzheimer's disease polygenic score on Alzheimer's disease incidence compared with men (P < 0.05 for sex by Alzheimer's disease polygenic score interaction) adjusting for race and other covariates. The total impact of Alzheimer's disease polygenic scores on Alzheimer's disease incidence was mostly direct, while the effect of race on all-cause dementia incidence was mediated through socio-economic, lifestyle and health-related factors. Finally, among the 30 polygenic scores we examined, the total effects on the pathway Alzheimer's disease polygenic score --> Other polygenic score --> Incident Alzheimer's or all-cause dementia, were statistically significant for all, driven primarily by the controlled direct effect (P< 0. 001). In conclusion, both race and Alzheimer's disease polygenic scores were associated independently with Alzheimer's disease and all-cause dementia incidence. Alzheimer's disease polygenic score was more strongly linked to incident Alzheimer's disease among women, while racial difference in all-cause dementia was explained by other factors including socio-economic status.

Alzheimer’s disease polygenic scores predict changes in executive function across 12 years in late middle age

Genome-wide association studies are instrumental in quantifying genetic influences underlying Alzheimer's disease (AD), and applications of polygenic scores derived from association studies have already shed light on early disease pathology. For example, AD polygenic scores (AD-PGS) are associated with amnestic mild cognitive impairment (MCI) diagnoses in midlife. What remains unclear is how AD-PGS relate to objectively measured cognitive changes across midlife. Moreover, executive function abilities have been somewhat neglected despite prominent executive impairments in MCI and AD. Here we tested the hypothesis that an AD-PGS would be associated with executive function and episodic memory changes across late midlife.We examined 1412 men in the Vietnam Era Twin Study of Aging (VETSA) who were cognitively normal at their first assessment and had up to 3 cognitive assessments across 10-12 years (mean ages 56, 62, and 68). Latent growth models of executive function were based on 6 tasks spanning inhibition, shifting, and working memory subdomains and growth models of episodic memory were based on 7 subtests from the Logical Memory, Visual Reproductions, and California Verbal Learning tests. The AD-PRS (Lambert et al. 2013) significantly differentiated MCI and cognitively normal participants in earlier VETSA investigations.Latent growth models of executive function and memory indicated that, compared to baseline performance (i.e., intercept at mean age 56), 10-year variability in cognitive change was comparatively larger for executive function (e.g., slope variance/intercept variance ratio=39% for executive function, 22% for memory). Importantly, individuals with higher AD-PGS had sharper declines in executive functioning (r= -.24, 95% CI [-.41, -.08]) but not episodic memory (r= -.11, 95% CI [-.25, .04]). Baseline executive function (r=.00) and memory (r=-.02) were not associated with PD-PGS.AD genetic risk was associated with executive function changes, but not episodic memory changes, across midlife. These findings highlight the importance of considering executive function changes in midlife, especially for predicting disease progression and AD biology. Executive functions are one of the first cognitive abilities to decline in midlife in normal aging. This study is among the first to demonstrate that this decline also relates to AD genetic influences.

From Polygenic Scores to Precision Medicine in Alzheimer's Disease: A Systematic Review.

Background:Late-onset Alzheimer’s disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis, and ubiquitination. Polygenic scores (PRS), which weight the sum of an individual’s risk alleles, have been used to draw inferences about the pathological processes underpinning AD.Objective:This paper aims to systematically review how AD PRS are being used to study a range of outcomes and phenotypes related to neurodegeneration.Methods:We searched the literature from July 2008–July 2018 following PRISMA guidelines.Results:57 studies met criteria. The AD PRS can distinguish AD cases from controls. The ability of AD PRS to predict conversion from mild cognitive impairment (MCI) to AD was less clear. There was strong evidence of association between AD PRS and cognitive impairment. AD PRS were correlated with a number of biological phenotypes associated with AD pathology, such as neuroimaging changes and amyloid and tau measures. Pathway-specific polygenic scores were also associated with AD-related biologically relevant phenotypes.Conclusion:PRS can predict AD effectively and are associated with cognitive impairment. There is also evidence of association between AD PRS and other phenotypes relevant to neurodegeneration. The associations between pathway specific polygenic scores and phenotypic changes may allow us to define the biology of the disease in individuals and indicate who may benefit from specific treatments. Longitudinal cohort studies are required to test the ability of PGS to delineate pathway-specific disease activity.