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Polygenic Score for Alzheimer Disease and cognition: The mediating role of personality.

ABSTRACT: Alzheimer's disease (AD) polygenic risk score (PGS) is associated with lower cognitive functioning even among older individuals without dementia. We tested the hypothesis that personality traits mediate the association between AD genetic risk and cognitive functioning. Participants (N?>?7,000, aged 50-99 years old) from the Health and Retirement Study were genotyped and completed personality and cognition tests at baseline. Cognition was assessed again four years later. Bootstrap analysis revealed that a higher AD polygenic risk score was associated with lower cognitive scores at baseline through higher neuroticism, lower conscientiousness, and lower levels of the industriousness facet of conscientiousness. In addition, a higher polygenic score for AD was associated with decline in cognition over four years in part through higher neuroticism and lower conscientiousness. The findings support the hypothesis that the genetic vulnerability for AD contributes to cognitive functioning in part through its association with personality traits.

SUBMITTER: Stephan Y

PROVIDER: S-EPMC6346269 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Polygenic Score for Alzheimer Disease and cognition: The mediating role of personality.

Stephan Yannick Y Sutin Angelina R AR Luchetti Martina M Caille Pauline P Terracciano Antonio A

Journal of psychiatric research 20181023

Alzheimer's disease (AD) polygenic risk score (PGS) is associated with lower cognitive functioning even among older individuals without dementia. We tested the hypothesis that personality traits mediate the association between AD genetic risk and cognitive functioning. Participants (N > 7,000, aged 50-99 years old) from the Health and Retirement Study were genotyped and completed personality and cognition tests at baseline. Cognition was assessed again four years later. Bootstrap analysis reveal ...[more]

PMID: 30384091

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Project description:BackgroundIdentifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction.Methods and findingsUsing genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10-5). We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer's Disease Genetics Consortium (ADGC), providing a polygenic hazard score (PHS) for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer's Disease Center [NIA ADC], and Alzheimer's Disease Neuroimaging Initiative [ADNI], total n = 20,680). Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62-4.24, p = 1.0 × 10-22). In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10-26) and longitudinal progression from normal aging to AD (NIA ADC, Cochran-Armitage trend test, p = 1.5 × 10-10), and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10-6, and Consortium to Establish a Registry for Alzheimer's Disease score for neuritic plaques, p = 6.8 × 10-6) and in vivo markers of AD neurodegeneration (ADNI, volume loss within the entorhinal cortex, p = 6.3 × 10-6, and hippocampus, p = 7.9 × 10-5). Additional prospective validation of these results in non-US, non-white, and prospective community-based cohorts is necessary before clinical use.ConclusionsWe have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials.

Project description:Background and objectivesBrain amyloid deposition, a major risk factor for Alzheimer's disease (AD), is currently estimated by measuring cerebrospinal fluid or plasma amyloid peptide levels, or by positron-emission tomography imaging. Assessing genetic risks relating to amyloid deposition before any accumulation has occurred would allow for earlier intervention in persons at increased risk for developing AD. Previous work linking amyloid burden and genetic risk relied almost exclusively on APOE, a major AD genetic risk factor. Here, we ask whether a polygenic risk score (PRS) that incorporates an optimized list of common variants linked to AD and excludes APOE is associated with brain amyloid load in cognitively unimpaired elderly adults.MethodsWe included 291 elderly asymptomatic participants from the INveStIGation of AlzHeimer's PredicTors (INSIGHT-preAD) cohort who underwent amyloid imaging, including 83 amyloid-positive (+) participants. We used an Alzheimer's (A) PRS composed of 33 AD risk variants excluding APOE, and selected the 17 variants that showed the strongest association with amyloid positivity to define an optimized (oA) PRS. Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study [228 participants, 90 amyloid (+)] were tested as a validation cohort. Finally, 2,300 AD patients and 6,994 controls from the European Alzheimer's Disease Initiative (EADI) were evaluated.ResultsA-PRS was not significantly associated with amyloid burden in the INSIGHT or ADNI cohorts with or without correction for APOE genotype. However, oA-PRS was significantly associated with amyloid status independently of APOE adjustment (INSIGHT OR: 5.26 [1.71-16.88]; ADNI OR: 3.38 [1.02-11.63]). Interestingly, oA-PRS accurately discriminated amyloid (+) and (-) APOE ε4 carriers (INSIGHT OR: 181.6 [7.53-10,674.6]; ADNI OR: 44.94 [3.03-1,277]). A-PRS and oA-PRS showed a significant association with disease status in the EADI cohort (OR: 1.68 [1.53-1.85] and 2.06 [1.73-2.45] respectively). Genes assigned to oA-PRS variants were enriched in ontologies related to Aβ metabolism and deposition.DiscussionPRSs relying on AD genetic risk factors excluding APOE may improve risk prediction for brain amyloid, allowing stratification of cognitively unimpaired individuals at risk of AD independent of their APOE status.

Dataset Information

Polygenic Score for Alzheimer Disease and cognition: The mediating role of personality.

Publications

Polygenic Score for Alzheimer Disease and cognition: The mediating role of personality.

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