Dataset Information

Testing a polygenic risk score for morphological microglial activation in Alzheimer's disease and aging.

ABSTRACT: Neuroinflammation and the activation of microglial cells are among the earliest events in Alzheimer's disease (AD). However, direct observation of microglia in living people is not currently possible. Here, we indexed the heritable propensity for neuroinflammation with polygenic risk scores (PRS), using results from a recent genome-wide analysis of a validated post-mortem measure of morphological microglial activation. We sought to determine whether a PRS for microglial activation (PRS _mic ) could augment the predictive performance of existing AD PRSs for late-life cognitive impairment. First, PRS _mic were calculated and optimized in a calibration cohort (Alzheimer's Disease Neuroimaging Initiative (ADNI), n=450), with resampling. Second, predictive performance of optimal PRS _mic was assessed in two independent, population-based cohorts (total n=212,237). Our PRS _mic showed no significant improvement in predictive power for either AD diagnosis or cognitive performance. Finally, we explored associations of PRS _mic with a comprehensive set of imaging and fluid AD biomarkers in ADNI. This revealed some nominal associations, but with inconsistent effect directions. While genetic scores capable of indexing risk for neuroinflammatory processes in aging are highly desirable, more well-powered genome-wide studies of microglial activation are required. Further, biobank-scale studies would benefit from phenotyping of proximal neuroinflammatory processes to improve the PRS development phase.

SUBMITTER: Tio ES

PROVIDER: S-EPMC10055438 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Testing a polygenic risk score for morphological microglial activation in Alzheimer's disease and aging.

Tio Earvin S ES Hohman Timothy J TJ Milic Milos M Bennett David A DA Felsky Daniel D

medRxiv : the preprint server for health sciences 20230315

Neuroinflammation and the activation of microglial cells are among the earliest events in Alzheimer's disease (AD). However, direct observation of microglia in living people is not currently possible. Here, we indexed the heritable propensity for neuroinflammation with polygenic risk scores (PRS), using results from a recent genome-wide analysis of a validated post-mortem measure of morphological microglial activation. We sought to determine whether a PRS for microglial activation (PRS <sub>mic< ...[more]

PMID: 36993775

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Project description:The heritability of Alzheimer's disease estimated from twin studies is greater than the heritability derived from genome-based studies, for reasons that remain unclear. We apply both approaches to the same twin sample, considering both Alzheimer's disease polygenic risk scores and heritability from twin models, to provide insight into the role of measured genetic variants and to quantify uncaptured genetic risk. A population-based heritability and polygenic association study of Alzheimer's disease was conducted between 1986 and 2016 and is the first study to incorporate polygenic risk scores into biometrical twin models of Alzheimer's disease. The sample included 1586 twins drawn from the Swedish Twin Registry which were nested within 1137 twin pairs (449 complete pairs and 688 incomplete pairs) with clinically based diagnoses and registry follow-up (M age = 85.28, SD = 7.02; 44% male; 431 cases and 1155 controls). We report contributions of polygenic risk scores at P < 1 × 10-5, considering a full polygenic risk score (PRS), PRS without the APOE region (PRS.no.APOE) and PRS.no.APOE plus directly measured APOE alleles. Biometric twin models estimated the contribution of environmental influences and measured (PRS) and unmeasured genes to Alzheimer's disease risk. The full PRS and PRS.no.APOE contributed 10.1 and 2.4% to Alzheimer's disease risk, respectively. When APOE ɛ4 alleles were added to the model with the PRS.no.APOE, the total contribution was 11.4% to Alzheimer's disease risk, where APOE ɛ4 explained 9.3% and PRS.no.APOE dropped from 2.4 to 2.1%. The total genetic contribution to Alzheimer's disease risk, measured and unmeasured, was 71% while environmental influences unique to each twin accounted for 29% of the risk. The APOE region accounts for much of the measurable genetic contribution to Alzheimer's disease, with a smaller contribution from other measured polygenic influences. Importantly, substantial background genetic influences remain to be understood.

Dataset Information

Testing a polygenic risk score for morphological microglial activation in Alzheimer's disease and aging.

Publications

Testing a polygenic risk score for morphological microglial activation in Alzheimer's disease and aging.

Similar Datasets

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