Polygenic risk of Alzheimer disease is associated with early- and late-life processes

Abstract

Objective: To examine associations between aggregate genetic risk and Alzheimer disease (AD) markers in stages preceding the clinical symptoms of dementia using data from 2 large observational cohort studies.

Methods: We computed polygenic risk scores (PGRS) using summary statistics from the International Genomics of Alzheimer's Project genome-wide association study of AD. Associations between PGRS and AD markers (cognitive decline, clinical progression, hippocampus volume, and β-amyloid) were assessed within older participants with dementia. Associations between PGRS and hippocampus volume were additionally examined within healthy younger participants (age 18-35 years).

Results: Within participants without dementia, elevated PGRS was associated with worse memory (p = 0.002) and smaller hippocampus (p = 0.002) at baseline, as well as greater longitudinal cognitive decline (memory: p = 0.0005, executive function: p = 0.01) and clinical progression (p < 0.00001). High PGRS was associated with AD-like levels of β-amyloid burden as measured with florbetapir PET (p = 0.03) but did not reach statistical significance for CSF β-amyloid (p = 0.11). Within the younger group, higher PGRS was associated with smaller hippocampus volume (p = 0.05). This pattern was evident when examining a PGRS that included many loci below the genome-wide association study (GWAS)-level significance threshold (16,123 single nucleotide polymorphisms), but not when PGRS was restricted to GWAS-level significant loci (18 single nucleotide polymorphisms).

Conclusions: Effects related to common genetic risk loci distributed throughout the genome are detectable among individuals without dementia. The influence of this genetic risk may begin in early life and make an individual more susceptible to cognitive impairment in late life. Future refinement of polygenic risk scores may help identify individuals at risk for AD dementia.

Figure 1. Polygenic risk score (PGRS) discrimination between patients with Alzheimer disease (AD) dementia and older clinically normal (CN) participants

Multiple PGRS iterations were examined that incorporated different quantities of loci based on p value significance thresholds from the large International Genomics of Alzheimer's Project (IGAP) meta-analysis. Significance is shown on the y-axis (negative log p value), and corresponds to the independent contribution of PGRS in predicting diagnosis in our analysis of Alzheimer's Disease Neuroimaging Initiative patients with AD dementia compared to CN participants (controlling for APOE4, age, sex, and 5 multidimensional scaling principal components). The x-axis shows the p value threshold applied to the IGAP summary statistics file to determine which single nucleotide polymorphisms (SNP) to include in each PGRS iteration. The effect using a threshold of p = 0.01 is shown by the gray filled diamond. The horizontal dashed line reflects the significance value corresponding to a conservative PGRS that only incorporated 18 SNP that were significant in the IGAP meta-analysis.

Figure 2. Polygenic risk score (PGRS) vs cognition and hippocampus volume in older participants without dementia

PGRS vs baseline and longitudinal change in memory (A, D), executive function (EF) (B, E), and hippocampus volume (C, F). Baseline associations are shown in A–C, while longitudinal effects are shown in D–F. Plotted values are residualized by model covariates. aHV = adjusted hippocampus volume.

Figure 3. Polygenic risk score (PGRS) (residuals) vs β-amyloid (Aβ) in older participants without dementia

The association between PGRS and Aβ was examined across 2 independent samples of older individuals without dementia: (A) ADNI1 with CSF (n = 272) and (B) ADNI2 with florbetapir PET imaging (n = 505). Plotted values are adjusted for model covariates.