Association of Alzheimer’s disease polygenic risk scores with amyloid accumulation in cognitively intact older adults

Abstract

Background Early detection of individuals at risk for Alzheimer’s disease (AD) is highly important. Amyloid accumulation is an early pathological AD event, but the genetic association with known AD risk variants beyond the APOE4 effect is largely unknown. We investigated the association between different AD polygenic risk scores (PRS) and amyloid accumulation in the Flemish Prevent AD Cohort KU Leuven (F-PACK). Methods We calculated PRS with and without the APOE region in 90 cognitively healthy F-PACK participants (baseline age 67.8 (52–80) years, 41 APOE4 carriers), with baseline and follow-up amyloid-PET (time interval 6.1 (3.4–10.9) years). Individuals were genotyped using Illumina GSA and imputed. PRS were calculated using three p-value thresholds (pT) for variant inclusion: 5 × 10−8, 1 × 10−5, and 0.1, based on the stage 1 summary statistics from Kunkle et al. (Nat Genet 51:414–30, 2019). Linear regression models determined if these PRS predicted amyloid accumulation. Results A score based on PRS excluding the APOE region at pT = 5 × 10−8 plus the weighted sum of the two major APOE variants (rs429358 and rs7412) was significantly associated with amyloid accumulation (p = 0.0126). The two major APOE variants were also significantly associated with amyloid accumulation (p = 0.0496). The other PRS were not significant. Conclusions Specific PRS are associated with amyloid accumulation in the asymptomatic phase of AD.

Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum

“…These findings suggest that other genetic variants, independent of APOE, may play a role in modulating the risk of AD and potentially compensate for or complement the effect of APOE in genetic predisposition to the disease. Our results align with previous studies, 41,42 emphasizing the importance of considering additional APOE-independent mechanisms when exploring genetic predisposition to AD. This illustrates how the use of PRS can reveal additional pathophysiological pathways with potential for prevention, 43 which is relevant since the pathophysiology of AD has not yet been fully elucidated and the best biological characterization to date focuses on the determination of AD biomarkers.…”

Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer’scontinuum

“…The study also revealed an increased genetic predisposition to AD in ALFA participants, even in the absence of the APOE-4 allele. This suggests that other variants (APOEindependent mechanisms) associated with AD appear to compensate for or complement the effect of APOE in genetic predisposition to AD, which is consistent with other studies (Luckett et al, 2022;Skoog et al, 2021). This illustrates how the use of PRS can reveal additional pathophysiological pathways with potential for prevention.…”

Contributions of rare and common variation to early-onset and atypical dementia risk

“…Accumulation of amyloid-β protein in the brain is characteristic of Alzheimer’s disease and can occur many years before the onset of symptoms (Luckett et al 2022). As a prominent example, APOE , the largest genetic risk factor for AD, has been associated with amyloid-β accumulation in the brain, therefore identifying genetic risk variants prior to symptom onset is critical for treatment decisions and potential enrollment in prevention trials.…”