Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.

BACKGROUND

Accumulation of brain amyloid beta (Aβ), a key pathological hallmark of Alzheimer's disease (AD), begins decades before cognitive symptoms. Being able to predict the risk of Aβ accumulation, or the age at which Aβ exceeds a critical threshold, may enable intervention to delay or prevent onset of AD.

METHODS

Using published genome-wide association studies (GWASs), we developed polygenic scores (PGS) for AD risk (PGSrisk) and resilience (PGSresilience), and tested whether these predicted (i) if an individual is an Aβ accumulator ('Accumulator Status'), and (ii) in accumulators, the age at which brain Aβ exceeds a 20 centiloid (CL) threshold ('Age at onset of Aβ'; AAO-Aβ) in 2175 participants (1158 with AAO-Aβ) from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study. We also performed GWASs on these traits to develop phenotype-specific PGSs.

FINDINGS: Higher genetic risk of AD predicted increased odds of Aβ accumulation (OR = 1.16; 95% CI = 1.05-1.29; p = 0.003) and younger AAO-Aβ (β = -1.32; SE = 0.31; p = 1.63 × 10-5). Higher genetic resilience to AD predicted later AAO-Aβ (β = 0.91; SE = 0.29; p = 0.002) but did not predict Aβ accumulation. These associations were independent of APOE ε4 status, the strongest genetic risk factor for AD. Phenotype-specific PGSs were not significantly associated with either trait.

INTERPRETATION: Polygenic scores, alongside other risk factors, may help identify individuals at risk of accumulating Aβ, and predict the age at which this exceeds a critical threshold. This could provide a window for administering disease-modifying treatment or lifestyle interventions to prevent or delay the onset of AD.

FUNDING: National Institutes of Health (R01-AG058676-01A1) and Australian National Health and Medical Research Council (GNT1161706; GNT2001320).