Association of -Independent Alzheimer Disease Polygenic Risk Score With Brain Amyloid Deposition in Asymptomatic Older Adults.

BACKGROUND AND OBJECTIVES

Brain amyloid deposition, a major risk factor for Alzheimer disease (AD), is currently estimated by measuring CSF or plasma amyloid peptide levels or by PET 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 , 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 is associated with brain amyloid load in cognitively unimpaired older adults.

METHODS

We included 291 asymptomatic older participants from the INveStIGation of AlzHeimer's PredicTors (INSIGHT pre-AD) cohort who underwent amyloid imaging, including 83 amyloid-positive (+) participants. We used an Alzheimer's (A) PRS composed of 33 AD risk variants excluding 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 patients with AD and 6,994 controls from the European Alzheimer's Disease Initiative (EADI) were evaluated.

RESULTS

A-PRS was not significantly associated with amyloid burden in the INSIGHT or ADNI cohorts with or without correction for the genotype. However, oA-PRS was significantly associated with amyloid status independently of adjustment (INSIGHT odds ratio [OR]: 5.26 [1.71-16.88]; ADNI OR: 3.38 [1.02-11.63]). Of interest, oA-PRS accurately discriminated amyloid (+) and (-) 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 β-amyloid metabolism and deposition.

DISCUSSION

PRSs relying on AD genetic risk factors excluding may improve risk prediction for brain amyloid, allowing stratification of cognitively unimpaired individuals at risk of AD independent of their status.