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

Abstract

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 APOE, 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 APOE 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 APOE 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 APOE genotype. However, oA-PRS was significantly associated with amyloid status independently of APOE 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 (-) APOE 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 APOE may improve risk prediction for brain amyloid, allowing stratification of cognitively unimpaired individuals at risk of AD independent of their APOE status.

Figure 1. PRS in Amyloid (+) and Amyloid (−) Participants From the INSIGHT Cohort: A-PRS (A and B) and oA-PRS (C and D)

Green-colored violin plots correspond to amyloid (−) participants, and orange-colored plots correspond to amyloid (+) participants. Each participant is represented by a colored dot corresponding to their APOE status: dark green for ε2/ε2, orange for ε2/ε3, violet for ε3/ε3, pink for ε3/ε4, and light green for ε4/ε4. For the stratified graphs, participants who did not carry any ε4 allele were classified as an “E4 noncarrier,” and those who did were classified as an “E4 carrier.” The A-PRS is not associated with amyloid status in the whole INSIGHT cohort (A) and in the ε4 carriers (B). The oA-PRS is significantly associated with amyloid status (C) (p = 0.005), and this association persists in the ε4 carriers (p = 0.0034) (D); asterisks indicate statistically significant differences (*p < 0.05, **p < 0.001). The A-PRS and oA-PRS were not significantly different between APOE statuses among amyloid (+) and (−) participants. A-PRS = Alzheimer's PRS; oA-PRS = optimized Alzheimer's PRS; PRS = polygenic risk score.

Figure 2. Overlap Between Enriched GO Biological Processes in the A-PRS and oA-PRS

In bold are GO biological processes involved in amyloid pathology. A-PRS = Alzheimer's PRS; GO = Gene Ontology; oA-PRS = optimized Alzheimer's PRS; PRS = polygenic risk score.

Figure 3. PRS in Amyloid (+) and Amyloid (−) Participants From the ADNI Cohort: A-PRS (A and B) and oA-PRS (C and D)

Green-colored violin plots correspond to amyloid (−) participants, whereas orange-colored plots correspond to amyloid (+) participants. Each participant is represented by a colored dot corresponding to their APOE status: dark green for ε2/ε2, orange for ε2/ε3, violet for ε3/ε3, pink for ε3/ε4, and light green for ε4/ε4. For the stratified graphs, participants who did not carry any ε4 allele were classified as “E4 noncarrier,” and those who did were classified as “E4 carrier.” The A-PRS was not significantly associated with amyloid status in the whole ADNI cohort (A) (p = 0.05) or in the APOE-stratified groups (B). The oA-PRS is significantly associated with amyloid status in the whole cohort (C) (p = 0.049) and in the ε4 carriers (D) (p = 0.012); asterisks indicate statistically significant differences (*p < 0.05). The A-PRS and oA-PRS were not significantly different between APOE statuses among amyloid (+) and (−) participants. A-PRS = Alzheimer's PRS; oA-PRS = optimized Alzheimer's PRS; PRS = polygenic risk score.