Combating Genetic Heterogeneity for Polygenic Prediction of Susceptibility to Brain β-Amyloid Deposition: Beyond APOE

Abstract

Background and objectives: The APOE (apolipoprotein E) ε4 allele is the strongest known genetic risk factor for sporadic Alzheimer disease (AD) and for brain amyloidosis, an early marker of disease pathophysiology. However, APOE ε4 is present in only 25% of the general population and is by itself inadequate for explaining susceptibility to amyloid accumulation or AD diagnosis. Existing studies have been limited by potential confounding due to inclusion of individuals carrying APOE ε4 or ε2 (which has a modest protective association). We hypothesized that genome-wide association study (GWAS) and genetic risk score (GRS) analyses in APOE ε3/ε3 individuals would uniquely identify novel predictors of β-amyloid pathology in older adults.

Methods: We analyzed data from the Mayo Clinic Study of Aging (MCSA), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Rush Religious Orders Study and Memory and Aging Project. Frequency of APOE ε3/ε3 in those samples ranged from 48% to 61%. A GWAS was performed across 1,496 individuals with amyloid PET to identify candidate variants for GRS generation. Postmortem neuropathologic data (N = 710) were used to refine the variant list to capture high-likelihood true associations. An independent sample (N = 641) with plasma p-tau₁₈₁ data was used for validation.

Results: The GWAS identified previously implicated (e.g., PICALM and RBFOX1) and novel potential associations with amyloid PET burden. A non-APOE GRS of top variants was strongly associated with amyloid PET levels in the MCSA (p = 4.34 × 10^-9, β = 5.88) and ADNI (p = 1.87 × 10^-8, β = 12.1) cohorts. In both cohorts, this non-APOE amyloid GRS outperformed a comparator GRS (based on variants associated with clinically diagnosed AD dementia risk) in explaining phenotypic variation. The non-APOE amyloid GRS was also associated with postmortem neuropathologic β-amyloid and neurofibrillary tangle burden and in an independent sample was associated with plasma p-tau₁₈₁ concentrations (a robust indicator of cerebral amyloidosis).

Discussion: Our non-APOE amyloid GRS, which appropriately includes variants associated with amyloid deposition in APOE ɛ4/ɛ2 noncarriers, may advance personalized prediction of genetic susceptibility to β-amyloid accumulation within the large segment of the population that is APOE ε3/ε3. This may have future implications for risk modification, trial enrollment, and treatment selection.

Figure 1. Summary of Study Design

A flowchart describes the overall study design and the analytical phases for generating and validating the non-APOE amyloid genetic risk score (GRS). Created in BioRender. MD, V. (2025) BioRender.com/qri2rns.

Figure 2. Manhattan Plot of GWAS Meta-Analysis of Amyloid PET in APOE ε3/ε3 Participants

Observed -log₁₀ p values are displayed (y-axis) for all SNVs tested in the GWAS meta-analysis of amyloid PET burden across APOE ε3/ε3 participants from the MCSA and ADNI cohorts (total N = 1,496). No genome-wide significant associations (p < 5 × 10⁻⁸) were identified (red line). A total of 8 independent loci displayed suggestive association p < 5 × 10⁻⁶ (blue line) in the meta-analysis, with top findings annotated in the figure. ADNI = Alzheimer's Disease Neuroimaging Initiative; GWAS = genome-wide association study; MCSA = Mayo Clinic Study of Aging.

Figure 3. Hypothetical Model of Tiered Genetic Testing for Risk Stratification in the Population

A conceptual model is presented demonstrating how genetic testing may be used in future clinical practice to guide individuals on risk of developing brain amyloidosis. In this hypothetical model, individuals carrying APOE ɛ4 (the strongest known individual genetic risk factor of brain amyloidosis) would be counseled on its implications and directed to potential therapeutic interventions or prevention trials. For most of the general population who do not carry APOE ε4, the non-APOE amyloid GRS would be used to stratify individuals into those who may still be at high risk of brain amyloidosis (despite being APOE ε4 negative) vs those for whom non-Alzheimer paths to future cognitive decline would be prioritized for consideration.