Developing Topics

Alzheimers Dement. 2025 Dec;21 Suppl 7:e108473. doi: 10.1002/alz70861_108473.

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) is a multifactorial disease influenced by both genetic and clinical risk factors, yet how these factors are associated with AD-specific or neurodegeneration pathologies remain unclear. Clinical risk scores (CRS) reflect susceptibility to cognitive decline based on lifestyle and other modifiable factors. Genetically, APOE ε4 is the strongest known risk factor for AD, but additional genetic contributions can be captured through polygenic risk scores (PRS). This study investigates how APOE-ε4, PRS, and CRS independently contribute to amyloid-β/tau (i.e. AD) and neurodegenerative pathways in the Healthy Aging Brain Study-Health Disparities (HABS-HD) cohort.

METHODS: In HABS-HD (N =1,890; mean age=67±7.7; African-descent=328, Amerindian-descent=647, European-descent=915), we constructed AD-PRS using PRS-CSx-auto with ancestry-specific AD genome-wide association study summary statistics from European, African American, East Asian, and Caribbean Hispanic populations. The Cognitive Health and Dementia Risk Assessment score (CogDrisk), a CRS, was calculated using 17 risk factors for dementia (e.g. age, sex, education, hypertension). Structural equation modeling was used to derive an AD latent variable, indicated by plasma /Aβ₄₀ ratio, plasma pTau₁₈₁, Aβ PET positivity, and global SUVR; and a neurodegeneration latent variable, indicated by plasma NfL, cortical thickness, and hippocampal volume (Figure 1). Latent variables were regressed on AD-PRS, CogDrisk, and APOE-ε4 status, adjusting for race and population stratification.

RESULTS: APOE-ε4 was significantly associated with both AD (β=0.30, p <0.001) and neurodegeneration latent variables (β=0.11, p<0.001). AD-PRS was significantly associated with the AD (β=0.089, p=8.22e-3) but not with the neurodegeneration latent variable (β=0.039, p=0.21). In contrast, CogDrisk was significantly associated with both the AD (β=0.34, p<0.001) and the neurodegeneration latent variables (β=0.72, p<0.001).

CONCLUSIONS: APOE-ε4 and CRS captures changes related to both neurodegeneration and AD neuropathological proteins, whereas PRS is more specific to AD with the smallest effects. APOE-ε4 remains as the stronger genetic predictor. These findings highlight distinct yet orthogonal roles of genetic and clinical risk factors in dementia pathogenesis.

PMID:41433582 | DOI:10.1002/alz70861_108473