Abstract INTRODUCTION Alzheimer's disease (AD) is a genetically heterogeneous disease, with various genetic variants potentially influencing disease mechanisms differently. Pathway‐based polygenic risk scores (p‐PRS) can be used to examine how groups of risk genes with similar biological functions impact disease‐related endophenotypes such as cognitive decline. potentially aiding in differentiating pre‐clinical dementia from normal age‐related cognitive decline. METHODS Data from 1,737 participants (53.5% female) from the Betula study were analyzed. AD‐weighted p‐PRS were calculated for five AD‐related pathways: immune response, tau, cholesterol, protein–lipid, and amyloid. The p‐PRS were tested for associations with all‐cause dementia risk ( n = 315 cases), with follow‐up analyses restricted to AD ( n = 168) or vascular dementia (VD) ( n = 110), in comparison to a genome‐wide (gw) PRS. Linear mixed effect models were used to examine the same genetic predictors in relation to cognitive decline in subsequently demented and non‐demented. RESULTS All‐cause dementia risk was significantly predicted by the gw‐ and immune PRS. Hazard ratios for gw‐, immune‐, tau‐, cholesterol‐, and amyloid p‐PRS were larger for prediction of AD risk and smaller for VD risk relative to all‐cause dementia, while the opposite was seen for the protein–lipid p‐PRS. Cognitive decline was stronger associated with the immune p‐PRS than the gw‐PRS, and this effect was driven by participants that remained non‐demented (linear age‐effects). Amyloid p‐PRS showed accelerated age‐effect at the oldest age in both non‐demented and subsequently demented. DISCUSSION Our results show that AD‐weighted p‐PRS have differential roles on dementia risk and cognitive decline. Specifically, results suggest a broad role of immune p‐PRS in both age‐related cognitive decline and dementia risk, while amyloid p‐PRS influences AD risk and pre‐clinical cognitive decline, and protein‐lipid p‐PRS does not influence AD risk nor cognitive decline but show a potential role in VD. Results are of value for development of precision medicine based on genetic risk profiling. Highlights All‐cause dementia and Alzheimer's disease (AD) risk is strongest predicted by apolipoprotein E ( APOE) ε4 and global polygenic risk scores (PRS). Cognitive decline is stronger predicted by immune pathway‐based PRS (p‐PRS) relative to global PRS. Effect of APOE ε4 on cognitive decline is driven by pre‐clinical dementia. Immune p‐PRS predicts cognitive decline unrelated to subsequent dementia. Protein–lipid p‐PRS may have a stronger role in vascular dementia than AD.
Romic et al. (2026) studied this question.