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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.