Genetic effects on longitudinal cognitive decline during the early stages of Alzheimer's disease

Abstract

Background: Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability.Methods: In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence and educational attainment) to predict longitudinal cognitive change (measured by MMSE) over a mean of 4.2 years. We included 260 b-amyloid (Ab) negative cognitively unimpaired (CU) individuals, 121 Ab-positive CU (preclinical AD), 50 Ab-negative mild cognitive impairment (MCI) patients, and 127 Ab-positive MCI patients (prodromal AD). Results: The polygenic score (PGS) for intelligence (p = 2.9e-02, beta = 0.1) was protective in CU and MCI participants regardless of Ab status, while polygenic risk score for AD (p = 8.2e-03, beta = -0.12) was correlated with rate of cognitive impairment and was partially mediated by Ab-pathology (mediation effect 20 %). There was no influence of education PGS, implying that educational achievement and rate of cognitive impairment are unrelated.Conclusions: Genetic variants associated with intelligence mitigate cognitive decline independent of Ab-pathology, but the effects of genetic variants associated with AD are partly mediated by Ab-pathology.