Whole blood gene expression moderates associations between AD biomarkers and cognitive decline in cognitively unimpaired older adults.

INTRODUCTION: Early biological pathways explaining the risk for Alzheimer's disease (AD)-related cognitive decline remain poorly understood. METHODS: Using linear mixed-effects models, we investigated whether whole blood gene expression (RNA sequencing) moderates the relationship between AD biomarkers measured by amyloid beta (Aβ) and tau-PET (positron emission tomography) imaging and longitudinal cognition in 770 cognitively unimpaired older adults (Agemean = 71.3, 62% female) from Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) (A4/LEARN). RESULTS: We identified protective and AD risk-related gene expression signatures on the autosome and X chromosome. Six genes (ngenes(%); 2(33%) X-linked) interacted with Aβ-PET, whereas 103 genes (3(3%) X-linked) interacted with neocortical tau-PET, to influence cognitive decline. A total of 110 genes (17(15%) X-linked) and 3156 genes (121(4%) X-linked) were moderated by both sex and Aβ- or tau-PET, respectively. Pathway enrichment analyses reflected immunity, protein synthesis, and lipid metabolism. DISCUSSION: These findings underscore the importance of peripheral transcriptomic markers in identifying sex-differentiated pathways related to risk of and protection from cognitive decline in preclinical AD.