Abstract 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 (Age mean = 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 (n genes (%); 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.
Klinger et al. (Sun,) studied this question.
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