Associations of cortical SPP1 and ITGAX with cognition and common neuropathologies in older adults

Abstract INTRODUCTION The secreted phosphoprotein 1 ( SPP1 ) gene expressed by CD11c + cells is known to be associated with microglia activation and neuroinflammatory diseases. As most studies rely on mouse models, we investigated these genes and proteins in the cortical brain tissue of older adults and their role in Alzheimer's disease (AD) and related disorders. METHODS We leveraged protein measurements, single‐nuclei, and RNASeq data from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) of over 1200 samples for association analysis. RESULTS Expression of SPP1 and its encoded protein osteopontin were associated with faster cognitive decline and greater odds of common neuropathologies. At single‐cell resolution, integrin subunit alpha X ( ITGAX ) was highly expressed in microglia, where specific subpopulations were associated with AD and cerebral amyloid angiopathy. DISCUSSION The study provides evidence of SPP1 and ITGAX association with cognitive decline and common neuropathologies identifying a microglial subset associated with disease.