Genetic, clinical underpinnings of subtle early brain change along Alzheimer’s dimensions

Alzheimer’s disease (AD) is associated with heterogeneous atrophy patterns,1,2 which are increasingly manifested throughout the disease course, driven by underlying neuropathologic processes. Herein, we show that manifestations of these brain changes in early asymptomatic stages can be detected via a novel deep semi-supervised representation learning method.3 We first identified two dominant dimensions of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients4: the “diffuse-AD” (R1) dimension shows widespread brain atrophy, and the “MTL-AD” (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with known genetic risk factors (e.g., APOE ε4) of AD in MCI and AD patients at baseline. We then showed that brain changes along these two dimensions were independently detected in early stages in a cohort representative of the general population5 and two cognitively unimpaired cohorts of asymptomatic participants.6,7 In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were also enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). The longitudinal progression of R1 and R2 in the cognitively unimpaired populations, as well as in individuals with MCI and AD, showed variable associations with established AD risk factors, including APOE ε4, tau, and amyloid. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases8, inflammation,9–11 and hormonal dysfunction12,13 – driven by genes different from APOE – which collectively contribute to the early pathogenesis of AD.