Abstract
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.
Competing Interest Statement
DAW served as Site PI for studies by Biogen, Merck, and Eli Lilly Avid. He has received consulting fees from GE Healthcare and Neuronix. He is on the DSMB for a trial sponsored by Functional Neuromodulation. AJS receives support from multiple NIH grants, P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U01 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, and U01 AG068057 and U01 AG072177. He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly, in kind contribution of PET tracer precursor, Bayer Oncology Scientific Advisory Board, Eisai Scientific Advisory Board, Siemens Medical Solutions USA, Inc. Dementia Advisory Board, Springer-Nature Publishing Editorial Office Support as Editor in Chief, Brain Imaging, and Behavior. ME receives support from multiple NIH grants, the Alzheimers Association, and the Alzheimer Therapeutic Research Institute. HJG has received travel grants and speaker honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen Cilag as well as research funding from Fresenius Medical Care. HJG had personal contracts approved by the university administration for speaker honoraria and one IIT with Fresenius Medical Care. AA was supported by grants 191026 and 206795 from the Swiss National Science Foundation
