Faculty Collaboration Database

Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum. Transl Psychiatry 2024 Oct 05;14(1):420

Date

10/06/2024

Pubmed ID

39368996

Pubmed Central ID

PMC11455841

DOI

10.1038/s41398-024-03121-5

Scopus ID

2-s2.0-85205758659 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: 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 widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. 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 enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. 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 diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .

Author List

Wen J, Yang Z, Nasrallah IM, Cui Y, Erus G, Srinivasan D, Abdulkadir A, Mamourian E, Hwang G, Singh A, Bergman M, Bao J, Varol E, Zhou Z, Boquet-Pujadas A, Chen J, Toga AW, Saykin AJ, Hohman TJ, Thompson PM, Villeneuve S, Gollub R, Sotiras A, Wittfeld K, Grabe HJ, Tosun D, Bilgel M, An Y, Marcus DS, LaMontagne P, Benzinger TL, Heckbert SR, Austin TR, Launer LJ, Espeland M, Masters CL, Maruff P, Fripp J, Johnson SC, Morris JC, Albert MS, Bryan RN, Resnick SM, Ferrucci L, Fan Y, Habes M, Wolk D, Shen L, Shou H, Davatzikos C

Author

Gyujoon Hwang PhD Assistant Professor in the Psychiatry and Behavioral Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Aged, 80 and over
Alzheimer Disease
Apolipoprotein E4
Atrophy
Brain
Cognitive Dysfunction
Female
Genome-Wide Association Study
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Temporal Lobe