| Title: | Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum |
| Journal: | Translational Psychiatry |
| Published: | 5 Oct 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39368996/ |
| DOI: | https://doi.org/10.1038/s41398-024-03121-5 |
Publication 13273
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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 APOEε4, 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/.</p>
14 Keywords
- 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
50 Authors
- Junhao Wen
- Zhijian Yang
- Ilya M. Nasrallah
- Yuhan Cui
- Guray Erus
- Dhivya Srinivasan
- Ahmed Abdulkadir
- Elizabeth Mamourian
- Gyujoon Hwang
- Ashish Singh
- Mark Bergman
- Jingxuan Bao
- Erdem Varol
- Zhen Zhou
- Aleix Boquet-Pujadas
- Jiong Chen
- Arthur W. Toga
- Andrew J. Saykin
- Timothy J. Hohman
- Paul M. Thompson
- Sylvia Villeneuve
- Randy Gollub
- Aristeidis Sotiras
- Katharina Wittfeld
- Hans J. Grabe
- Duygu Tosun
- Murat Bilgel
- Yang An
- Daniel S. Marcus
- Pamela LaMontagne
- Tammie L. Benzinger
- Susan R. Heckbert
- Thomas R. Austin
- Lenore J. Launer
- Mark Espeland
- Colin L. Masters
- Paul Maruff
- Jurgen Fripp
- Sterling C. Johnson
- John C. Morris
- Marilyn S. Albert
- R. Nick Bryan
- Susan M. Resnick
- Luigi Ferrucci
- Yong Fan
- Mohamad Habes
- David Wolk
- Li Shen
- Haochang Shou
- Christos Davatzikos
1 Application
| Application ID | Title |
|---|---|
| 35148 | iSTAGING (Imaging-based coordinate SysTem for AGing and NeurodeGenerative diseases) |
Enabling scientific discoveries that improve human health