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Cited by 56Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment

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Hill, Mason A., Gammie, Stephen C.·2022·Scientific Reports
DOI 10.1038/s41598-022-22179-zPMC PMC9561721
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Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that affects multiple brain regions and is difficult to treat. In this study we used 22 AD large-scale gene expression datasets to identify a consistent underlying portrait of AD gene expression across multiple brain regions. Then we used the portrait as a platform for identifying treatments that could reverse AD dysregulated expression patterns. Enrichment of dysregulated AD genes included multiple processes, ranging from cell adhesion to CNS development. The three most dysregulated genes in the AD portrait were the inositol trisphosphate kinase, ITPKB (upregulated), the astrocyte specific intermediate filament protein, GFAP (upregulated), and the rho GTPase, RHOQ (upregulated). 41 of the top AD dysregulated genes were also identified in a recent human AD GWAS study, including PNOC, C4B, and BCL11A. 42 transcription factors were identified that were both dysregulated in AD and that in turn affect expression of other AD dysregulated genes. Male and female AD portraits were highly congruent. Out of over 250 treatments, three datasets for exercise or activity were identified as the top three theoretical treatments for AD via reversal of large-scale gene expression patterns. Exercise reversed expression patterns of hundreds of AD genes across multiple categories, including cytoskeleton, blood vessel development, mitochondrion, and interferon-stimulated related genes. Exercise also ranked as the best treatment across a majority of individual region-specific AD datasets and meta-analysis AD datasets. Fluoxetine also scored well and a theoretical combination of fluoxetine and exercise reversed 549 AD genes. Other positive treatments included curcumin. Comparisons of the AD portrait to a recent depression portrait revealed a high congruence of downregulated genes in both. Together, the AD portrait provides a new platform for understanding AD and identifying potential treatments for AD.

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  • Downregulation of WASF1 expression in the AD brain has also been observed in publicly available datasets.

    “Downregulation of WASF1 expression in the AD brain has also been observed in publicly available datasets144,145.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [145]

    The Methods section describes publicly available AD brain-expression datasets, but the passages in our copy do not report whether WASF1 is downregulated. Searches for WASF1, WAVE1, and its full gene name found no passage addressing that specific result. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

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Authors
Hill, M. A., & Gammie, S. C.
Affiliations
University of Wisconsin–Madison (US)
Corresponding author
Gammie, Stephen C.
ORCID
Gammie, Stephen C.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2022-10-13
Volume
12
Issue
1
Pages
17189-17189
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-022-22179-z
PMC
PMC9561721
OpenAlex
W4304974810
Cited by
56
References
12
Citations by year
2026: 15 · 2025: 15 · 2024: 17 · 2023: 9
FWCI
1.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Mayo Clinic (P50 AG016574, R01 AG032990)
  • Arizona Department of Health Services (P50 AG016574, RF1AG057440, R01 AG032990)
  • Rush University (P30AG10161, R01 AG15819)
  • National Center for Geriatrics and Gerontology
  • Arizona Biomedical Research Commission
  • National Institutes of Health (U01AG006576, AG016574, R01AG025711, R01AG003949, R01AG017216)
  • National Institute on Aging (R01AG017917, U01AG046170, R01AG018023, R01AG036836, U01AG046152, U01AG006786, R01AG015819, RF1AG057440, P30AG010161, U01AG061356, R01AG032990, P30AG019610, P01AG017216, U01AG046139, U24AG061340, P30AG072975, P50AG016574)
  • National Institute of Neurological Disorders and Stroke (R01NS080820, U24NS072026)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, dysregulated genes, exercise therapy, fluoxetine, curcumin, ITPKB, glial fibrillary acidic protein, transcription factors, sex differences, depression, neurodegeneration, treatment prediction, brain regions
MeSH terms
Alzheimer Disease, Curcumin, Female, Fluoxetine, Humans, Inositol, Interferons, Male, Transcription Factors, Gene Expression, rho GTP-Binding Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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