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Cited by 9Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Exploring the Genetic Heterogeneity of Alzheimer’s Disease: Evidence for Genetic Subtypes

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Elman, Jeremy A., Schork, Nicholas J., Rangan, Aaditya V., for the Alzheimer’s Disease Neuroimaging Initiative·2024·Journal of Alzheimer’s Disease
DOI 10.3233/jad-231252PMC PMC11636402

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Abstract

Background: Alzheimer’s disease (AD) exhibits considerable phenotypic heterogeneity, suggesting the potential existence of subtypes. AD is under substantial genetic influence, thus identifying systematic variation in genetic risk may provide insights into disease origins. Objective: We investigated genetic heterogeneity in AD risk through a multi-step analysis. Methods: We performed principal component analysis (PCA) on AD-associated variants in the UK Biobank (AD cases = 2,739, controls = 5,478) to assess structured genetic heterogeneity. Subsequently, a biclustering algorithm searched for distinct disease-specific genetic signatures among subsets of cases. Replication tests were conducted using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (AD cases = 500, controls = 470). We categorized a separate set of ADNI individuals with mild cognitive impairment (MCI; n = 399) into genetic subtypes and examined cognitive, amyloid, and tau trajectories. Results: PCA revealed three distinct clusters (“constellations”) driven primarily by different correlation patterns in a region of strong LD surrounding the MAPT locus. Constellations contained a mixture of cases and controls, reflecting disease-relevant but not disease-specific structure. We found two disease-specific biclusters among AD cases. Pathway analysis linked bicluster-associated variants to neuron morphogenesis and outgrowth. Disease-relevant and disease-specific structure replicated in ADNI, and bicluster 2 exhibited increased cerebrospinal fluid p-tau and cognitive decline over time. Conclusions: This study unveils a hierarchical structure of AD genetic risk. Disease-relevant constellations may represent haplotype structure that does not increase risk directly but may alter the relative importance of other genetic risk factors. Biclusters may represent distinct AD genetic subtypes. This structure is replicable and relates to differential pathological accumulation and cognitive decline over time.

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  • Proteomic clustering has identified subgroups particularly responsive to drugs that modulate synaptic function and restore blood-brain barrier integrity.

    “Proteomic clustering has identified subgroups particularly responsive to drugs that modulate synaptic function and restore BBB integrity342,345,347,350,352,399,400.”

    From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [350]

    The Results (Gene set enrichment results of disease-specific biclusters; page unavailable) identify Alzheimer’s disease subgroups with enrichment for synaptic-transmission gene sets. But these are genetic, not proteomic, clusters, and the paper does not report that either subgroup responds particularly well to drugs targeting synaptic function or blood–brain barrier integrity. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Elman, J. A., Schork, N. J., Rangan, A. V., & Initiative, F. T. A. D. N.
Affiliations
  • University of California San Diego (US)
  • Translational Genomics Research Institute (US)
Corresponding author
Elman, Jeremy A.
ORCID
Venue
Journal of Alzheimer’s Disease
Publisher
SAGE Publications
Published
2024-07-08
Volume
100
Issue
4
Pages
1209-1226
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-231252
PMC
PMC11636402
OpenAlex
W4400582889
Cited by
9
References
8
Citations by year
2026: 4 · 2025: 4 · 2024: 1
FWCI
2.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Alzheimer s Disease (publishedVersion)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, other-oa)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • U.S. Department of Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH1220012, AG024904)
  • Foundation for the National Institutes of Health (W81XWH-12-2-0012, U01AG024904, Grant U01 AG024904, U24AG078753, UH3-AG064706, U19 AG065169-01A1, AG024904)
  • Alzheimer's Association (U01 AG024904, W81XWH-12-2-0012)
  • Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Eli Lilly and Company (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Pfizer (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • University of Southern California (W81XWH-12-2-0012, U01 AG024904)
  • F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-, Department of Defense award number W81XWH-12-2-0012)
  • BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
  • Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012)
  • Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • National Institutes of Health (3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, AG065169, AG023122, U01-AG024904, Grant U01 AG024904, AG024904, AG064706)
  • Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012)
  • National Institute on Aging (U01-AG-024904, AG 023122, W81XWH-12-2–0012, AG 024904, UH3AG064706, K01AG063805, UH2AG064706, R01AG050595, U19AG065169, R01AG076838, U24AG078753, U19AG023122)
  • National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, U01 AG024904, AG024904)
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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
Alzheimer's disease, genetic heterogeneity

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.

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