ArticleJournal of Alzheimer's disease : JAD2024
Exploring the Genetic Heterogeneity of Alzheimer's Disease: Evidence for Genetic Subtypes.
Article in Journal of Alzheimer's disease : JAD, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Novel Plasma Proteins Associated With Alzheimer's Disease Risk in APOE ε4 Carriers and Non-carriers.Research square · 2026Article
- Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions.Acta pharmaceutica Sinica. B · 2025Review
- Heterogeneity Analysis of Associations Involving the Large-Scale Online MindCrowd Survey Memory Test.Gerontology · 2025Article
- Heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar-disorder.ArXiv · 2024Article
- On the effect heterogeneity of established disease susceptibility loci for Alzheimer's disease across different genetic ancestries.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Synergistic activity of nootropic herbs as potent therapeutics for Alzheimer's disease: A cheminformatics, pharmacokinetics, and system pharmacology approach.Journal of Alzheimer's disease reports · 2024Article
- Unveiling unified patterns in Alzheimer's disease subtypes: An SCCA clustering approach integrating PET imaging and genomics data.Imaging neuroscience (Cambridge, Mass.)Article
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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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.