The multiplex model of the genetics of Alzheimer's disease
Abstract
Genes play a strong role in Alzheimer's disease (AD), with late-onset AD showing heritability of 58-79% and early-onset AD showing over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 50 loci are now implicated for AD, suggesting that AD is a disease of multiple components, as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD heritability has been captured, allowing researchers to calculate the accumulation of AD genetic risk through polygenic risk scores. A polygenic risk score predicts disease with up to 90% accuracy and is an exciting tool in our research armory that could allow selection of those with high polygenic risk scores for clinical trials and precision medicine. It could also allow cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflects the combination of some, or all, of these model components (genetic and environmental), in a tissue-specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell and synaptic loss observed in AD.
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APOE4 is the strongest genetic risk factor for AD with high prevalence.
“In conclusion, APOE4 is the strongest genetic risk factor for AD with high prevalence (Saunders et al 1993, Sims et al 2020).”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Sims et al 2020
The ‘Late-onset AD Genetics: Common Variation’ section (p. 3) calls APOE the strongest genetic risk factor and says the ε4 allele increases AD risk. It does not establish that APOE4 has high prevalence; the reference to common forms of late-onset AD describes the disease, not the allele’s prevalence. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAPOE ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease.
“the ε4 allele is the strongest genetic risk factor for late-onset AD”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Sims et al 2020
The risk for AD is 3-4-fold higher in individuals carrying one APOE ε4 allele and about 10-15-fold higher in those carrying two APOE ε4 alleles.
“The risk for AD is 3–4-fold higher in individuals carrying one APOE ε4 allele and about 10–15-fold higher in those carrying two APOE ε4 alleles”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Sims et al 2020
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- Authors
- Sims, R., Hill, M., & Williams, J.
- Affiliations
- Cardiff University (GB)
- UK Dementia Research Institute (GB)
- Corresponding author
- Williams, Julie
- Venue
- Nature Neuroscience
- Published
- 2020-02-28
- Volume
- 23
- Issue
- 3
- Pages
- 311-322
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W3007931728
- Cited by
- 466
- References
- 53
- Citations by year
- 2026: 45 · 2025: 68 · 2024: 71 · 2023: 88 · 2022: 87 · 2021: 84 · 2020: 23
- FWCI
- 9.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- Medical Research Council (MR/L023784/1, MR/L023784/2, MR/K013041/1, MR/N029402/1, MR/M009076/1, MC_PC_17112, MR/L501517/1)
- 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 susceptibility loci, polygenic risk score, late-onset Alzheimer's disease, early-onset Alzheimer's disease, heritability, genetic association, pathway analysis, amyloid-beta processing, cholesterol transport, ubiquitination, endocytosis, immune pathways, synaptic loss, precision medicine, clinical trial selection
- MeSH terms
- Alzheimer Disease, Animals, Humans, Models, Genetic, Signal Transduction
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