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Cited by 39Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Challenge accepted: uncovering the role of rare genetic variants in Alzheimer’s disease

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Khani, Marzieh, Gibbons, Elizabeth, Bras, Jose, Guerreiro, Rita·2022·Molecular Neurodegeneration
DOI 10.1186/s13024-021-00505-9PMC PMC8744312
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Abstract

The search for rare variants in Alzheimer's disease (AD) is usually deemed a high-risk - high-reward situation. The challenges associated with this endeavor are real. Still, the application of genome-wide technologies to large numbers of cases and controls or to small, well-characterized families has started to be fruitful.Rare variants associated with AD have been shown to increase risk or cause disease, but also to protect against the development of AD. All of these can potentially be targeted for the development of new drugs.Multiple independent studies have now shown associations of rare variants in NOTCH3, TREM2, SORL1, ABCA7, BIN1, CLU, NCK2, AKAP9, UNC5C, PLCG2, and ABI3 with AD and suggested that they may influence disease via multiple mechanisms. These genes have reported functions in the immune system, lipid metabolism, synaptic plasticity, and apoptosis. However, the main pathway emerging from the collective of genes harboring rare variants associated with AD is the Aβ pathway. Associations of rare variants in dozens of other genes have also been proposed, but have not yet been replicated in independent studies. Replication of this type of findings is one of the challenges associated with studying rare variants in complex diseases, such as AD. In this review, we discuss some of these primary challenges as well as possible solutions.Integrative approaches, the availability of large datasets and databases, and the development of new analytical methodologies will continue to produce new genes harboring rare variability impacting AD. In the future, more extensive and more diverse genetic studies, as well as studies of deeply characterized families, will enhance our understanding of disease pathogenesis and put us on the correct path for the development of successful drugs.

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  • A significant proportion of AD-linked genes are associated with microglia and the immune response.

    “A significant proportion of these AD‐linked genes are associated with microglia and the immune response, reinforcing the necessity to understand the intersection of immunity and AD pathogenesis in the development of novel AD therapeutics.”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [6]

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Authors
Khani, M., Gibbons, E., Bras, J., & Guerreiro, R.
Affiliations
  • University of Tehran (IR)
  • Van Andel Institute (US)
Corresponding author
Guerreiro, Rita
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2022-01-09
Volume
17
Issue
1
Pages
3-3
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-021-00505-9
PMC
PMC8744312
OpenAlex
W4206272286
Cited by
39
References
125
Citations by year
2026: 8 · 2025: 5 · 2024: 11 · 2023: 10 · 2022: 5
FWCI
1.07
Type
journal article
Language
en
Update notices
correction (2022-11-01)
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (R01AG067426)
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, rare variants, genetic risk factors, Notch3, TREM2, SORL1, ABCA7, BIN1, clusterin, Nck2, AKAP9, UNC5C, PLCγ2, ABI3, replication of genetic associations, pathogenesis, therapeutic target
MeSH terms
Alzheimer Disease, Humans, ATP-Binding Cassette Transporters, Genetic Predisposition to Disease, LDL-Receptor Related Proteins, Membrane Transport Proteins, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study

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