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Cited by 135Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Protective genes and pathways in Alzheimer’s disease: moving towards precision interventions

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Seto, Mabel, Weiner, Rebecca L., Dumitrescu, Logan, Hohman, Timothy J.·2021·Molecular Neurodegeneration
DOI 10.1186/s13024-021-00452-5PMC PMC8086309
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Abstract

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder that is characterized by neurodegeneration, cognitive impairment, and an eventual inability to perform daily tasks. The etiology of Alzheimer’s is complex, with numerous environmental and genetic factors contributing to the disease. Late-onset AD is highly heritable (60 to 80%), and over 40 risk loci for AD have been identified via large genome-wide association studies, most of which are common variants with small effect sizes. Although these discoveries have provided novel insight on biological contributors to AD, disease-modifying treatments remain elusive. Recently, the concepts of resistance to pathology and resilience against the downstream consequences of pathology have been of particular interest in the Alzheimer’s field as studies continue to identify individuals who evade the pathology of the disease even into late life and individuals who have all of the neuropathological features of AD but evade downstream neurodegeneration and cognitive impairment. It has been hypothesized that a shift in focus from Alzheimer’s risk to resilience presents an opportunity to uncover novel biological mechanisms of AD and to identify promising therapeutic targets for the disease. This review will highlight a selection of genes and variants that have been reported to confer protection from AD within the literature and will also discuss evidence for the biological underpinnings behind their protective effect with a focus on genes involved in lipid metabolism, cellular trafficking, endosomal and lysosomal function, synaptic function, and inflammation. Finally, we offer some recommendations in areas where the field can rapidly advance towards precision interventions that leverage the ideas of protection and resilience for the development of novel therapeutic strategies.

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Authors
Seto, M., Weiner, R. L., Dumitrescu, L., & Hohman, T. J.
Affiliations
  • Vanderbilt University (US)
  • Vanderbilt University Medical Center (US)
Corresponding author
Hohman, Timothy J.
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2021-04-29
Volume
16
Issue
1
Pages
29-29
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-021-00452-5
PMC
PMC8086309
OpenAlex
W3159386190
Cited by
135
References
225
Citations by year
2026: 7 · 2025: 32 · 2024: 36 · 2023: 23 · 2022: 34 · 2021: 3
FWCI
3.20
Type
journal article
Language
en
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 Institute on Aging (R01-AG059716, K01-AG049164), R01-AG061518)
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, protective genes, genetic resilience, late-onset Alzheimer's disease, genetic susceptibility loci, lipid metabolism, cell trafficking, synaptic function, neuroinflammation, precision medicine, therapeutic target
MeSH terms
Klotho Proteins, Alzheimer Disease, Apolipoproteins E, Homeostasis, Humans, Immunity, Inflammation, Lysosomes, Nerve Tissue Proteins, Endosomes, Synapses, Age of Onset, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Lipid Metabolism, Genome-Wide Association Study, Precision Medicine, Disease Resistance, Gene Ontology

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