Genetic Heterogeneity in Alzheimer Disease and Implications for Treatment Strategies
Open accessAbstract
Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer's disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.
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Mutations in both APP and PSEN1 cause aberrant APP cleavage and clearance that lead to neuroinflammation, activation of astrocytes and microglia, and changes in bioenergetics.
“Mutations in both APP and PSEN1 cause aberrant APP cleavage and clearance4,47 that lead to neuroinflammation, the activation of astrocytes and microglia, and changes in bioenergetics44,48.”
From Magnetic resonance microscopy maps widespread effects of Alzheimer’s disease on brain structures and behavior in mice (2026) · cites this paper as [4]
The 'Amyloid Precursor Protein' and 'The Presenilins' sections (pages not supplied) describe how APP and PSEN1 mutations alter APP cleavage and Aβ production. The 'Autosomal dominant forms of AD' section distinguishes reduced Aβ clearance in late-onset AD from increased Aβ synthesis in PSEN1 mutation carriers; it does not establish aberrant clearance for both mutations. The later inflammation, glial-activation, and bioenergetics claims carry separate citations. (LLM, conf=0.86)
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- Authors
- Dominantly Inherited Alzheimer Network, Ringman, J. M., Goate, A., Masters, C. L., Cairns, N. J., Danek, A., Graff-Radford, N., Ghetti, B., & Morris, J. C.
- Affiliations
- University of California, Los Angeles (US)
- The University of Melbourne (AU)
- Washington University in St. Louis (US)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Ringman, John M.
- Venue
- Current Neurology and Neuroscience Reports
- Published
- 2014-09-14
- Volume
- 14
- Issue
- 11
- Pages
- 499-499
- ISSN
- 1528-4042 (ISSN-L)
- 1534-6293
- PMC
- PMC4162987
- OpenAlex
- W2093198322
- Cited by
- 96
- References
- 96
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 9 · 2023: 7 · 2022: 10 · 2021: 12 · 2020: 11 · 2019: 10 · 2018: 3 · 2017: 9 · 2016: 6 · 2015: 4
- FWCI
- 0.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Current Neurology and Neuroscience Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- DZNE Pub (submittedVersion, other-oa)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Funders
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- National Institute on Aging (AG-016570, P50AG016570, P 50 AG05681, UF1AG032438, P50AG005681, P01 AG0 3991, P01AG003991, P01AG026276)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Alzheimer's disease, genetic heterogeneity, autosomal dominant Alzheimer's disease, PSEN1 mutations, APP mutations, PSEN2 mutations, APOE ε4, Down syndrome, preclinical Alzheimer's disease, clinical trial design, treatment response, genetic risk factors
- MeSH terms
- Alzheimer Disease, Animals, Humans, Membrane Proteins, Amyloid beta-Protein Precursor, Genetic Heterogeneity, Presenilin-1, Presenilin-2
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