Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer's disease
Open accessAbstract
Synapses are essential for transmitting, processing, and storing information, all of which decline in aging and Alzheimer's disease (AD). Because synapse loss only partially accounts for the cognitive declines seen in aging and AD, we hypothesized that existing synapses might undergo molecular changes that reduce their functional capacity. Microarrays were used to evaluate expression profiles of 340 synaptic genes in aging (20-99 years) and AD across 4 brain regions from 81 cases. The analysis revealed an unexpectedly large number of significant expression changes in synapse-related genes in aging, with many undergoing progressive downregulation across aging and AD. Functional classification of the genes showing altered expression revealed that multiple aspects of synaptic function are affected, notably synaptic vesicle trafficking and release, neurotransmitter receptors and receptor trafficking, postsynaptic density scaffolding, cell adhesion regulating synaptic stability, and neuromodulatory systems. The widespread declines in synaptic gene expression in normal aging suggests that function of existing synapses might be impaired, and that a common set of synaptic genes are vulnerable to change in aging and AD.
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Early transcriptomic studies utilizing microarrays revealed alterations in synaptic, immune, and metabolic pathways that appear even before clinical symptoms.
“Early transcriptomic studies utilizing microarrays revealed alterations in synaptic, immune, and metabolic pathways that appear even before clinical symptoms, underscoring the potential for pre-symptomatic intervention120,125,161.”
From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [161]
The Introduction reports microarray findings of synaptic and energy-related gene downregulation and immune-related gene upregulation with aging; the Results also document synaptic changes in aging and Alzheimer’s disease. The paper does not establish that these changes appeared before clinical symptoms: its comparison with normal aging is not a longitudinal assessment of presymptomatic Alzheimer’s disease. (LLM, conf=0.86)
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Neuropathological stageing of Alzheimer-related changes.
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“…declines in gene expression in limbic regions are consistent with the documented neuronal and synaptic loss in these regions in AD, most particularly in the HC (De Leon et al., 1997; Gomez-Isla et al., 1996), and with declining temporal lobe function characteristic of AD (Sperling et al., 2010).”
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Self-citationA Systems Level Analysis of Transcriptional Changes in Alzheimer's Disease and Normal Aging
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- Authors
- Berchtold, N. C., Coleman, P. D., Cribbs, D. H., Rogers, J., Gillen, D. L., & Cotman, C. W.
- Affiliations
- University of California, Irvine (US)
- University of Rochester Medicine (US)
- Banner Sun Health Research Institute (US)
- Corresponding author
- Berchtold, Nicole C.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 34
- Issue
- 6
- Pages
- 1653-1661
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC4022280
- OpenAlex
- W2061116800
- Cited by
- 298
- References
- 8
- Citations by year
- 2026: 21 · 2025: 33 · 2024: 31 · 2023: 25 · 2022: 30 · 2021: 31 · 2020: 26 · 2019: 33 · 2018: 19 · 2017: 12 · 2016: 11 · 2015: 12 · 2014: 10 · 2013: 4
- FWCI
- 5.57
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01 AG23173, AG34667, P50 AG16573, AG00538, RO1 AG36400, AG7367)
- Alzheimer Association (IIRG 91822)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- synaptic genes, Alzheimer's disease, normal brain aging, gene downregulation, synaptic function, synaptic vesicle trafficking, neurotransmitter receptors, postsynaptic density, cell adhesion, neuromodulatory systems, cognitive decline
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain Chemistry, Female, Humans, Male, Middle Aged, Synapses, Synaptic Vesicles, Down-Regulation, Gene Expression Profiling, Young Adult
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