Functional Integrity of Synapses in the Central Nervous System of Cognitively Intact Individuals with High Alzheimer’s Disease Neuropathology Is Associated with Absence of Synaptic Tau Oligomers
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Background: Certain individuals, here referred to as Non-Demented with Alzheimer Neuropathology (NDAN), do not show overt neurodegeneration (N-) and remain cognitively intact despite the presence of plaques (A+) and tangles (T+) that would normally be consistent with fully symptomatic Alzheimer’s disease (AD). Objective: The existence of NDAN (A + T+N-) subjects suggests that the human brain utilizes intrinsic mechanisms that can naturally evade cognitive decline normally associated with the symptomatic stages of AD (A + T+N+). Deciphering the underlying mechanisms would prove relevant to develop complementing therapeutics to prevent progression of AD-related cognitive decline. Methods: Previously, we have reported that NDAN present with preserved neurogenesis and synaptic integrity paralleled by absence of amyloid oligomers at synapses. Using postmortem brain samples from age-matched control subjects, demented AD patients and NDAN individuals, we performed immunofluorescence, western blots, micro transplantation of synaptic membranes in Xenopus oocytes followed by twin electrode voltage clamp electrophysiology and fluorescence assisted single synaptosome-long term potentiation studies. Results: We report decreased tau oligomers at synapses in the brains of NDAN subjects. Furthermore, using novel approaches we report, for the first time, that such absence of tau oligomers at synapses is associated with synaptic functional integrity in NDAN subjects as compared to demented AD patients. Conclusion: Overall, these results give further credence to tau oligomers as primary actors of synaptic destruction underscoring cognitive demise in AD and support their targeting as a viable therapeutic strategy for AD and related tauopathies.
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Unlike in AD subjects with dementia, no phosphorylated tau accumulation occurs within synapses of AsymAD brains.
“unlike in the brains of AD subjects with dementia, no phosphorylated tau accumulation occurs within the synapses of AsymAD brains [73, 83].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [83]
The Results (‘Decreased tau oligomers at synapses in NDAN subjects’; page unavailable) find substantially more synaptic tau oligomers in AD cases than in cognitively intact NDAN cases. The Discussion reports an absence of synaptic oligomeric tau in NDAN subjects, but the paper does not establish that no phosphorylated tau accumulates there: its synaptic analyses measure oligomeric or total tau, not specifically phosphorylated tau. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAsymAD individuals have neuritic plaque and NFTs Braak stages at autopsy comparable to those of AD subjects with dementia.
“These individuals have neuritic plaque and NFTs Braak stages at autopsy comparable to those of AD subjects with dementia, and the literature refers to them as resilient [31], Nondemented with AD Neuropathology (NDAN) [83], or asymptomatic AD (AsymAD) [22, 42].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [83]
Table 1 (Materials and Methods; page unavailable) shows overlapping plaque scores in the NDAN and AD groups, and some NDAN cases have Braak scores of 5–6, comparable to the AD cases. But NDAN Braak scores range from 2–6, while AD scores are 5–6, so the table does not support an unqualified claim that their Braak stages are comparable. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAsymAD cases exhibit an overall deficiency in oligomeric and soluble phospho-tau species, indicating fewer pathological tau species in these cases than in AD cases.
“Consistent with our findings, previous studies have shown that AsymAD cases exhibit an overall deficiency in oligomeric and soluble phospho-tau species, indicating fewer pathological tau species in these cases than in AD cases [8, 73, 83].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [83]
The Results section (“Reduced tau oligomer levels in the CNS of NDAN subjects as compared to AD patients”; page unavailable) reports significantly lower tau oligomers in NDAN than in AD in the frontal cortex and hippocampus. The paper does not report a corresponding comparison of soluble phospho-tau species, so that part of the attributed claim is unsupported by this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTauO plays a critical role in synaptic dysfunction and cognitive impairment in AD patients.
“This study further supports the critical role of TauO in synaptic dysfunction and cognitive impairment in AD patients.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [176]
In cognitively normal individuals with moderate-to-high AD neuropathology, functional integrity of synapses is linked to an absence of synaptic TauO.
“In our recent study, we demonstrated that the functional integrity of synapses in cognitively normal individuals with moderate‐to‐high AD neuropathology is linked to an absence of synaptic TauO.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [176]
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Self-citationPostsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology
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Cognitive impairment of Alzheimer disease.
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Self-citationA method to determine insulin responsiveness in synaptosomes isolated from frozen brain tissue
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Self-citationAlzheimer's therapy development: A few points to consider
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Immunotherapy for the treatment of Alzheimer's disease: amyloid-β or tau, which is the right target?
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Flagged first, then by citations
Research works printed but not linked: 1
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Cited by
Sorted by citations
Gaikwad, S., Senapati, S., Haque, M. A., & Kayed, R. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13490 · Cited by 117 · see citing works
Self-citationTau Oligomer–Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease
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Self-citationPreserved autophagy in cognitively intact non‐demented individuals with Alzheimer's neuropathology
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“These individuals have neuritic plaque and NFTs Braak stages at autopsy comparable to those of AD subjects with dementia, and the literature refers to them as resilient [31], Nondemented with AD Neuropathology (NDAN) [83], or asymptomatic AD (AsymAD) [22, 42].”
BackgroundResultWang, T., Liu, X., Wang, X., Hua, F., & Yan, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1739875 · Cited by 14 · see citing works
- Authors
- Singh, A., Allen, D., Fracassi, A., Tumurbaatar, B., Natarajan, C., Scaduto, P., Woltjer, R., Kayed, R., Limon, A., Krishnan, B., & Taglialatela, G.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Oregon Health & Science University (US)
- Mitchell Center for Neurodegenerative Diseases, Department of Neurology, UTMB Galveston, TX, USA
- Corresponding author
- Krishnan, Balaji
- Taglialatela, Giulio
- ORCID
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2020-12-08
- Volume
- 78
- Issue
- 4
- Pages
- 1661-1678
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC7836055
- OpenAlex
- W3102566653
- Cited by
- 56
- References
- 97
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 8 · 2023: 11 · 2022: 13 · 2021: 3
- FWCI
- 4.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Alzheimer s Disease (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG042890, R01AG063945, R21AG059223, P30AG066518, R01AG054025)
- 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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Cognition, Female, Frontal Lobe, Hippocampus, Humans, Male, Middle Aged, Synapses, Neurofibrillary Tangles, tau Proteins, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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