Preserved autophagy in cognitively intact non‐demented individuals with Alzheimer's neuropathology
Open accessAbstract
INTRODUCTION: Growing evidence supports that dysfunctional autophagy, the major cell mechanism responsible for removing protein aggregates and a route of clearance for Tau in healthy neurons, is a major finding in demented Alzheimer's disease (AD) patients. However, the association of autophagy with maintenance of cognitive integrity in resilient individuals who have AD neuropathology but remain non‐demented (NDAN) has not been evaluated. METHODS: Using post mortem brain samples from age‐matched healthy control, AD, and NDAN subjects, we evaluated autophagy in relation to Tau pathology using Western blot, immunofluorescence and RNA‐seq. RESULTS: Compared to AD patients, NDAN subjects had preserved autophagy and reduced tauopathy. Furthermore, expression of autophagy genes and AD‐related proteins were significantly associated in NDAN compared to AD and control subjects. DISCUSSION: Our results suggest preserved autophagy is a protective mechanism that maintains cognitive integrity in NDAN individuals. This novel observation supports the potential of autophagy‐inducing strategies in AD therapeutics. Highlights: NDAN subjects have preserved autophagic protein levels comparable with control subjects. Compared to control subjects, NDAN subjects have significantly reduced Tau oligomers and PHF Tau phosphorylation at synapses that negatively correlate with autophagy markers. Transcription of autophagy genes strongly associates with AD‐related proteins in NDAN donors.
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Elevated gene expression related to the early stages of autophagy is responsible for maintaining synaptic integrity through the efficient removal of tau oligomers in the hippocampus of AsymAD subjects.
“These findings align with a recent study in which elevated gene expression related to the early stages of autophagy was demonstrated to be responsible for maintaining synaptic integrity through the efficient removal of tau oligomers in the hippocampus of AsymAD subjects [98].”
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 [98]
Section 3.2 (page unavailable) reports higher levels of early-autophagy proteins in NDAN hippocampi than in AD hippocampi. Section 3.4 reports a negative correlation between autophagy proteins and tau oligomers, while the Discussion proposes tau clearance as a protective mechanism. These findings do not demonstrate that elevated gene expression causes efficient tau-oligomer removal or thereby maintains synaptic integrity. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPhagocytosis and endocytosis might underlie synaptic resilience in AsymAD individuals.
“previous evidence suggest that phagocytosis and endocytosis might underlie synaptic resilience in AsymAD individuals [92, 98].”
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 [98]
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Jamison, D., Kadamangudi, S., Tumurbaatar, B., Zhang, W.-R., Palmer, L. K., Kunkel, S., Kayed, R., Limón, A., & Taglialatela, G. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251352382 · Cited by 6 · see citing works
Self-citationResistance and Resilience to Alzheimer's DiseasePreprint
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Self-citationSub-Immunosuppressive Tacrolimus Ameliorates Amyloid-Beta and Tau Pathology in 3xTg-AD Mice
Silva, J. D., Tumurbaatar, B., Guptarak, J., Zhang, W.-R., Fracassi, A., & Taglialatela, G. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26051797 · Cited by 3 · see citing works
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Mitochondrial Fragmentation as a Key Driver of Neurodegenerative Disease
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Overexpression of MTMR14 induced learning and memory impairments in 2-month-old C57 mice
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Roles of autophagy in brain homeostasis and disease
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Impaired MAPT/tau-secretory lysosomes are linked to cognitive vulnerability in Alzheimer patients
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From Amyloid Exposure to Genetic Causality: Converging hiPSC-Based Models of Alzheimer’s Disease
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- Authors
- Tumurbaatar, B., Fracassi, A., Scaduto, P., Guptarak, J., Woltjer, R., Jupiter, D., & Taglialatela, G.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Oregon Health & Science University (US)
- Corresponding author
- Taglialatela, Giulio
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2023-05-16
- Volume
- 19
- Issue
- 12
- Pages
- 5355-5370
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC10651802
- OpenAlex
- W4376642545
- Cited by
- 32
- References
- 68
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 8 · 2023: 4
- FWCI
- 5.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alzheimer's Association (AARF-22-973974)
- National Institutes of Health (3r01ag060718-01a1s1)
- National Institute on Aging (AG073133, R01-AG060718, RF1AG060718, R01AG073133, P30AG066518)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- autophagy, Alzheimer's disease
- MeSH terms
- Neuropathology, Alzheimer Disease, Autophagy, Brain, Humans, Neurons, Amyloid beta-Peptides, tau Proteins
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