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Synaptic Resilience to Tau in Alzheimer's Disease

Award Number: R21AG085379
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Synaptic Resilience to Tau in Alzheimer's Disease - Project Summary Approximately one-third of individuals without dementia at the time of death are found to harbor high levels of Alzheimer’s disease (AD) pathology, including amyloid-β plaques and neurofibrillary tangles, at autopsy. We hypothesize that such individuals exhibit physiological resilience that confers the ability to maintain cognitive function despite the accumulation of AD-related pathologies. The identification of the specific mechanisms by which these older individuals with Alzheimer’s disease pathology avoid dementia is one of the most pivotal, unanswered questions in the field. Cognitive impairment in AD is the result of synapse loss in brain regions that are critical for memory processes. Our work and that of others has demonstrated that synaptic markers and dendritic spine loss correlate more strongly with cognitive impairment in Alzheimer’s disease than accumulation of amyloid-β plaques and neurofibrillary tangles. This implies that the ability to maintain cognitive function in an environment of AD pathology must be linked to the preservation and maintenance of synapses or spines. Aberrant tau accumulation is a strong pathological correlate of cognitive decline both in normal aging and Alzheimer’s disease. Abnormal tau initially accumulates in somatodendritic compartments among layer 2/3 neurons in the entorhinal cortex, and is thought to spread to anatomically connected regions via synaptic connections. These findings suggest that aberrantly phosphorylated tau seeds residing in synaptic compartments are crucial to the spread or propagation of tau pathology in aging and Alzheimer’s disease patients. The extent of neurofibrillary tangle spread through the brain correlates with the severity of cognitive impairment, and thus, halting spread of tau pathology may represent a plausible mechanism of resilience to age- related memory loss or Alzheimer’s disease. This raises important questions: do resilient patients harbor less pathogenic tau seeds in synaptic compartments or are their synapses more resilient to tau? What are the synaptic proteins and cellular pathways that associate with tau seeding and tau-induced synaptotoxicity in resilient patients? The goal of this R21 is to address these provocative questions to open new doors of investigation by identifying putative therapeutic protein targets that are linked to modulating tau seeding, tau- induced synaptic dysfunction and synapse preservation in Alzheimer’s disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $181,988 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	001	2	4/28/2025	NON-COMPETING CONTINUATION	$18,199
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	2	3/31/2025	NON-COMPETING CONTINUATION	$163,789
														Subtotal = $181,988

Issue Date FY: 2024 ( Subtotal = $219,113 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	1	7/12/2024	NEW	$219,113
														Subtotal = $219,113

Grand Total All Awards = $401,101

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Synaptic Resilience to Tau in Alzheimer's Disease

Award Number: R21AG085379

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/15/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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