# Synaptic Resilience to Tau in Alzheimer's Disease

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $219,113

## Abstract

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.

## Key facts

- **NIH application ID:** 10984162
- **Project number:** 1R21AG085379-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Jeremy H. Herskowitz
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $219,113
- **Award type:** 1
- **Project period:** 2024-07-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984162

## Citation

> US National Institutes of Health, RePORTER application 10984162, Synaptic Resilience to Tau in Alzheimer's Disease (1R21AG085379-01A1). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10984162. Licensed CC0.

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