# Vulnerability Profiles of Comorbid Alzheimer and TDP-43 Proteinopathies in Amnestic Dementia

> **NIH NIH R56** · NORTHWESTERN UNIVERSITY · 2023 · $603,031

## Abstract

ABSTRACT. Comorbid pathologies are extremely common in the aging population. In recent years, inclusions
containing the hyperphosphorylated form of transactive response DNA-binding protein 43 (TDP-43) have been
found in a vast proportion of elderly with common amnestic dementia and pathologically confirmed Alzheimer’s
disease (AD; characterized by amyloid plaques and tau-containing tangles). These cooccurring diseases,
referred here to as “AD/TDP”, impact cognition, functioning, and brain integrity, and target older adults—a
population that continues to rise globally. Despite this, the clinical and biologic features of AD/TDP
remain
undefined. The major goal of this study is to identify the clinical, cellular, and pathologic signatures of AD/TDP
using brain specimens from participants who were characterized by rigorous neuropsychological tests during life
and neuropathologically after death. This project is carefully designed to focus on affected neurons in the
corticolimbic system that play a critical role in memory, cognition, and mood/behavior. It is anchored to neuronal
groups in anatomic regions that typically show early susceptibility to 1) AD but not TDP-43 (Ch4 cells of the
nucleus basalis); 2) TDP-43 but not AD (e.g., dentate gyrus); 3) both (e.g., amygdala); and 4) neither (e.g., visual
cortex). It is based on longitudinal data acquired over decades, along with unbiased stereological quantification
in corticolimbic regions from AD/TDP, AD, cognitively-healthy controls, and persons found to show TDP-43 of
the FTLD-type. Clinicopathologic information on AD/TDP will help characterize its syndromic phenotype, clarify
the link between clinical syndrome and neuropathology, and can address critical questions about the
determinants of selective vulnerability and disease spread in dementia. Through longitudinal psychometric
analysis, Aim 1 will identify the shared versus distinct clinical, neuropsychological, and psychiatric features of
AD/TDP , with a focus on initial symptom onset and patterns of decline. Aim 2 will determine the cellular features
and distribution of TDP-43 and AD-related pathology in amnestic dementia. The design confined to neuronal
groups that show early susceptibility to either AD, TDP-43, both, or neither, will allow us to glean novel insights
into the substrates of neurodegeneration. Stereological and digital analysis of pathology in white & grey matter
microglia, cell number/size, dendritic trees & spines, and synapses will be performed in hemispheric regions.
Aim 3 will investigate the well-known trans-synaptic circuitry of the memory-related hippocampus as a putative
anatomic mechanism for spread and memory dysfunction in AD/TDP. Relationships between antemortem (Aim
1) and postmortem findings (Aims 2 & 3) will establish clinicopathologic concordance between the unique
phenotype and anatomic vulnerability profile of AD/TDP. The study will leverage the resources of the
Northwestern ADRC and will be carried out by a tea...

## Key facts

- **NIH application ID:** 10901010
- **Project number:** 1R56AG075600-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Tamar D Gefen
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $603,031
- **Award type:** 1
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901010

## Citation

> US National Institutes of Health, RePORTER application 10901010, Vulnerability Profiles of Comorbid Alzheimer and TDP-43 Proteinopathies in Amnestic Dementia (1R56AG075600-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10901010. Licensed CC0.

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