# From cells to complex syndromes: using networks to understand heterogeneity in TDP-related frontotemporal degeneration and aging

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $2,479,787

## Abstract

Frontotemporal degeneration (FTD) is an understudied clinical neurodegenerative condition that is the most
common dementia after Alzheimer disease (AD) in people younger than 65. The most common pathology
associated with FTD is frontotemporal lobar degeneration due to transactive DNA/RNA binding protein of ~43
kD (TDP-43 (FTLD-TDP), and this is also the underlying pathology in the vast majority of patients who have
co-occurring amyotrophic lateral sclerosis (FTD-ALS) spectrum disorders as well as a critical force in age-
related disorders such as limbic-predominant age-related TDP-43 encephalopathy (LATE). Since discovering a
role for TDP-43 pathology in human disease, important progress has been made in experimental cellular and
animal models of disease. However, the human brain has many unique properties associated with distinctly
human clinical disorders that are not easily replicated in these experimental models. Major gaps in knowledge
thus constrain the development of disease-modifying treatment trials. Among these is our limited knowledge of
the pathophysiologic consequences of the accumulation and progression of abnormal TDP-43 at a molecular
level. At a microscopic level, a major limitation is that most patients with accumulating TDP-43 have sporadic
disease that can be identified reliably only at autopsy, although ~20% of cases have familial FTLD (fFTLD) with
known pathology during life. We are limited at translating this knowledge to a macroscale level where FTLD-
TDP pathology is manifested in humans with heterogeneous clinical features as diverse as emotional
dysregulation and impaired language both with and without a motor disorder. Moreover, there is limited
knowledge of the factors contributing to the highly varying rates of disease progression. In five novel,
independent but synergistic Projects and five Cores that support each of the Projects, this unique,
multidisciplinary, Program Project Grant (PPG) adopts the innovative perspective of investigating the
TDP-43-associated breakdown of neural networks at molecular, microscopic and macroscale levels in
humans. We hypothesize that our novel, well-integrated, network perspective will fill major gaps in
knowledge by elucidating mechanistic insights into the pathophysiology of abnormal TDP-43 and the
associated pattern of disease progression, and offer a fresh perspective on the identification of
accumulating TDP-43 pathology during life and its longitudinal course. This proposal is consistent with
the highest priorities for FTD at the 2019 Alzheimer’s Disease and Related Disorders (ADRD) summit. By
focusing on disruption of neural networks at molecular, microscopic and macroscale levels of brain functioning,
our multidisciplinary network approach will elucidate the pathophysiology and spread of abnormal TDP-43 in
humans, and examine the consequences of TDP-43 pathology for clinical disease during life in dementia and
aging using fresh approaches to improve our mechanistic understan...

## Key facts

- **NIH application ID:** 10454262
- **Project number:** 5P01AG066597-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** David John Irwin
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,479,787
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454262

## Citation

> US National Institutes of Health, RePORTER application 10454262, From cells to complex syndromes: using networks to understand heterogeneity in TDP-related frontotemporal degeneration and aging (5P01AG066597-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10454262. Licensed CC0.

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