# Age-related TDP-43 neuropathology: using disease-driving mechanisms to guide classification

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2024 · $790,914

## Abstract

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common
pathology of aging, associated with an amnestic syndrome mimicking Alzheimer’s disease (AD). The co-
morbid pathologic and genetic risk factors of LATE-NC remain incompletely understood. The goals of this
proposal are to clarify the mechanisms underlying LATE-NC, to determine how these mechanisms interact and
affect subregions of human amygdalae, and to generate a practical classification scheme of LATE-NC that is
necessary to guide future studies. The amygdala is the first brain region affected in LATE-NC and therefore
represents the best anatomic region to understand LATE-NC in its earliest phase(s). A major challenge has
been to reconcile mechanisms underlying TDP-43 proteinopathy in community-based autopsy cohorts of older
adults (which show a spectrum of complex age-related diseases such as LATE-NC, and mixed pathologies),
with results in hospital/clinic-based cohorts that tend to include autopsy patients with less common but “pure”
TDP-43 proteinopathies, such as FTLD-TDP and ALS. Therefore, we will combine results from a high quality
community-based autopsy cohort (U. Kentucky) with an excellent hospital-based cohort (Houston Methodist
Hospital) to analyze common disease-driving mechanisms. The study will incorporate well-characterized
human brains (N>1400 total) of patients with ALS-FTD spectrum disorders, and AD neuropathologic changes
(ADNC), with and without comorbid LATE-NC. We will characterize the comorbid proteinopathies and vascular
pathologies associated with the earliest foci of TDP-43 pathology, including co-localization of TDP-43 and
other misfolded proteins, such as Tau. We hypothesize that the initiation of LATE-NC in human amygdalae
results from a selective cellular vulnerability that varies in association with specific genetic risk factors. We will
examine and contrast the proteomic profiles of susceptible and resistant subregions of human amygdalae, both
within individuals and across disease states (e.g., LATE-NC versus ADNC, LATE-NC versus ALS-FTD
spectrum, including FTLD-TDP cases. We also hypothesize that pathologically and genetically distinct forms of
age-related TDP-43 proteinopathy exist in human brains, including: (a) an ADNC-related subtype influenced by
APOE, (b) a FTLD-related subtype affected by GRN and TMEM106B, and (c) an arteriosclerosis-related
subtype associated with ABCC9 gene variant. We will test methods of disease delineation - areas of overlap
and points of difference - and evaluate how these hypothesized mechanism-classified subtypes synergize or
negate each other when they are comorbid, and how the disease subtypes manifest clinically. The multimodal
data may indicate a practical classification scheme. The two-institution study design enables us to evaluate
inter-rater reliability and to emphasize replicability. Overall, the project will clarify mechanisms contributing to
age-related TDP-43 pathology, ...

## Key facts

- **NIH application ID:** 10984953
- **Project number:** 4R01NS118584-02
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** MATTHEW DANIEL CYKOWSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $790,914
- **Award type:** 4N
- **Project period:** 2020-09-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984953

## Citation

> US National Institutes of Health, RePORTER application 10984953, Age-related TDP-43 neuropathology: using disease-driving mechanisms to guide classification (4R01NS118584-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10984953. Licensed CC0.

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