# Genomic Architecture of a Key Alzheimer's Disease Mimic: CARTS

> **NIH NIH R56** · UNIVERSITY OF KENTUCKY · 2020 · $525,141

## Abstract

Brain diseases other than Alzheimer’s disease (AD) are common but understudied causes of dementia. A
particularly prevalent subtype of non-Alzheimer’s dementia is termed hippocampal sclerosis dementia, or
cerebral age-related TDP-43 with sclerosis (CARTS). This neuropathology (NP) defined disease, which is often
misdiagnosed clinically as AD, affects ~20% of the elderly, with substantial impact on cognition. The long-term
goal is to resolve the genomic factors that modulate CARTS severity and heterogeneity. To accomplish this, we
will establish, test, and apply a robust pipeline to elucidate the mechanisms influenced by genetic risk factors for
CARTS, factoring in other non-AD brain pathologies. This requires a seasoned, multidisciplinary team with
expertise in NP, molecular biology, neuroimaging, “large data” analyses, and, in particular, statistical genomics.
The central hypothesis, based on considerable preliminary data, is that alleles modifying CARTS risk that were
discovered via candidate gene and genome-wide association studies (GWAS) are proxies for phenomena more
directly involved in disease pathogenesis. To test this hypothesis, the team will execute the following Specific
Aims: 1. Develop and validate a classification framework to analyze the genetic drivers of CARTS. The
proposed effort to optimize classification of CARTS for genotyping will test and validate a revised set of
pathology-based criteria to differentiate CARTS, AD-related TDP-43 pathology, and brain arteriolosclerosis (B-
ASC) to refine understanding of disease-defining “border zones.” Disease severity will be operationalized for use
as a quantitative trait, and rubrics for disease subtypes will be developed for correlation with genomic studies.
2. Construct a robust and harmonized ‘omics database and localize genetic regions influencing CARTS.
Genetics data augmented with rich NP endophenotypes will enable discovery and refinement of novel insights
regarding the mechanisms driving CARTS dementia. Large-scale datasets (NACC, ADGC, ADNI, ADSP, AMP-
AD) will be aggregated and harmonized to test the genetic drivers of clinical and NP-based CARTS
endophenotypes, prioritizing subtype-specific candidate genetic regions.
3. Develop a systems biology analytic pipeline that extends beyond DNA variation to establish and test
candidate functional molecular outcomes of specific gene variants/regions that are associated with
CARTS pathology. Most GWAS findings are not causal but rather proxies for true underlying genetic influences
of disease manifested through mechanisms that include (a) expression quantitative trait loci (eQTL), (b)
differential isoform splicing QTL (sQTL), (c) brain imaging QTL (iQTL), and (d) protein QTL (pQTL). These will
be detected with recently developed statistical methodologies. Successful completion of the aims will produce
mechanistic insights into CARTS, potentially leading to new therapeutics. The proposed studies are distinct from
prior efforts, exploit...

## Key facts

- **NIH application ID:** 9926199
- **Project number:** 5R56AG057191-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** David William Fardo
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $525,141
- **Award type:** 5
- **Project period:** 2019-05-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926199

## Citation

> US National Institutes of Health, RePORTER application 9926199, Genomic Architecture of a Key Alzheimer's Disease Mimic: CARTS (5R56AG057191-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9926199. Licensed CC0.

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