# KLOTHO and Resilience to Synaptic Dysfunction in Preclinical AD

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $777,480

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD), a progressive and debilitating neurological disorder of old age, is
clinically hallmarked by memory loss and neuropathologically by accumulation of Aβ plaques and
neurofibrillary tangles in the brain. Synaptic dysfunction has recently emerged as another early
key feature of AD; evidence suggests that synaptic density decreases up to 30% in preclinical
stages of AD and correlates more closely with cognitive deficits than Aβ pathology. Although age
is the single biggest risk factor for developing AD, the observation that even individuals at genetic
risk for AD or harboring AD neuropathology are able to remain cognitively normal as they age has
refocused research away from risk and underscored the need for investigations of the factors that
confer resilience in hopes of reducing disability and disease incidence. KLOTHO is dubbed an
anti-aging and longevity gene, and plays a key role in cellular metabolism, central nervous system
maturation, and synaptic plasticity. Critical to this proposal is that KLOTHO also seems to
enhance synaptic integrity and protects from neurodegeneration. Thus, this integrative, clinically
relevant project will rigorously investigate whether KLOTHO 1) confers resilience against age-
and AD-related synaptic dysfunction, and 2) modifies the relationship between such dysfunction
and cognitive decline both cross-sectionally and longitudinally. The proposed study will be
embedded within the robust framework of two well-characterized and longitudinally followed
cohorts of ~2,000 at-risk, late-middle-aged adults (the Wisconsin Registry for Alzheimer’s
Prevention [WRAP] and the Wisconsin Alzheimer’s Disease Research Center [WADRC]). All
participants are already genotyped for KLOTHO and have been cognitively phenotyped for up to
20 years under WRAP/WADRC. The R01 will provide resources for a subset of these participants
(N=150) to undergo multimodal biomarker assessment ([11C]UCB-J PET imaging, CSF and
blood-based biomarkers) at baseline and 2-year follow-up. Completion of this study has the
potential to provide invaluable insights and druggable targets for forestalling brain/cognitive
deterioration with advancing age or AD pathological burden.

## Key facts

- **NIH application ID:** 10814796
- **Project number:** 5R01AG077507-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Ira Frahmand
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $777,480
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814796

## Citation

> US National Institutes of Health, RePORTER application 10814796, KLOTHO and Resilience to Synaptic Dysfunction in Preclinical AD (5R01AG077507-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10814796. Licensed CC0.

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