# Hypothalamic and metabolic dysfunction in Alzheimer's disease

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $423,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly with currently no cure or effective
disease-modifying therapy. The pathogenesis of AD is unclear; however, a leading hypothesis is that
accumulation of amyloid-beta (Aβ) peptides derived from the amyloid precursor protein is one of the earliest
pathological events resulting in neuronal dysfunction, at least in part by dysregulating intracellular Ca2+
homeostasis, and disruption of neural networks culminating in dementia. While cognitive impairment is the major
manifestation of AD, non-cognitive manifestations such as unintentional body weight loss often occurs prior to
the cognitive decline. Furthermore, weight loss in AD correlates with worsening disease progression and
increased mortality, while weight gain is protective. Collectively, this suggests that brain regions such as the
hypothalamus that regulate body weight and systemic metabolism may be selectively vulnerable to Aβ early in
the pathogenesis of AD during the presymptomatic or preclinical stages. However, the cellular and molecular
mechanisms underlying the early systemic metabolic dysfunction in AD have remain largely unexplored.
Therefore, the goal of this application is to test the hypothesis that hypothalamic networks regulating systemic
metabolism are selectively vulnerable to Aβ pathology and contribute to the early pathogenesis of AD. We will
use a “bench-to-bedside” strategy using state-of-the-art molecular, neurophysiological, imaging, and genomic
approaches in genetic mouse models, and verify key findings in clinically relevant human studies. We will test
the following working hypotheses: (a) disruption of intracellular Ca2+ homeostasis by Aβ is an early pathological
event leading to dysfunction of leptin-responsive hypothalamic NPY/AgRP neurons; (b) Aβ causes disruption of
hypothalamic networks regulating systemic metabolism; and (c) central leptin signaling dysfunction is an early
manifestation of human subjects with Alzheimer’s disease. The findings from this project will shed light on the
mechanisms underlying early selective vulnerability in the hypothalamic network regulating systemic metabolism
and identify the cell types affected, thereby filling a knowledge gap in our understanding of one of the earliest
clinical manifestations of AD.

## Key facts

- **NIH application ID:** 10126469
- **Project number:** 1R01AG070868-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Makoto Ishii
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,750
- **Award type:** 1
- **Project period:** 2021-01-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126469

## Citation

> US National Institutes of Health, RePORTER application 10126469, Hypothalamic and metabolic dysfunction in Alzheimer's disease (1R01AG070868-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10126469. Licensed CC0.

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