# Role of Lifespan Intervention on the Regulation and Progression of Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $773,850

## Abstract

Project Summary/Abstract
Our long-term goal is to identify therapeutic agents that can prevent the pathogenesis of Alzheimer’s disease
(AD). The number of AD cases is rising dramatically worldwide, and there is an urgent need to develop new
therapies that are more efficacious than the four currently approved drugs for AD which provide only modest
symptomatic relief. Every clinical trial to date has failed to demonstrate disease-modifying efficacy for AD, which
may in part be due to our limited understanding of the mechanisms that precede the pathogenesis of AD, and
that are distinct from normal healthy aging. The overall aims of our proposal are to further understand the
mechanisms underlying dysregulation of the autophagy-inflammation network that becomes progressively
dysregulated with age, and accelerated by pathological conditions. Systemic inflammation is a biomarker of this
dysregulation, as exemplified by its prevalence in many aging-related disorders including cardiovascular disease,
diabetes, cancers, and neuroinflammation in neurodegenerative disorders such Alzheimer’s disease (AD). We
hypothesize that mechanisms which drive systemic inflammation are common to both the biology of aging and
AD and propose that interventions which target the shared feature of systemic inflammation, via regulation of
the autophagy-inflammation network, may have potential as therapeutic agents for the prevention of conversion
to disease pathogenesis in AD, as well as improve healthspan and longevity in aging populations. For this
proposal we will use a combination of genetic and pharmacological tools to understand which brain specific cell
types may be involved in the regulation of the autophagy-inflammation network via both mTOR dependent and
mTOR-independent mechanisms that modulate inflammation. Findings from our studies will provide mechanistic
insights at a cellular level and innovative therapeutic strategies for further research. Specifically, we will
investigate the individual cell types that contribute to the neuroprotective effects of mTOR inhibition in
progressive AD, and confirm and extend the data on the beneficial effects of lifespan and healthspan in sporadic
AD with prophylactic treatment of rapamycin. Critically, since age and genetics are the leading risk factors for
AD, we will evaluate interventions in preclinical model systems that incorporate both aging and genetic risk
factors for AD. We will therefore test the role of direct manipulation of AMPK on modulation of lifespan and
healthspan in normal aging and in AD susceptible models, and the beneficial role of MAG lipase inhibition in
normal healthy aging and in the pathogenesis of AD in comparison to the effects of rapamycin in a mouse model
of late onset AD.

## Key facts

- **NIH application ID:** 9969650
- **Project number:** 1R01AG067289-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Stacey J Rizzo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $773,850
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969650

## Citation

> US National Institutes of Health, RePORTER application 9969650, Role of Lifespan Intervention on the Regulation and Progression of Alzheimer's Disease (1R01AG067289-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9969650. Licensed CC0.

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