# Clinical Manipulation of Testosterone and Its Impact on Dementia and Health

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2021 · —

## Abstract

The number of veterans with Alzheimer’s disease (AlzD) is dramatically increasing. Testosterone is
hypothesized to have an important role in risk, onset, and progression of AlzD in men. Testosterone deficiency
prior to AlzD onset can promote AlzD pathophysiology during the preclinical phase when interventions may
have the greatest success. Androgen deprivation therapy (ADT) for prostate cancer and testosterone
replacement therapy (TRT) for age-related hypogonadism that directly target testosterone levels provide
valuable opportunities to examine the impact of this androgen on the risk of developing AlzD, its prodromal
condition mild cognitive impairment (MCI), and co-morbid health conditions. In the proposed study, we will
utilize genetic and clinical data from the Million Veteran Program (MVP) to determine the impact of low
testosterone, ADT, and TRT on the relative risk for MCI and AlzD. We hypothesize that the long-term impact
of low testosterone, ADT, and TRT will be regulated by polygenic risk for AlzD and variation in the androgen
receptor (AR) gene. These genetic factors represent critical, pre-existing markers of disease vulnerability and
hormone sensitivity that have yet to be incorporated into research on protective and beneficial effects of
testosterone on cognition and health. In our study, we will first determine if the risks of MCI, AlzD, and co-
morbid medical disorders that promote dementia are increased by low testosterone levels in the MVP cohort.
Next, we will determine if the clinical manipulation of testosterone levels is associated with differences in risks
for MCI and AlzD. We hypothesize that individuals who undergo ADT will be at increased risk for MCI, AlzD
and co-morbid health conditions relative to men with a history of prostate cancer but who have not been
treated with ADT. We further hypothesize that men who receive TRT will be at decreased risks for these same
conditions relative to men with low testosterone who do not receive hormone replacement therapy. We will
next test whether pre-existing genetic risk for AlzD modifies the impact of testosterone-centered treatments on
MCI and AlzD. We hypothesize that the observed effects of ADT and TRT on the cognitive and health
outcomes will be greater in individuals at greater genetic risk for AlzD. Finally, we will determine whether
genetically driven changes in androgen sensitivity due to CAG repeat length or ligand and DNA binding domain
mutations regulate the long-term risks and benefits of ADT and TRT. We hypothesize that a more sensitive
variant of the AR gene will confer greater risk for MCI and AlzD following ADT. Furthermore, we hypothesize
that more androgen-sensitive individuals will benefit more from TRT, and will therefore show a reduced risk for
MCI and AlzD. With its large sample size, extensive genetic data, and curated medical record data, the MVP
represents an ideal resource with which to explore impact of testosterone-centered treatments on dementia
risk,...

## Key facts

- **NIH application ID:** 9934863
- **Project number:** 5I01CX001727-02
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** RICHARD L HAUGER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934863

## Citation

> US National Institutes of Health, RePORTER application 9934863, Clinical Manipulation of Testosterone and Its Impact on Dementia and Health (5I01CX001727-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934863. Licensed CC0.

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