# Evaluation of Brain and Cognitive Changes in Older Adults with MCI Taking Lithium to Prevent Alzheimer Type Dementia

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $1,005,414

## Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in adults 65 years and older. Unchecked, the
disease will reach epidemic proportions in the United States and worldwide by 2050, and presently, there is no
intervention that has shown a clear effect on AD progression. Over the past several years, there has been
increasing interest in repurposing the use of lithium for diseases involving neurodegeneration. Lithium treatment
has been associated with neurogenesis in the hippocampus, up-regulation of important neurotrophic factors such
as B-cell lymphoma 2 (Bcl-2) and brain-derived neurotrophic factor (BDNF), and inhibition of glycogen synthase
kinase 3 (GSK-3) isoforms α and β. In particular, GSK-3α interacts with gamma-secretase playing a critical role
in the conversion of amyloid precursor protein (APP) to amyloid-beta (Aβ); lithium has been shown to reduce Aβ
production and memory deficits in AD transgenic mouse models. GSK-3β phosphorylates tau, a critical step in
the formation of neurofibrillary tangles, and lithium has been shown to reduce tau phosphorylation in vivo and in
vitro. That lithium may alter the AD trajectory is supported by numerous observational reports showing delay of
dementia onset in those treated with it. However, the results of the few human lithium trials conducted have been
mixed. Additional research is needed to determine whether lithium has a role as an anti-dementia agent. In
contrast to previous studies, we will implement an RCT with a more integrative, comprehensive approach than
done before involving state-of-the-art ultra-high field (7T) human MRI, neurocognitive assessment, and blood-
and CSF- based biomarker measurement to investigate the role of lithium as an anti-dementia agent. The specific
aim of this pilot-feasibility study is to examine the potential disease modifying properties of lithium in individuals
with mild cognitive impairment (MCI) in delaying conversion to dementia. The study will enroll and randomly
assign 80 individuals 60 years and older with MCI (amnestic type, single or multiple domain) to take lithium,
titrated to a maximally tolerated blood level (0.5 to 0.8 meq/L), or placebo for two years to assess lithium’s effects
on preserving cognition and delaying conversion to dementia. Participants will receive annual neurocognitive
assessment, blood- and CSF-based biomarker measurement, and 7T MR imaging of structural brain volumes
(e.g., hippocampal, total cortical gray). At baseline, all subjects will undergo PET imaging for Aβ. The following
hypotheses will be tested: H1: a) Participants randomized to take lithium for two years, compared to placebo,
will better maintain cognitive function, primarily in memory, which b) will be associated with changes in
biomarkers (e.g., GSK-3β, BDNF). H2: a) Participants randomized to take lithium, compared to placebo, will
have larger hippocampal volumes and lower total gray matter thinning, which b) will be associated with changes
in biomarkers an...

## Key facts

- **NIH application ID:** 10192622
- **Project number:** 5R01AG055389-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ariel Gerard Gildengers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,005,414
- **Award type:** 5
- **Project period:** 2017-06-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10192622

## Citation

> US National Institutes of Health, RePORTER application 10192622, Evaluation of Brain and Cognitive Changes in Older Adults with MCI Taking Lithium to Prevent Alzheimer Type Dementia (5R01AG055389-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10192622. Licensed CC0.

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