Lithium As a Treatment to Prevent Impairment of Cognition in Elders

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 re-purposing
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 Randomized Controlled Trial (RCT) with a
more integrative, comprehensive approach than done before involving state-of-the-art
ultra-high field (7T) human Magnetic Resonance Imaging (MRI), neurocognitive assessment, and
blood- and Cerebrospinal Fluid (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 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 MRI of structural brain volumes (e.g., hippocampal, total cortical gray). At baseline,
all subjects who are able will undergo Positron Emission Tomography (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 and c) better cognitive function, primarily in memory. The exploratory aim
examines whether lithium is related to additional markers of enhanced brain integrity (e.g.,
lower level of microbleeds, higher white matter integrity, better network connectivity, or
decreased CSF phospho tau levels).

Inclusion Criteria:

1. 60 years or older

2. Diagnosis of Mild Cognitive Impairment

Exclusion Criteria:

1. Major psychiatric illness (mild psychiatric illness may be included)

2. Major neurologic illness (e.g., multiple sclerosis)

3. Contraindication to lithium (e.g., renal insufficiency)

4. Unable to complete neuropsychological testing due to non-remediable impairment (e.g.,
blindness)