Lithium As a Treatment to Prevent Impairment of Cognition in Elders (LATTICE)

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

Alzheimer's disease (AD) is the most common cause of dementia in adults 65 years and older. AD leads to a complete loss of memory and independent function, and presently there is no cure. Many studies suggest that lithium treatment may delay dementia onset or slow its progression. However, more research is needed to understand the extent of its anti-dementia properties if it will be deployed broadly in the general population. This study will examine whether lithium has anti-dementia properties in older adults who have mild cognitive impairment and are at risk of becoming demented.

Study Overview

• Status: Completed
• Conditions: Mild Cognitive Impairment
• Intervention / Treatment: Drug: Lithium Carbonate; Drug: Placebo oral capsule

Detailed Description

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).

The following amendments were made with entering the results to correct mistakes in the original registration:

1. Primary Outcome 6 was corrected to Cerebral Cortical Gray Matter Volume.
2. Primary Outcome 7 was correct to Hippocampal Volume.
3. The outcome measure "Change From Baseline Brain Integrity Measures Over 2 Years as Measured by Structural Imaging (7T MRI)" was corrected to Other Pre-Specified Outcome Measure(s).
4. The outcome measure "NIH Toolbox" was corrected to PostHoc Outcome Measure(s).

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lithium carbonate; Lithium carbonate will be initiated at 150 mg per day and increased based on blood levels until a steady blood level between 0.6 and 0.8 meq/L is achieved. Participants will continue at the dose achieved for 2 years with quarterly monitoring.	Drug: Lithium Carbonate; See lithium carbonate arm
Placebo Comparator: placebo; Matching placebo will be initiated and increased based on pretend blood levels. Participants will take placebo for 2 years with quarterly monitoring.	Drug: Placebo oral capsule; See placebo arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
California Verbal Learning Test II	California Verbal Learning Test II. Long-delay free recall. Scores range from 0 - 16; higher means better.	Year 1 and Year 2
Brief Visuospatial Memory Test - Revised	Brief Visuospatial Memory Test - Revised. Delayed Recall. Scores range from 0 - 12; higher means better.	Year 1 and Year 2
Preclinical Alzheimer Cognitive Composite Composed of Memory and Other Cognitive Tests	Cognitive testing measures with a composite of memory, executive function, processing speed, activities of daily living, and general cognition tests. Values are Z-scores. Higher values mean better cognition. A Z-score of 0 represents the population mean, while Z-scores of ±1 capture approximately 68% of the data around the mean and Z-scores of ±2 capture approximately 95% of the data in a normal distribution.	Year 1 and Year 2
Glycogen Synthase Kinase-3 Beta (GSK-3β) Activity	Values of blood-based biomarkers	Year 1 and Year 2
Brain-derived Neurotrophic Factor	Brain-Derived Neurotrophic Factor (BDNF) supports neuron survival and growth; reduced levels linked to neurodegeneration. Nucleic Acid-Linked Immuno-Sorbent Assay (NULISA) measures BDNF using nucleic acid-tagged antibody pairs recognizing different BDNF epitopes. Sequential capture/purification via polyA/biotin tails, then ligation and next-generation sequencing quantification achieves attomolar sensitivity alongside hundreds of other proteins.	Year 1 and Year 2
Cerebral Cortical Gray Matter Volume	Cerebral cortical gray matter volume as measured by structural imaging (7T MRI) corrected for age, sex, and intracranial volume	Year 1 and Year 2
Hippocampal Volume	Hippocampal volume values as measured by structural imaging (7T MRI) corrected for age, sex, and intracranial volume	Year 1 and Year 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebrospinal Fluid Phospho Tau Level (CSF)	Cerebrospinal fluid phospho tau levels	Year 1 and Year 2

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain Integrity as Measured by Structural Imaging (7T MRI)	Exploratory analyses of additional measures of brain integrity, such as lower level of microbleeds, higher white matter integrity, or better network connectivity	Year 1 and Year 2

Collaborators and Investigators

• Sponsor: Ariel Gildengers, MD
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Ariel Gildengers, MD, University of Pittsburgh

Publications and helpful links

General Publications

• Gildengers AG, Ibrahim TS, Zeng X, Aizenstein HJ, Alkhateeb SK, Anderson SJ, Chu C, Diaz JL, Emanuel JE, Karikari TK, Li J, Lopez OL, Lopresti BJ, Royse SK, Sajewski AN, Santini T, Weinstein AM, Wu M, Butters MA. The LATTICE Study: Design of a pilot feasibility randomized controlled trial of lithium to delay cognitive decline in mild cognitive impairment. Alzheimers Dement (N Y). 2025 Jun 11;11(2):e70112. doi: 10.1002/trc2.70112. eCollection 2025 Apr-Jun.

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2018
• Primary Completion (Actual): August 6, 2024
• Study Completion (Actual): August 6, 2024

Study Registration Dates

• First Submitted: April 24, 2017
• First Submitted That Met QC Criteria: June 9, 2017
• First Posted (Actual): June 14, 2017

Study Record Updates

• Last Update Posted (Estimated): September 11, 2025
• Last Update Submitted That Met QC Criteria: August 26, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: MRI; imaging; amyloid; plaques; tau; Alzheimer's Disease; PET; Mild Cognitive Impairment; MCI; Dementia; Prevention; Alzheimer; Memory; Cognition; Lithium; Thinking; tangles
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Pathological Conditions, Anatomical; Metabolic Diseases; Neurocognitive Disorders; Cognition Disorders; Tauopathies; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Frontotemporal Lobar Degeneration; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Cognitive Dysfunction; Alzheimer Disease; Dementia; Frontotemporal Dementia; Plaque, Amyloid; Substandard Drugs; Pharmaceutical Preparations; Inorganic Chemicals; Alkalies; Carbon Compounds, Inorganic; Carbonates; Carbonic Acid; Lithium Compounds; Lithium Carbonate; Counterfeit Drugs
• Other Study ID Numbers: PRO17030527; R01AG055389-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified participant data will be shared with the National Cell Repository for Alzheimer's Disease (NCRAD).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes