Lithium for Alzheimers disease?
NPR summary, not technical
Aug 28, 2025 5:10 PM EST
A recent study from Harvard Medical School asks whether the element lithium might be a key factor in whether someone develops Alzheimer’s disease.
Led by Dr. Bruce Yankner, professor of genetics and neurology at Harvard Medical School, the almost-decade long study says it is the first to show that lithium is found naturally in the brain in small amounts and suggests that the element plays an important role in the prevention and treatment of cognitive decline.
The study published in Nature this month found a link between lithium deficiency in the brain and an increase in amyloid plaques and tau tangles — known contributors to the development of Alzheimer’s disease. In trials on mice, researchers found they were able to reverse the disease, prevent brain cell damage and restore memory loss through a small dosage of a lithium compound called lithium orotate.
Proposed of of action
https://pmc.ncbi.nlm.nih.gov/articles/PMC12065699/
The primary molecular targets of lithium include glycogen synthase kinase-3 beta (GSK-3β), inositol monophosphatase (IMPase), and the mammalian target of rapamycin (mTOR). Lithium acts as a potent dual inhibitor of GSK-3β, a proline-directed serine-threonine kinase that serves as a crucial hub in intracellular signaling (Fenech et al. 2023; Mendes et al. 2009; Monaco et al. 2018) due to its numerous regulatory loops and downstream effects (Peineau et al. 2008). The inhibition of GSK-3β prevents the phosphorylation of key substrates, including glycogen synthase, microtubule-associated proteins such as MAP1B and Tau, presenilin-1, CREB, and beta-catenin. This interference affects several physiological processes, including energy metabolism, neural cell development, neuronal plasticity, and gene regulation (Klein and Melton 1996; Lau et al. 1999). Overactive GSK-3β significantly contributes to the pathogenesis of AD by promoting the excessive production of amyloid-β peptide and the hyperphosphorylation of Tau, both of which are linked to the formation of senile plaques and neurofibrillary tangles—key pathological features of AD (Hooper et al. 2008). Furthermore, lithium has been shown to enhance the synthesis and release of brain-derived neurotrophic factor (BDNF) (De-Paula et al. 2016a, b; Leyhe et al. 2009), thereby supporting neuronal communication, survival, and synaptic plasticity, all essential for preserving cognitive health. Additionally, lithium is known to enhance mitochondrial function (Singulani et al. 2021) and assist in telomere maintenance (Cardillo et al. 2018; Martinsson et al. 2013), thus reducing telomere shortening and promoting cellular integrity.
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Original Investigation
Low-Dose Lithium for Mild Cognitive Impairment
A Pilot Randomized Clinical Trial
Ariel G. Gildengers, MD1; Tamer S. Ibrahim, PhD2; Stewart J. Anderson, PhD3 et al
Author Affiliations
Article Information
JAMA Neurol
Published Online: March 2, 2026
doi: 10.1001/jamaneurol.2026.0072
related iconRelated Articlesfigure iconFiguresattach iconSupplemental Content
Key Points
Question Can low-dose lithium treatment delay cognitive decline in older adults with mild cognitive impairment?
Findings In this pilot randomized clinical trial of 80 participants, none of the 6 coprimary outcomes reached the prespecified significance threshold; for verbal memory, scores declined by 1.42 points annually in the placebo group vs 0.73 points in the lithium group, which did not meet the prespecified threshold for multiple comparisons. Exploratory analyses suggested possible larger effects among amyloid-positive participants.
Meaning This pilot trial provides effect size estimates and methodological insights to inform adequately powered confirmatory trials of low-dose lithium in older adults with amyloid-positive mild cognitive impairment.
Abstract
Importance Lithium deficiency may contribute to Alzheimer disease pathogenesis. No randomized clinical trial has examined lithium’s effects on cognition, neuroimaging, and plasma biomarkers in mild cognitive impairment (MCI).
Objective To examine the feasibility, safety, and preliminary efficacy of lithium carbonate for delaying cognitive decline in older adults with MCI.
Design, Setting, and Participants This single-site, randomized, double-blind, placebo-controlled pilot feasibility clinical trial was conducted at the University of Pittsburgh School of Medicine from February 2018 to August 2024, with 2-year follow-up. Analyses used linear mixed-effects models in the intention-to-treat population. Adults aged 60 years or older with MCI who were free of major psychiatric or neurologic illness and contraindications to lithium were included. Of 170 individuals assessed, 83 were randomized (41 lithium vs 42 placebo), with 80 starting treatment (41 lithium vs 39 placebo). Data were analyzed from August 2024 to December 2025.
Intervention Daily low-dose lithium carbonate or placebo for 2 years.
Main Outcomes and Measures Six prespecified coprimary outcomes included cognitive performance (California Verbal Learning Test-II [CVLT-II] delayed recall, Brief Visuospatial Memory Test-Revised, preclinical Alzheimer cognitive composite), hippocampal volume, cortical gray matter volume, and brain-derived neurotrophic factor.
Results Among 80 participants (mean [SD] age, lithium: 72.93 [8.77] years; placebo: 71.22 [6.47] years; 56% female), none of the 6 coprimary outcomes met the prespecified significance threshold. Mean (SD) CVLT-II baseline scores were 7.95 (3.4) for lithium and 7.90 (3.9) for placebo; scores declined 1.42 points annually in the placebo group vs 0.73 points in the lithium group (difference, 0.69 points per year; 95% CI, 0.01-1.37; P = .05). Hippocampal and cortical volumes showed a decline over time in both groups, but no significant treatment × time interactions. Serious adverse events occurred in 12 of 41 (29%) receiving lithium vs 9 of 39 (23%) receiving placebo; none were definitely treatment related. One death occurred in the placebo group. Common adverse events included increased creatinine levels (12 of 41 [29%] with lithium vs 12 of 39 [31%] with placebo), diarrhea (12 of 41 [29%] vs 6 of 39 [15%]), tiredness (12 of 41 [29%] vs 6 of 39 [15%]), and tremor occurrence (10 of 41 [24%] vs 6 of 39 [15%]).
Conclusions and Relevance This pilot randomized clinical trial established feasibility, confirmed safety and tolerability, and generated effect size estimates for future trials of low-dose lithium in MCI. None of the coprimary outcomes met the prespecified significance threshold.
Trial Registration ClinicalTrials.gov Identifier: NCT03185208
Introduction
Lithium deficiency, resulting from its sequestration by amyloid plaques, may underlie the multisystem neurodegeneration of Alzheimer disease (AD).1 This finding provides a framework for understanding evidence that lithium can protect against dementia in studies ranging from cellular and animal experiments to human clinical trials to epidemiological investigations.2-12 A 2015 systematic review and meta-analysis of the 3 randomized clinical trials (RCTs) available at that time, aggregating 232 participants with AD and mild cognitive impairment (MCI), found that lithium significantly decreased cognitive decline compared with placebo.13 While not all studies have shown that lithium is neuroprotective, the evidence suggests that lithium deficiency may represent a modifiable risk factor for AD. A key mechanism underlying lithium’s neuroprotection appears to be its inhibition of GSK-3α/β.1,14 Lithium also increases brain-derived neurotrophic factor (BDNF) expression and activity, which may additionally contribute to neuroprotection.14
To our knowledge, no study has examined lithium’s human effects in a prospective RCT that combines cognitive assessment with neuroimaging and plasma biomarkers. The methods used in the Lithium as a Treatment to Prevent Impairment of Cognition in Elders (LATTICE) pilot-feasibility RCT have been reported.15 Here, we report the main outcomes of the study examining the potential disease-modifying properties of lithium in individuals with MCI in delaying conversion to dementia. The study addressed the following hypotheses: (1) participants randomized to take lithium for 2 years, compared with placebo, will better maintain cognitive function, primarily in memory, which will be associated with changes in GSK-3β activity and BDNF levels; and (2) participants randomized to take lithium for 2 years, compared with placebo, will have larger hippocampal volumes (ie, lower rate of reduction) and lower total gray matter thinning, which will be associated with changes in GSK-3β activity and BDNF levels and better cognitive function, primarily in memory.
Methods
Study Design
LATTICE was a single-site, randomized clinical trial conducted at the University of Pittsburgh School of Medicine. The University of Pittsburgh Human Research Protection Office approved the protocol (Supplement 1). The study was overseen by an independent Data Safety and Monitoring Board (DSMB) that reviewed and approved study procedures before enrollment began on September 1, 2017. The DSMB met approximately every 6 months postenrollment and approved all proposed study modifications and requests for study continuation. Protocol modifications made during trial conduct are detailed in our published methodology report.15 There was no formal patient or public involvement in the design, conduct, or reporting of this research. All participants provided written informed consent. This study was conducted and reported according to CONSORT guidelines.
Participants
Eligibility required (1) age 60 years or older; (2) diagnosis of MCI per Petersen criteria, operationalized as cognitive performance 1 to 2 SDs below the age-adjusted and education-adjusted norms in at least 1 cognitive domain; (3) preserved activities of daily living; (4) absence of major psychiatric illness per Mini-International Neuropsychiatric Interview16 (MINI) structured interview; (5) absence of major neurologic illness; (6) no contraindications to lithium; and (7) ability to complete neuropsychological testing (excluding those with nonremediable sensory or motor impairments, such as blindness). Race and ethnicity were self-reported by participants using categories defined by the National Institutes of Health (NIH). Race categories included Asian, Black or African American, and White. Ethnicity was reported separately as Hispanic or Latino or not Hispanic or Latino. Race and ethnicity were assessed to characterize the study sample and to meet NIH requirements for reporting demographic characteristics in clinical research.
Recruitment and Screening Methods
Recruitment involved senior center presentations, educational outreach, internet advertising, University of Pittsburgh Alzheimer’s Disease Research Center partnerships, and primary care collaborations. The occurrence of the COVID-19 pandemic necessitated transitioning from in-person to digital and print recruitment methods. Initial screening helped identify candidates for comprehensive evaluation by excluding potential participants who were clearly cognitively normal or severely cognitively impaired.
Before the COVID-19 pandemic, the team conducted screening in person using 3 assessments: Modified Mini-Mental State Examination (3MS),17 Trail Making Test Parts A and B (TMT A/B),18 and Quick Mild Cognitive Impairment screen (Qmci).19 Participants qualified for a comprehensive evaluation if they scored beyond 1 SD below expected performance on any single test. Exclusion criteria were performance exceeding 2 SDs below expected on 2 or more tests, or 3MS scores less than 84. The Qmci was age adjusted and education adjusted, while TMT norms incorporated age, education, sex, and race factors.
During the COVID-19 pandemic, screening shifted to telephone assessments using the modified Telephone Interview for Cognitive Status (mTICS)20 and Hayling Sentence Completion Test (HSCT).21 Participants qualified for comprehensive evaluation with mTICS scores in the MCI range (19-38 of 50) or HSCT scaled scores of 4 or less on any component.
Those who qualified for comprehensive evaluation underwent in-person assessment with the MINI to exclude major psychiatric illness and the medication management portion of the Performance Assessment of Self-Care Skills (PASS)22 to confirm safe medication handling ability. Eligible participants then provided written informed consent in accordance with the Helsinki protocol and completed a comprehensive neuropsychological evaluation.
Participants underwent comprehensive neuropsychological evaluation, including Clinical Dementia Rating (CDR)23; Everyday Cognition Scale (ECog),24 with both self and informant reports; the Wide Range Achievement Test-4th edition (WRAT-4)25 Reading subtest; Boston Naming Test26; Clock Drawing Test27; the Wechsler Adult Intelligence Scale (WAIS)-IV Digit Span subtest28; the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS),29 using 2 counterbalanced alternate forms to minimize practice effects; and select Delis-Kaplan Executive Function System (D-KEFS)30 subtests (Verbal Fluency, Trail Making Test, and Color Word Interference). Functional assessment used the PASS subtests of shopping, medication management, and bill payment.31 Trained psychometrists administered the battery of assessments, lasting 4 to 5 hours with breaks. If the participant entered the RCT, these tests were repeated at 1 and 2 years, excluding the WRAT-4 Reading, to track cognitive status and determine whether participants reverted to normal cognition, remained stable with MCI, or progressed to dementia.
MCI diagnosis required multidisciplinary adjudication (neuropsychologist, neurologist, geriatric psychiatrist) using National Alzheimer’s Coordinating Center/Revised Petersen criteria: (1) subjective cognitive concern (Ecog), (2) objective impairment 1 to 2 SDs below expectation on 2 tests within 1 domain or 3 tests across domains, (3) preserved functional independence (CDR and PASS), and (4) absence of dementia.32,33 Performances were standardized using demographic-adjusted norms. Participants who met all inclusion criteria, had no exclusion criteria, and agreed to enter the RCT received PET imaging to measure brain amyloid. Participants received modest stipends for completing study assessments.
Randomization and Masking
Participants were randomly assigned (1:1) to lithium or placebo using permuted blocks with even-numbered block sizes, ranging from 2 to 16. Randomization was stratified by the presence of amyloid-beta (Aβ) plaque (positive, negative, or unknown). The study statistician (S.J.A.) generated the randomization sequence using the sample function in R statistical software. He had no role in enrollment or treatment assignment. The data manager assigned participants to trial groups and had no direct contact with participants.
Procedures
Participants who entered the RCT received either a 150-mg or 300-mg dose of lithium carbonate or placebo in identical over-encapsulated pills. Participants started 1 pill daily or every other day, based on general medical status and concomitant medications. Doses were adjusted weekly to the maximum tolerated dose and decreased if needed to achieve tolerability. All participants underwent lithium blood level monitoring. An unmasked team member obtained lithium level results and reported either actual values (lithium group) or algorithm-generated false values (placebo group) to the masked research team, maintaining treatment allocation concealment except during medical emergencies. Participants were seen weekly during initial titration, then roughly every 3 months through study completion. eTable 1 in Supplement 2 displays the assessments.
Neurocognitive Assessment
The RCT cognitive assessment battery included (1) an adapted preclinical Alzheimer cognitive composite (PACC)34 consisting of the 3MS, RBANS delayed list recall, RBANS coding, D-KEFS Trail Making condition 4, and PASS cognitive-instrumental activities of daily living (IADL) tasks; (2) the Brief Visuospatial Memory Test-Revised (BVMT-R)35; and (3) the California Verbal Learning Test-II (CVLT-II).36 The BVMT-R and CVLT-II were administered after MCI diagnosis was confirmed and before starting the study medication.
Magnetic Resonance Imaging
Ultrahigh-field 7-T magnetic resonance imaging (MRI) was conducted using an MRI scanner (MAGNETOM; Siemens) with radio frequency coil hardware (Tac G1 and G2/Tic Tac Toe) that delivers whole-brain homogenous imaging at 7T.37,38 Longitudinal baseline-weighted images (0.75-mm isotropic resolution) were processed using FreeSurfer, version 8 with a pipeline adapted for 7-T images, including bias and gradient distortion corrections.39 Manual quality assurance was performed. Participants or data points with excessive motion (2 participants at all 3 time points: baseline [T1], year 1 [T2], and year 2 [T3]) or incidental findings (1 participant at all 3 time points and 1 participant at time point 2) were excluded. Morphometrics were adjusted for age at baseline, sex, intracranial volume, and follow-up duration.
Positron Emission Tomography Imaging
For concurrent imaging with positron emission tomography (PET) and MRI, we used a Biograph mMR scanner (Siemens) with simultaneous 3-T capability. PET imaging with [11C]-labeled Pittsburgh Compound-B (PiB; 15.0 mCi nominal) was used to assess cerebral Aβ plaque burden (acquired 50 to 70 minutes postinjection), and concurrent T1-weighted magnetization-prepared rapid gradient-echo and Dixon sequences were collected for PET image sampling and attenuation correction. FreeSurfer-based analysis yielded standardized uptake value ratios (SUVRs) for a composite 9-region global index of Aβ burden (GBL9). Aβ positivity (Aβ+) was defined as GBL9 SUVR of 1.346 or greater based on sparse k-means clustering from 61 cognitively normal participants.40,41
Blood Sampling
Safety monitoring included a basic metabolic panel and thyroid-stimulating hormone at T1, T2, and T3, and an electrocardiogram at baseline and follow-up as needed; urinalysis and urine osmolality at baseline and T3; and lithium levels at biweekly titration visits and quarterly visits. Weekly safety laboratory review monitored kidney, thyroid, and parathyroid function. Biomarker blood collection occurred at entry, then every 6 months for apolipoprotein E (APOE) genotype (baseline only), to measure BDNF using a NULISAseq CNS Disease Panel 120 assay (Alamar Biosciences).42
Additional Assessments
Medical comorbidity (Cumulative Illness Rating Scale-Geriatric [CIRS-G]),43 cardiovascular risk (Framingham Stroke Risk Profile [FSRP]),44 mood (Patient Health Questionnaire-9 [PHQ-9]),45 physical activity (Physical Activity Scale for the Elderly [PASE]),46 drug compliance (Brief Adherence Rating Scale [BARS]),47 and adverse effects (Udvalg for Kliniske Undersøgelser [UKU] Side Effect Rating Scale48 and spontaneous reporting of adverse effects [SRSE]) were assessed. Anticholinergic burden was calculated by summing medication scores (0 indicates no activity, 1 indicates serum activity without cognitive effects, 2 indicates clinically relevant activity, 3 indicates high potency).49
Outcomes
Six coprimary outcomes were prespecified: cognitive measures including overall cognitive function (PACC), verbal memory (CVLT-II delayed recall), and visual memory (BVMT-R delayed recall); neuroimaging measures including hippocampal volume and total cerebral cortical gray matter (cortex volume); and 1 plasma biomarker (BDNF). GSK-3 activity was originally planned as an additional biomarker outcome, but the assays failed quality control and could not be assessed. We assessed compliance, safety, and adverse events with the BARS and UKU adverse effect rating scale and SRSE.15
As required by the National Institute on Aging, we impaneled an external DSMB with expertise in clinical trials, geriatrics, AD and AD-related dementias, and statistics. Investigators met with the DSMB semiannually. Participants’ clinical status was reviewed weekly, and all serious adverse events were reported to the DSMB within 24 hours.
Statistical Analysis
The statistical analysis plan was specified previously and approved by the DSMB before enrollment in September 2017 (eMethods in Supplement 2). Data were analyzed from August 2024 to December 2025.
Power calculations based on 80 randomized participants (64 completers with 32 per group) with 3 measurement time points indicated that by using a 2-sided significance level of .05 and 80% power, we could detect a medium effect size (Cohen d = 0.57) when observations had a 0.5 correlation across time. We also computed the effect size for a 2-sided significance level of .01, a more conservative alpha for testing multiple outcomes, and a power of 80%, resulting in an effect size that ranged from 0.54 to 0.72 as the correlation between repeated observations ranged from 0.1 to 0.6. We used the .01 threshold for our primary analyses.
Analyses began with descriptive methods and 2-sample tests (t tests, Wilcoxon tests, χ2 tests) to compare the intervention and control groups. Baseline characteristics and outcome data were compared using t tests, rank sum tests, or χ2 tests as appropriate. All tests were 2-sided. We report uncorrected P values and note which findings meet the P < .01 threshold. Primary longitudinal analyses employed linear mixed-effects trajectory models, including time (as a continuous variable using actual sampling times), group, and time-by-group interaction terms. Intercept and slope parameters were assumed to have random effect components. Of primary interest was the treatment × time interaction effect, evaluating whether decline rates differed between groups. Missing longitudinal outcomes were handled under the missing at random assumption using mixed-effects models.
Prespecified completer analyses were performed using simple t tests to compare treatment groups according to individuals’ change in outcome values between baseline (time point 1) and study end (time point 3). The completer analyses included a preplanned subgroup analysis of participants who were Aβ+ based on PiB-PET. Statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc) and statistical graphics through R, version 4.4.2 (R Foundation for Statistical Computing).
Results
Between February 2, 2018, and August 6, 2022, 170 individuals were assessed for eligibility. Of these, 12 withdrew, and 75 met exclusion criteria. Thus, 83 participants were randomized (41 lithium and 42 placebo). Three of the 83 randomized participants withdrew before starting the trial, leaving 80 (41 lithium and 39 placebo) (Figure 1). Among participants in the lithium group, the mean (SD) age was 72.93 (8.77) years, with 23 female (56%) and 18 male (44%); among those in the placebo group, the mean (SD) age was 71.22 (6.47) years, with 22 female (56%) and 17 male (44%). The trial was completed as planned with no early stopping.
Figure 1. CONSORT Diagram of Participant Flow in the LATTICE Trial
CONSORT Diagram of Participant Flow in the LATTICE Trial(opens in new tab)
Participant flow through screening, randomization, and follow-up phases. Of 170 individuals assessed for eligibility, 83 were randomized (41 lithium vs 42 placebo), with 80 starting treatment (41 lithium vs 39 placebo). CONSORT indicates Consolidated Standards of Reporting Trials; LATTICE, Lithium as a Treatment to Prevent Impairment of Cognition in Elders; MCI, mild cognitive impairment.
Baseline demographic and clinical data were well balanced (Table 1). Study medication discontinuation occurred in 29 of 80 participants (36%) overall: 14 of 41 participants (34%) in the lithium group by 2 years and 15 of 39 (38%) in the placebo group by 2 years (Figure 2). Testing for nonproportional hazards in medication discontinuation between treatment groups using the Grambsch-Therneau test50 yielded P = .29, and additional tests weighted toward early discontinuation events (Tarone-Ware51 and Gehan52 tests) both yielded P > .75. Retention for outcome assessments exceeded 80% at year 2.
Table 1. Baseline Characteristics by Treatment Groupa
Baseline Characteristics by Treatment Groupa(opens in new tab)
Characteristic Lithium (n = 41) Placebo (n = 39)
Demographic
Age, mean (SD), y 72.93 (8.77) 71.22 (6.47)
Sex, No. (%)
Female 23 (56) 22 (56)
Male 18 (44) 17 (44)
Education, mean (SD), y 15.46 (2.66) 16.54 (1.80)
Race, No. (%)
Asian 0 1 (3)
Black or African American 3 (7) 5 (13)
White 38 (93) 33 (85)
Ethnicity, No. (%)
Hispanic or Latino 0 1 (3)
Not Hispanic or Latino 41 (100) 38 (97)
Clinical characteristics
Aβ status, No.
Aβ− 27 (66) 27 (69)
Aβ+ 11 (27) 10 (26)
Aβ unknown 3 (7) 2 (5)
MCI type, No. (%)
Amnestic 34 (83) 28 (72)
Nonamnestic 7 (17) 11 (28)
APOE ε4 carriers, No. (%) 15 (37) 13 (33)
Clinical measures, mean (SD)
FSRP 0.13 (0.12) 0.11 (0.12)
CIRS-G total 11.07 (4.67) 9.90 (3.61)
Creatinine, mg/dL 0.84 (0.16) 0.92 (0.14)
GFR, mL/min per 1.73 m2 84.23 (11.74) 77.95 (13.11)
Medication count 7.78 (5.22) 6.64 (4.84)
Anticholinergic burden 2.53 (2.39) 2.34 (2.85)
PASE 117.01 (73.65) 90.20 (50.91)
PHQ-9 3.88 (3.27) 3.49 (3.46)
Neuropsychological and neuroimaging characteristics
BVMT-R, mean (SD)b 6.23 (3.11) [n = 40] 6.56 (2.86) [n = 39]
CVLT-II, mean (SD)b 7.95 (3.40) [n = 40] 7.90 (3.90) [n = 39]
PACC score, mean (SD)b −0.36 (3.59) [n = 41] 0.41 (3.16) [n = 36]
Brain volume, mean (SD), mm3 n = 33 n = 29
Hippocampalb 7387.23 (1293.01) 7199.39 (801.07)
Cerebral cortical gray matterb 416 997.07 (51 633.65) 410 702.08 (40 439.38)
Plasma biomarker data n = 36 n = 37
BDNF (log-transformed), mean (SD)b 14.61 (0.83) 14.41 (1.47)
Figure 2. Kaplan-Meier Curve Showing Time to Treatment Discontinuation by Treatment Group
Kaplan-Meier Curve Showing Time to Treatment Discontinuation by Treatment Group(opens in new tab)
Kaplan-Meier curve showing the proportion of participants remaining on assigned treatment (lithium vs placebo) throughout the 2-year study period. Testing for nonproportional hazards between groups: Grambsch-Therneau test, P = .29; Tarone-Ware test, P > .75; Gehan test, P > .75. Numbers at risk shown below x-axis.
Among participants who completed the study, the mean (SD) daily dose of lithium was 195 (150) mg with a mean (SD) serum level of 0.17 (0.13) mEq/L (maximum, 0.5 mEq/L) and 98% pill compliance. The mean (SD) false dose in the placebo group was 279 (147) mg daily with 97% pill compliance.
There was 1 death in the placebo group that was not study related. There were no deaths in the lithium group. There were 41 serious adverse events (25 lithium vs 16 placebo), with none definitely related to study medication. Common adverse events included increased creatinine, diarrhea, tiredness, and tremor (eTables 2 and 3 in Supplement 2). At study end, the percentages of participants and staff who correctly guessed treatment assignment were as follows: 56% of participants, 55% of neuropsychology staff, 47% of clinical staff, and 54% of investigators.
We analyzed 6 coprimary outcomes using mixed-effects models: 3 cognitive (CVLT-II, BVMT-R, and PACC), 2 neuroimaging (cortex volume and hippocampal volume), and 1 biomarker (BDNF). Mean trajectories by treatment group are provided in Figure 3, and model results are summarized in Table 2. Significant declines during the study period were observed for CVLT-II and both neuroimaging measures. For the primary treatment comparisons (treatment × time interaction), only CVLT-II reached nominal significance (difference in annual decline, 0.69 points per year; 95% CI, 0.01-1.37; P = .05), which did not meet the prespecified threshold of P < .01.
Figure 3. Line Graphs Showing Cognitive, Neuroimaging, and Brain-Derived Neurotrophic Factor (BDNF) Trajectories by Treatment Group
Line Graphs Showing Cognitive, Neuroimaging, and Brain-Derived Neurotrophic Factor (BDNF) Trajectories by Treatment Group(opens in new tab)
Mean scores over 2 years for Preclinical Alzheimer Cognitive Composite (PACC) (A), Brief Visuospatial Memory Test-Revised (BVMT-R) delayed recall (B), California Verbal Learning Test-Second Edition (CVLT-II) delayed recall (C), cortical gray matter volume (cortex volume) (D), hippocampal volume (E), and BDNF (F) in lithium vs placebo groups. Error bars represent SEs.
Table 2. Mixed-Effects Model Results for Cognitive, Neuroimaging, and Biomarker Outcomes
Mixed-Effects Model Results for Cognitive, Neuroimaging, and Biomarker Outcomes(opens in new tab)
Effect Estimate (SE) df t Value 95% CI P value
PACC
Intercept 0.50 (0.61) 75 0.81 −0.73 to 1.72 .42
Intercept offset (lithium)a −0.77 (0.84) 75 −0.92 −2.44 to 0.90 .36
Time (y) −0.41 (0.26) 68 −1.60 −0.92 to 0.10 .11
Time × treatmentb 0.087 (0.34) 68 0.25 −0.59 to 0.77 .80
BVMT-R
Intercept 6.49 (0.47) 77 13.74 5.55 to 7.43 <.001
Intercept offset (lithium)a −0.28 (0.66) 77 −0.42 −1.60 to 1.04 .68
Time (y) −0.19 (0.23) 70 −0.83 −0.65 to 0.27 .41
Time × treatmentb −0.088 (0.31) 70 −0.29 −0.71 to 0.53 .78
CVLT-II
Intercept 7.92 (0.61) 77 12.88 6.69 to 9.14 <.001
Intercept offset (lithium)a −0.051 (0.86) 77 −0.06 −1.77 to 1.67 .95
Time (y) −1.42 (0.25) 70 −5.67 −1.92 to −0.92 <.001
Time × treatmentb 0.69 (0.34) 70 2.01 0.005 to 1.37 .05c
Cortex volume, mm3
Intercept 407 162 (4045) 61 100.67 399 074 to 415 299 <.001
Intercept offset (lithium)a 9699 (5582) 61 1.74 −1463 to 20 862 .09
Time (y) −2420 (939) 54 −2.58 −4303 to −536 .01
Time × treatmentb −352 (1254) 54 −0.28 −2866 to 2162 .78
Hippocampus volume, mm3
Intercept 7166 (148) 61 48.51 6870 to 7462 <.001
Intercept offset (lithium)a 259 (204) 61 1.27 −148 to 667 .21
Time (y) −121 (25) 54 −4.78 −172 to −70 <.001
Time × treatmentb 59 (34) 54 1.74 −9 to 127 .09
BDNF, ng/mL
Intercept 14.41 (0.19) 78 75.70 14.03 to 14.79 <.001
Intercept offset (lithium)a 0.18 (0.26) 78 0.70 −0.34 to 0.71 .49
Time (y) −0.058 (0.10) 68 −0.57 −0.26 to 0.14 .57
Time × treatmentb 0.012 (0.14) 68 0.09 −0.27 to 0.29 .93
Hippocampal volume decline was not significantly different between groups (difference in annual decline, 59 mm3 per year; 95% CI, −9 to 127; P = .09) (Table 2). Cortical gray matter volume showed no treatment × time interaction (difference in annual decline, −352 mm3 per year; 95% CI, −2866 to 2162; P = .78). BVMT-R, PACC, and BDNF showed no significant treatment × time interactions.
We performed prespecified analyses of participants who completed the study (eTable 4-6 in Supplement 2). Results in the overall completer sample (including both Aβ+ and Aβ-negative [Aβ−] participants) were consistent with the intention-to-treat analysis. In exploratory subgroup analyses stratified by amyloid status, sample sizes were limited. Effect sizes in Aβ+ completers were Hedges g = 0.74 for verbal memory, g = 0.82 for hippocampal volume, and g = 0.81 for hippocampal percentage change, compared with g = 0.32, g = 0.09, and g = 0.12, respectively, in Aβ− completers.
Discussion
This pilot randomized clinical trial established the feasibility of recruitment and retention and confirmed the safety and tolerability of low-dose lithium in older adults with MCI. It generated preliminary effect size estimates across cognitive, neuroimaging, and plasma biomarker measures to inform future adequately powered trials.
Among cognitive outcomes, CVLT-II showed the largest effect size. Scores declined 1.42 points per year in the placebo group compared with 0.73 points per year in the lithium group (difference in annual decline, 0.69 points per year; 95% CI, 0.01-1.37; P = .05), which did not meet our prespecified threshold (P < .01). Neither BVMT-R nor PACC showed significant change over time in either group, limiting interpretation of treatment effects on these measures. The absence of decline may reflect insufficient sensitivity of these measures to detect change in this MCI population during a 2-year period.
For neuroimaging outcomes, both cortical gray matter and hippocampal volumes declined over time in both treatment groups. For hippocampal volume, the difference in decline between the groups did not reach statistical significance. BVMT-R, PACC, cortical gray matter volume, and BDNF showed no significant treatment × time interactions.
Despite 36% medication discontinuation overall (34% lithium vs 38% placebo), retention for outcome assessments exceeded 80%, meeting our feasibility target. Also, there was no statistical difference in the pattern of early discontinuation between the 2 groups, although power to detect differences was limited. Regarding safety, there were no serious adverse events definitely related to study medication, and the 1 death in the study occurred in the placebo group.
Conducting this trial provided knowledge and experience to inform future trials of low-dose lithium in MCI. Most importantly, we observed that older adults have substantial difficulty tolerating doses greater than 300 mg daily. Thus, future trials should use doses of lithium carbonate in the range of 150 mg to 300 mg daily.
Among prior RCTs of lithium in older adults with MCI and AD, results have varied based on treatment duration.3,5,7,10 Shorter-term trials5,10 (10-12 weeks) generally found no cognitive benefit, while longer-term trials3,7 (15-24 months), including ours, found effects on specific cognitive measures. These findings suggest that to detect cognitive effects in MCI, clinical trials need to be much longer than 10 to 12 weeks to observe a change in a declining trajectory.
Limitations
Our study had some limitations. The RCT occurred during the COVID-19 pandemic, which affected in-person assessments and may have influenced medication discontinuation. Additionally, when the study was designed and launched between 2016 and 2017, we enrolled participants with syndromic MCI without requiring biomarker confirmation of AD pathology. At that time, screening for biological evidence of Alzheimer-type neurodegeneration was limited to amyloid PET imaging and lumbar puncture for cerebrospinal fluid analysis. Practical constraints for a pilot study led to this design decision: amyloid PET imaging was prohibitively expensive, and plasma biomarkers were unavailable. Our sample predominantly included participants with amnestic MCI but were Aβ−. This reflects our recruitment from the general community rather than memory disorders clinics, where prodromal AD is more prevalent.49 It may have diluted treatment effects. Exploratory analyses suggested larger effect sizes in Aβ+ participants, though small subgroup sizes limit interpretation. Trials can now use plasma-based biomarkers (eg, p-tau217) to enroll participants with AD pathology, thereby increasing statistical power.
Conclusion
This pilot randomized clinical trial established the feasibility of recruitment and retention and confirmed the safety and tolerability of low-dose lithium treatment in older adults with MCI. The trial generated preliminary effect size estimates across cognitive and neuroimaging outcomes. Together with findings from prior independent longer-term trials, these results support further investigation of lithium in adequately powered trials to assess its potential neuroprotective properties in MCI.
Article Information
Accepted for Publication: January 8, 2026.
Published Online: March 2, 2026. doi:10.1001/jamaneurol.2026.0072
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2026 Gildengers AG et al. JAMA Neurology.
Corresponding Author: Ariel G. Gildengers, MD, Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 O’Hara St, Pittsburgh, PA 15213 (ariel.gildengers@pitt.edu).
Author Contributions: Dr Gildengers had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Ibrahim and Anderson contributed equally to this work and share second authorship.
Concept and design: Gildengers, Ibrahim, Anderson, Emanuel, Lopresti, Lopez, Butters.
Acquisition, analysis, or interpretation of data: Gildengers, Ibrahim, Anderson, Emanuel, Santini, Diaz, Lopresti, Royse, Lopez, Zeng, de Almeida, Alkhateeb, Chu, Karikari, Lee, Weinstein, Butters.
Drafting of the manuscript: Gildengers, Anderson, Santini, Diaz, Lopez, Lee, Weinstein.
Critical review of the manuscript for important intellectual content: Gildengers, Ibrahim, Anderson, Emanuel, Santini, Lopresti, Royse, Lopez, Zeng, de Almeida, Alkhateeb, Chu, Karikari, Weinstein, Butters.
Statistical analysis: Gildengers, Ibrahim, Anderson, Santini, Diaz, Chu, Lee.
Obtained funding: Gildengers, Butters.
Administrative, technical, or material support: Gildengers, Ibrahim, Emanuel, Santini, Lopresti, Royse, Lopez, Zeng, de Almeida, Chu, Karikari, Weinstein, Butters.
Supervision: Gildengers, Ibrahim, Karikari, Butters.
Conflict of Interest Disclosures: Dr Gildengers reported receiving honoraria for invited lectures during the conduct of the study. Dr Ibrahim reported having consulted for DxTx Medical and having served as the chair for the External Advisory Committee on the Center of Biomedical Research Excellence project during the conduct of the study. Dr Anderson reported receiving consulting fees for analysis of breast cancer clinical trial data from NSABP Foundation, Inc; being a Data Monitoring and Safety Board member for 2 trials and a Mental Health & Behavioral Sciences-C review panel member; and being a statistical editor for JAMA Psychiatry outside the submitted work. Mr Emanuel reported receiving salary support through grants from the National Institutes of Health (NIH) outside the submitted work. Mr Lopresti reported receiving grants from NIH during the conduct of the study. Dr Karikari reported having consulted for Quanterix Corporation, SpearBio Inc, Neurogen Biomarking LLC, and Alzheon outside the submitted work; having served on advisory boards for Siemens Healthineers and Neurogen Biomarking LLC, outside the submitted work; having received in-kind research support from Janssen Research Laboratories, SpearBio Inc, and Alamar Biosciences, as well as meeting travel support from the Alzheimer’s Association and Neurogen Biomarking LLC, outside the submitted work; having received royalties from Bioventix for the transfer of specific antibodies and assays to third-party organizations; having received honoraria for speaker and grant review engagements from NIH, University of Pennsylvania, University of Wisconsin–Madison, the Cherry Blossom symposium, the Health and Aging Brain Study–Health Disparities and the fourth phase of the Alzheimer’s Disease Neuroimaging Initiative Health Enhancement Scientific Program, Advent Health Translational Research Institute, Brain Health conference, Barcelona-Pittsburgh conference, the International Neuropsychological Society, the Icahn School of Medicine at Mount Sinai, and the Quebec Centre for Drug Discovery (Canada) outside of the submitted work; and being an inventor on several patents and provisional patents regarding biofluid biomarker methods, targets, and reagents and compositions, that may generate income for the institution and/or self should they be licensed and/or transferred to another organization. Dr Lopez reported being a consultant for Novo Nordisk during the conduct of the study. Dr Zeng reported having a provisional patent for a method for the quantification of plasma amyloid-beta biomarkers in Alzheimer disease. No other disclosures were reported.
Funding/Support: This work was supported primarily by grant R01 AG055389 from the National Institute on Aging, National Institutes of Health, US Department of Health and Human Services. Additional support was provided by grants K23 AG076663 (Dr Weinstein) and R01 AG083874 (Dr Karikari). The 7T imaging sessions were conducted with the 7 Tesla Bioengineering Research Program. Some of the imaging developments were supported by grants R01MH111265, R01AG063525, and T32MH119168. This research was also supported in part by the University of Pittsburgh Center for Research Computing and Data, RRID:SCR_022735, through the resources provided. Specifically, this work used the H2P cluster, which is supported by National Science Foundation award OAC-2117681. Open access publication was supported by The Dale and Alvin Filstrup Charitable Gift Fund.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Meeting Presentation: This study was presented in part at the annual meeting of the International Group for the Study of Lithium-Treated Patients; October 3, 2025; Aarhus, Denmark.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank the National Institute on Aging program staff for oversight and guidance. We thank the Data and Safety Monitoring Board (DSMB) members for independent safety monitoring: Eric McDade, DO (Washington University School of Medicine), Eric Lenze, MD (Washington University School of Medicine), and Wesley Thompson, PhD (University of California San Diego); DSMB members received a modest stipend for their service. We thank Happy Fletcher, BS (data management; University of Pittsburgh), Denise Sorisio Brecht, BS (laboratory management; University of Pittsburgh), Lindy Kilby, MS (study coordination; University of Pittsburgh), Joelle Kincman, PhD (unblinded team member; University of Pittsburgh), Ellen Whyte, MD (clinical oversight; University of Pittsburgh), and Michelle Zmuda, BS (neuropsychological assessment; University of Pittsburgh) for their contributions to this study. Ms Fletcher, Ms Brecht, Ms Kilby, Dr Kincman, Dr Whyte, and Ms Zmuda were not compensated for their contributions beyond their usual salaries. We thank all study participants for their cooperation and commitment.
Additional Information: We used Claude (Anthropic, versions 4 and 4.5) and Gemini (Google) from August 2025 through January 2026 for specific tasks including searching literature to identify relevant publications, text revision and editing for clarity, proofreading for grammar and consistency, formatting references and tables, and generating Python code for figure 3 creation. AI was not used for data analysis, interpretation of results, or generation of scientific conclusions. All data input for the figure was provided by the authors from statistical analysis output files, and all plotted values were verified against original data. The authors take full responsibility for the integrity of all content, and all AI-generated suggestions were reviewed, verified, and modified by the authors.
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