Metformin as a Potential Prevention Strategy for Alzheimer’s Disease and Alzheimer’s Disease Related Dementias

Abstract

Background:

Metformin is a safe and effective medication for type 2 diabetes (T2D) that has been proposed to decrease the risk of aging related disorders including Alzheimer’s disease (AD) and Alzheimer’s disease related disorders(ADRD).

Objective:

This review seeks to summarize findings from studies examining the association of metformin with AD/ADRD related outcomes.

Methods:

Results:

Observational human studies are conflicting, but those with better study designs suggest that metformin use in persons with T2D is associated with a lower risk of dementia. However, these observational studies are limited by the use of administrative data to ascertain metformin use and/or cognitive outcomes. There are few clinical trials in persons without T2D that have small sample sizes and short durations but suggest that metformin could prevent AD/ADRD. There are ongoing studies including large clinical trials with long duration that are testing the effect of metformin on AD/ADRD outcomes in persons without T2D at risk for dementia.

Conclusions:

Clinical trial results are needed to establish the effect of metformin on the risk of AD and ADRD.

Keywords

Alzheimer’s disease dementia diabetes metformin

INTRODUCTION

The idea of repurposing medications for type 2 diabetes (T2D) for the prevention and treatment of Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD) is based on the observation that T2D is related to an increased risk of cognitive impairment including AD and ADRD [1, 2]. There are shared mechanisms between T2D and AD/ADRD [3]. Processes that contribute to cognitive impairment and dementia such as cerebrovascular disease (CVD) [4], neuroinflammation [5], oxidative stress [6], defective synapses and cell aging [7], are present in both AD/ADRD and T2D [8 –10]. However, it is still unclear whether T2D causes AD, characterized by brain accumulation of plaques of amyloid-β (Aβ) and tau neurofibrillary tangles [11]. Most neuropathology studies have not found a link between T2D and postmortem AD neuropathology [12 –18]. The majority of in vivo AD biomarker studies have also reported no association between T2D and brain Aβ ascertained by positron emission tomography (PET) [19 –21], or cerebrospinal fluid (CSF) [20, 22]. It has been speculated that T2D treatment with medications such as metformin could contribute to amyloid clearance and could explain this null association [23]. In most of these studies T2D was related to biomarkers of neurodegeneration ascertained on magnetic resonance imaging (MRI) [20], CSF t-tau [20], or fluorodeoxyglucose (FDG) PET [21]. Fewer studies have reported an association between T2D and higher AD pathology ascertained on postmortem neuropathology [24], CSF [25] or plasma biomarkers [26]. Other studies have reported lower AD pathology among persons with T2D, as ascertained on postmortem neuropathology [27, 28], Aβ PET imaging [29], and plasma biomarkers [30].

The overarching hypothesis linking T2D medications to AD is that improving peripheral insulin sensitivity affects AD risk through improvements in brain insulin signaling, amyloid clearance, inflammation, and oxidation [31]. Thus, the main T2D medications hypothesized to improve cognitive outcomes are those that improve insulin sensitivity directly or indirectly, usually involving weight loss. Medications in this category include metformin, thiazolidinediones, glucagon-like peptide receptor agonist (GLP-1ra), and dipeptidyl peptidase-4 (inhibitor (DPP-4i). Thiazolidinediones are powerful insulin sensitizers but have an adverse safety profile [32]. GLP-1ra [33] and DPP-4i [34, 35] have been proposed for the prevention and treatment of AD and clinical trials are currently under way [36]. Although metformin is the less powerful insulin sensitizer among these medications, it has certain advantages. Metformin is the most widely used medication for the treatment of T2D in general medical practice, alone or in combination with other T2D medications, as it is first line treatment for T2D [37]. It is inexpensive and safe when used in persons without contraindications (advanced renal disease [glomerular filtration rate <30 ml/min], liver disease other than non-alcoholic fatty liver disease, class III-IV congestive heart failure, alcohol abuse). The most common side effects are related to gastrointestinal intolerance (bloating, diarrhea). Rare side effects include cobalamin deficiency [38], which may be related to cognitive impairment, and lactic acidosis. In recent years there has been a call for repurposing metformin as a preventive therapy against cognitive decline given it potential beneficial pleotropic effects on conditions other than T2D and obesity including liver disease, cardiovascular disease, cancer, renal disease, and aging in general [39]. There are many non-human studies examining the effects of metformin on cognition and neurodegeneration, reviewed elsewhere [23], that have shown mixed results, suggesting both protective and deleterious effects through heterogenous mechanisms. This review focuses on human studies examining the association of metformin with AD/ADRDoutcomes.

METHODS

This is a narrative review of human studies, including observational studies and clinical trials, examining the association of metformin with cognitive and brain outcomes. We used PubMed as the main database for our literature search with a focus on English language human studies including observational studies and clinical trials. We prioritized studies published from 2013 until February 15, 2024. We searched both original and relevant review articles. We used the search term metformin paired with, cognition, cognitive, dementia, amyloid, tau, Alzheimer’s, neurodegenerative, neurodegeneration in abstract/title of each article or as a Medical Subject Headings (MeSH) term. Reference lists of included studies and relevant review articles were further reviewed to identify additional studies not identified through the PubMed search.

SUMMARY OF OBSERVATIONAL STUDIES

Observational studies showing adverse or null associations.

Clinical outcomes

A large population-based case-control study of adults ≥65 years old compared the use of metformin between 7,086 cases with AD and 7,086 controls without AD using administrative data from the United Kingdom General Practice Research Database (GPRD) to define all variables. History of 60 or more prescriptions of metformin was associated with slightly higher risk of developing AD after adjustment for use of other diabetes medications, smoking, body mass index, hypertension, dyslipidemia, and use of angiotensin converting enzyme inhibitors and statins. (OR = 1.71, 95% CI = 1.12–2.60) [40]. The authors concluded that the study did not provide evidence that the use of metformin reduces the risk of AD and suggested that the use of metformin could be related to a higher risk of AD. It is important to point out that this study included persons without diabetes, who comprised most of the sample. In addition, the higher odds of metformin use among persons with AD compared to those without AD was apparent in the adjusted model but not in the unadjusted model (OR = 1.06, 95% CI = 0.77–1.46). In another analysis examining an exposure variable defined by a history of diabetes treated with metformin only (no other diabetes medications), the odds of metformin use among cases with AD was not significantly higher than in controls without AD. An Australian cross-sectional study also examined the association of metformin with cognitive impairment combining samples from 4 sources that included persons with AD and MCI: the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, the Research in Memory (PRIME) clinics study, the Cognitive, Dementia, and Memory Services from the Barwon region of southeastern Australia, and persons with AD from private geriatric practices. The final analytic sample included 1,354 persons, 126 with diabetes, with a mean age of 73 years [41]. Levels of cognitive performance were defined by performance in the Mini-Mental Status Exam (MMSE). MMSE <18 was classified as most impaired, 18 to 23 as mildly impaired, 24 to 27 as minimally impaired, and 28 or more as not impaired. In analyses using ordinal logistic regression a history of diabetes was related to a higher risk of cognitive impairment (OR = 1.51; 95% CI = 1.03–2.21) after adjustment for age, sex, education, and history of depression. In an analysis restricted to the 126 participants with diabetes, metformin use was related to a higher risk of cognitive impairment after adjustment for age, sex, education, and history of depression (OR = 2.23, 95% CI = 1.05–4.75). This association was partially attenuated by adjustment for cobalamin levels. The investigators concluded that persons with diabetes taking metformin should be monitored for cognitive impairment. Kuan et al. [42] found that compared to persons not taking metformin, those taking metformin had an increased risk of all cause dementia (HR = 1.66, 95% CI = 1.35–2.04), AD (HR = 2.13, 05% CI = 1.20–3.79) and vascular dementia (HR = 2.30, 95% CI = 1.25–4.22) over 12 years follow-up in a cohort study of persons with T2D from the Taiwan’s National Health Insurance Research Database [42]. The definition of dementia and dementia subtypes was based on administrative data. A community-based cross-sectional study in 4,160 adults with and without hyperglycemia without dementia and a mean age of 74.1 years from the Trinity, Ulster and Department of Agriculture Study examined the association of metformin use and cognitive performance, assessed with the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) [43]. Compared with persons without hyperglycemia, persons with hyperglycemia using metformin had a higher risk of lower performance in the RBANS (OR = 1.36; 95% CI –1.03, 1.80) as well as with higher risk of vitamin B12 and B6 deficiency. A prospective cohort of older adults (n = 732, mean age = 76 years) by Koo and colleagues reported that among persons with T2D metformin use was associated with worse scores on MMSE and verbal immediate recall, and no association with the Korean Consortium to Establish a Registry for Alzheimer’s Diseases Assessment (CERAD) or activities of daily living after 2.9 years follow-up [44]. A single hospital retrospective cohort study in Northern Taiwan used administrative and hospital record data [45] to compare dementia risk among 67,281 persons with T2D aged approximately 62 years taking and not taking DPP-4i and found a higher risk of dementia (hazard ratio = 1.11; 95% confidence interval, 1.06–1.15, adjusting for age, sex, and comorbidities) among persons taking both metformin and a DPP4i. The Diabetes Prevention Program (DPP) was a randomized trial comparing metformin, lifestyle intervention, and placebo in persons at risk for T2D that has continued in an observation phase called the DPP Outcomes Study (DPPOS). The DPP reported that the risk of T2D was significantly decreased in the lifestyle and metformin arms compared with placebo after 3 years [46]. Cognitive performance was tested in DPPOS approximately 10 years after randomization in 2,280 participants aged 63 years on average at the time of cognitive assessment. Tests included the Spanish English Verbal Learning Test, the Digit Symbol Substitution Test, and letter and category fluency tests [47]. Cognitive performance was similar across the metformin, lifestyle, and placebo arms. In addition, cumulative metformin use, including study metformin and metformin prescribed for participants who developed T2D in the placebo and lifestyle arms, was not associated with cognitive performance. Compared to other observational studies, the DPP study had the most rigorous assessment of exposure and outcomes, although the cognitive assessment was conducted approximately a decade after randomization. A population based retrospective cohort study based in Ontario, Canada studied the association of the timing of metformin initiation with dementia risk in 12,331 persons with diabetes and initiation of metformin monotherapy with a mean age of approximately 72 years versus 22,369 persons not started on diabetes therapy [48]. It found that metformin initiation was not related to incident dementia, defined using administrative and medical recorddata.

Biomarker and neuropathology outcomes

There is a dearth of studies that have examined metformin use and neuropathology outcomes measured with brain imaging, blood biomarkers or postmortem neuropathology. A recent large prospective community-based observational study of older subjects without dementia, from the Sydney Memory and Ageing Study (n = 1,037, age = 70–90 years) reported no association between metformin use and the rate of changes in brain volume over 2 years [49]. A postmortem case-control study of persons with and without diabetes (n = 248, mean age at death = 81 years) from the Mount Sinai School of Medicine Brain Bank reported fewer neuritic plaques in persons who were taking a combination of insulin and any oral antidiabetic medications compared to those taking only one drug (either insulin or an oral drug) [50]. No differences were found for neurofibrillary tangles [50]. An autopsy study based in Chicago from 1,584 participants aged 80 years at autopsy reported no differences in AD pathology between users and non-users of metformin [51].

OBSERVATIONAL STUDIES SHOWING ASSOCIATIONS WITH IMPROVED OUTCOMES

Clinical outcomes

The following are examples of studies showing an association of metformin use with lower risk of cognitive impairment and dementia. In a retrospective cohort study of persons with T2D aged approximately 63 years comparing 15,676 metformin users to 15,676 non-users, Chin-Hsiao et al. reported that metformin use was associated with a lower risk of dementia after two years of follow-up (HR = 0.70, 95% CI = 0.63–0.79) [52]. In another retrospective study of 127,209 persons with T2D aged 50 years and older using administrative data from Taiwan’s National Health Insurance database [53]. Hsu et al. found that metformin was associated with lower risk of dementia (OR = 0.76, 95% CI = 0.58–0.98). Furthermore, the combination of metformin with sulfonylureas was associated with a lower risk of dementia over 8 years. Long-term use of metformin was related to lower risk of cognitive impairment (defined by a MMSE <24) over 4 years of follow-up in a population-based study of 365 adults aged approximately 66 years with T2D from the Singapore Longitudinal Aging Study (OR = 0.49, 95% CI 0.25–0.95) [54]. Similar findings were reported by Samaras and colleagues in the 1,037 participants without dementia in the Sydney Memory and Aging Study [49], Persons with T2D who took metformin had slower global cognition and executive function decline over 6 years compared to persons with T2D who did not take metformin. Those not taking metformin showed higher risk of incident dementia (OR = 5.29, 95% CI = 1.17–23.88) compared to those taking metformin [49]. The Personality and Total Health (PATH) Through Life Study reported that among 113 participants with diabetes taking oral diabetes medications, metformin use was associated with a better cognitive performance in the domains of verbal learning, working memory and executive function [55]. A retrospective cohort study using administrative data from 28,640 persons with T2D 65 years and older from the Veterans Administration system in the United States used inverse probability of treatment weighting to adjust for confounding by indication comparing the risk of dementia between users of metformin and user of sulfonylureas [56]. Metformin use of at least 2 years duration was associated with a lower risk of dementia compared to sulfonylureas during 5 years of follow-up in persons <75 years old (HR = 0.89, 95% CI = 0.79–0.89). A case-control study in Germany using an administrative database compared the use of metformin between 8,276 persons with T2D and dementia and 8,726 persons with T2D without dementia matched by demographics and other relevant variables. Metformin use as monotherapy (OR = 0.71, 95% CI = 0.66–0.76) or in combination with sulfonylureas (OR = 0.90; 95% CI = 0.89–0.92) was associated with a decreased risk of dementia [57]. A study in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) compared cognitive performance among 810 persons with mild cognitive impairment (MCI) grouped by the presence of T2D and/or metformin treatment [58]. The groups were paired by age, gender, education, and APOE status. Composite cognitive test scores and cognitive change in those with T2D treated with metformin were comparable to those without T2D and better than those with T2D not treated with metformin. There were similar findings for hippocampal volume and cortical thickness in AD signature areas. Another study in an administrative dataset from the United States compared the risk of dementia between 96,140 new users of metformin and 16,451 new users of sulfonylureas with a mean age of 66 years [59]. During 5 years of follow up, using inverse probability of treatment weighting (IPTW) to adjust for confounding by indication, the risk of dementia was lower in persons using metformin compared to those using sulfonylurea (HR = 0.80, 95% CI 0.73 to 0.88). A cohort study in 210,237 persons with T2D in the United Kingdom Clinical Practice Research Datalink [60] showed that metformin initiators (n = 114,628) compared with patients who received no diabetes medication (n = 95,609) had lower risk of dementia (adjusted hazard ratio = 0.88 [95% confidence interval: 0.84–0.92] and 0.90 [0.84–0.96]) in analyses adjusted for a propensity score, despite persons not on pharmacological treatment having better glycemia measured with Hemoglobin A1C. A study using the Taiwan National Insurance Research Database [61] examined the risk of dementia in 31,384 pairs with T2D that differed by metformin adherence and were matched by propensity score during 5 years of follow-up. Metformin adherence was associated with a lower risk of dementia (HR = 0.72, p < 0.001). A recent study from a cohort of 3,029 persons aged 78 years on average based in Chicago showed that metformin use was related to slower global cognitive decline [51]. This association was not observed when all diabetes medications were examined as the exposure. An analysis of 1,393 persons 50 years and older with type 2 diabetes and normal cognition from the National Alzheimer’s Coordinating Center (NACC) database found that participants taking metformin had a lower risk of incident dementia during a median of 4 years of follow-up [62]. An observational study based in the United Kingdom using the Clinical Practice Research Datalink in 211,396 persons with diabetes with a mean age of 63 years reported a lower risk of dementia and MCI among persons using metformin compared to other diabetes medications [63]. This observation was not modified by sex but was only evident in persons with less than 80 years of age. A health care system-based cohort study in California compared incident dementia between 12,220 early metformin terminators aged 59 years and 29,126 routine users aged 61 years [64]. It reported that early termination of metformin was related to increased dementia incidence, defined using medical record data. This finding was independent of changes in glycemia and use of insulin therapy.

Biomarker outcomes

In a cross-sectional study of late middle-aged adults without dementia (n = 350, mean age = 64 years) where metformin was the most commonly used medication (85.18% of all diabetes medications) diabetes medication use was associated with lower brain Aβ burden as measured on positron emission tomography imaging [65]. In an analysis of older adults without dementia (n = 900, mean age = 73.54) from the ADNI, McIntosh and colleagues, reported that untreated persons with T2D had higher CSF levels of p-tau, t-tau, and p-tau/Aβ_1 - 42 when compared to treated persons with T2D, persons with euglycemia or with pre-diabetes [25]. Although the study did not examine individual medications due to sample size and heterogeneity, metformin was the most commonly used diabetes medication in the study [25].

META-ANALYSES OF OBSERVATIONAL STUDIES RELATING METFORMIN AND COGNITIVE OUTCOMES

Several meta-analyses have reported that metformin use is not associated with better cognitive outcomes. In a meta-analysis of observational studies examining the association between metformin and neurodegenerative diseases (19 studies, n = 285,966), Ping and colleagues [66] reported a null association between metformin exposure and the incidence of overall neurodegenerative diseases (OR = 1.04, 95% CI = 0.92–1.17) including AD (OR = 0.96, 95% CI = 0.85–1.08). However, metformin exposure was related to higher risk of developing Parkinson’s disease (OR = 1.66, 95% CI = 1.14–2.42). Similarly, a meta-analysis of 6 studies (n = 544, 093) found no association of metformin with the incidence of dementia, although an association with lower dementia risk was nearly statistically significant (RR = 0.79, 95% CI = 0.62–1.01, p = 0.064) [67]. A pooled analysis from 5 major population based-cohorts also reported a null association of metformin with new-onset dementia and global cognitive function [68]. A meta-analysis by Luo et al. [69] included 10 observational studies with 229,110 patients and found no significant association between metformin exposure and AD incidence (OR 1.17, 95% CI 0.88–1.56) but found an association between metformin exposure and higher AD risk among Asians (OR 1.71, 95% CI 1.24–2.37).

Other meta-analyses have reported an association between metformin and better cognitive outcomes. Campbell et al. reported that metformin use was associated with less cognitive impairment in persons with T2D (OR = 0.55, 95% CI = 0.38–0.78) [70, 71] in three combined cross-sectional studies. Similarly, metformin use was associated with a lower incidence of dementia (HR = 0.76, 95% CI 0.39 to 0.88) in six combined longitudinal studies, according to the same meta-analysis [70, 71]. A metanalysis by Ji et al. using 14 observational studies including 396,332 participants [72] found that metformin exposure was associated with a lower risk of all cause dementia (RR = 0.79, 95% CI: 0.68,0.91) but found no association in participants of European descent (RR = 1.01, 95% CI 0.66–1.54). Lastly, Zhang et al. conducted a metanalysis relating metformin exposure to neurodegenerative diseases including AD/ADRD in 12 cohort studies including 194,792 participants with T2D. There was an inverse association between metformin exposure and neurodegenerative diseases (pooled relative risk = 0.77, 95 CI 0.67–0.88) [73]. This association was more prominent for metformin exposure of 4 years or longer. A metanalysis that included 100 reviews and observational studies totaling 3,046,661 persons reported that metformin was associated with a lower risk of dementia only in Western populations, particularly in the United States [74]. It is important to point out that most studies reviewed in meta-analyses used administrative data to ascertain metformin exposure and the cognitiveoutcomes.

SUMMARY OF CLINICAL TRIALS

Few clinical trials of metformin with primary cognitive outcomes have been conducted so far (Table 1). In a small one-year pilot randomized clinical trial (RCT) in subjects with amnestic MCI without T2D (n = 80, mean age = 65 years), randomization to 1000 mg of metformin twice daily was safe and feasible and resulted in better performance in memory, measured by the total recall in the Buschke selective reminding test compared to the placebo group [75]. Biomarker outcomes including plasma amyloid β42/40 ratio and FDG PET uptake in regions related to AD favored the metformin arm but were not significant compared with placebo. A six month randomized controlled trial examining the effects of metformin (1500 mg/day) and weight loss intervention on cognitive function among breast cancer survivors (n = 333, mean age = 62 years) found no significant difference on cognitive domains between metformin and placebo [76]. In An eight-week crossover RCT in persons with cognitive impairment due to AD without T2D (n = 20) metformin improved executive function, but its beneficial effect on learning/memory and attention was close to statistical significance (p = 0.06, p = 0.07 respectively) [77]. The same study reported no differences in CSF measures of Aβ_1 - 42, total tau, P-tau while an increase in cerebral blood flow using arterial spin label magnetic resonance imaging in orbitofrontal regions was observed in the metformin group [77]. Lastly, metformin therapy in conjunction with donepezil improved cognitive function compared to the acarbose-donepezil group after one-year RCT among subjects with non-dementia vascular cognitive impairment (n = 100, mean age ≈66 years) [78].

Table 1

Summary of randomized trials examining the effects of metformin on cognitive outcomes

Author, year	Design and participants	Outcomes	Results	Strengths and limitations
Luchsinger, 2016 [75]	1:1 randomized placebo-controlled, double blind trial of short acting metformin 2,000 mg a day; 12 months duration. Randomization was clustered by APOEɛ4 status; participants were 80 persons amnestic mild cognitive impairment aged 55 to 90 years old, without diabetes, with body mass index 25 mg/k² and higher, without contraindications to metformin	The two primary clinical outcomes were changes in total recall of the selective reminding test (SRT) and the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), measured every 3 months. The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography. Change in plasma Aβ₄₂ was an exploratory outcome.	Persons in the metformin group had significantly better improvements in the SRT compared with placebo. There were no differences in the ADAS-Cog. Changes in the secondary and exploratory outcomes favored metformin but were not significant.	The primary strength was the randomized design with meaningful cognitive and biomarker outcomes. Limitations included the small sample size and short study duration. Short acting Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose.
Koenig, 2017 [77]	Randomized, double blind, Placebo controlled cross-over study of 20 persons with mild cognitive impairment or mild dementia due to Alzheimer’s disease (AD), aged 55 to 80 years, without diabetes. Duration was 16 weeks. Participants were randomized to metformin 2,000 mg a day or placebo for 8 weeks and then crossed-over.	Cerebrospinal fluid biomarkers at baseline and week 8; Arterial Spin Label magnetic resonance imaging at baseline, week 8 and week 16. Cognitive measures administered at baseline, week 8, and week 16 included the ADAS-cog, the Cambridge Neuropsychological Test Automated Battery, Trails A and B, Digit span, Boston Naming test.	Metformin was associated with improved executive functioning, and trends suggested improvement in learning/memory and attention. No significant changes in cerebral blood flow (CBF) were observed, though post-hoc completer analyses suggested an increase in orbitofrontal CBF with metformin exposure.	Strengths include the randomized design and the use of a comprehensive set of biomarkers and cognitive tests in participants with early AD. Limitations include the short duration and the lack of a washout period during cross-over.
Lin, 2018 [78]	One hundred patients with vascular cognitive impairment (VCI) without dementia and impaired glucose tolerance (IGT) aged 68.1 years were randomly allocated into two groups: metformin and donepezil (n = 50) or acarbose and donepezil (n = 50). Study duration was 12 months.	Cognitive tests included the ADAS-Cog, the World Health Organization/University of California-Los Angeles Auditory Verbal Learning Test, and Trails A and B.	Ninety-four patients completed all the assessments and follow-up. After 12 months treatment, there was a decrease in Alzheimer’s disease Assessment Scale-Cognitive Subscale scores and the duration of the Trail Making Test in the metformin-donepezil group. There was a significant increase in World Health Organization– University of California– Los Angeles Auditory Verbal Learning Test scores after treatment.	Strengths include the comprehensive cognitive battery and the risk group of precipitants with VCI and IGT. Limitations include the small sample size, relatively short duration, and the absence of placebo group.
Hartman, 2019 [76]	Overweight/obese postmenopausal breast cancer survivors (n = 333) with a mean age of 63 years were randomized to a weight loss intervention versus control and metformin (maximum dose 1,500 mg a day) versus placebo in a 2×2 factorial design. Study duration was 6 months.	Cognitive functioning was assessed at the baseline and 6-month clinic visits using a 45- minute computerized testing battery designed to sample a range of cognitive domains (NeuroTrax).	There were no differences in cognitive outcomes between the study arms.	Strengths include relatively large sample size and randomized design. The main limitations is the short study duration. The proportion of participants tolerating the maximum dose was not explicitly reported.

One study simulated a clinical trial of metformin versus sulfonylurea in persons with T2D, aged 50 years and older, without prior diabetes treatment, without MCI or dementia at baseline, using electronic medical records from the United States Research Patient Data Registry (13,191 patients) and the United Kingdom Clinical Practice Research Datalink (108,025 patients) [79]. It found that the risk of dementia in persons on metformin was lower than those on sulfonylurea, but this effect dissipated over time.

LIMITATIONS OF REPORTED STUDIES

Overall, human studies relating metformin to cognitive and brain outcomes have inconsistent results. Observational studies are subject to various biases and confounding. Most observational studies examining the association of metformin with dementia do not clearly assess time-related biases [80]. In addition, they are subject to confounding by indication, that is, that persons with cognitive impairment are more likely to use metformin because of their cognitive status and related comorbidities rather than metformin influencing cognition. The few observational studies that have used propensity scores and techniques to account for confounding by indication such as IPTW reported an association between metformin exposure and lower risk of cognitive impairment including dementia. Observational studies are mostly limited to persons with T2D, who are subject to confounding by medications and comorbidities. This confounding can be partially adjusted by propensity scores and IPTW, but these techniques cannot eliminate unmeasured or residual confounding. Lastly, most observational studies have ascertained metformin exposure and the cognitive outcomes (e.g., dementia) using administrative data, which is subject to measurement bias. The only way to overcome the limitations of observational studies is by conducting clinical trials.

The existing clinical trials are small and of relatively short duration and are thus subject to chance findings. In addition, they are limited to persons without T2D to avoid confounding by the effects of diabetes medications other than metformin. There is a need to conduct clinical trials of metformin versus placebo of several years duration that include cognitive and biomarker outcomes. Other unanswered questions that need to be addressed in future studies include metformin dosage and side effects and the role of sex and genetics in the associations between metformin and cognitive function [81]. A detailed discussion of some of the important gaps on metformin and aging was thoroughly discussed in a recent review by Wang et al. [81]. One of the issues highlighted was finding the best dose of metformin that is both neuroprotective and has minimal side effects. This is crucial to ensure a benefit and long-term compliance. It should be noted that metformin has been used in clinical practice as first line therapy for T2D for decades and has been shown to be safe. Some side effects of metformin such as vitamin B12 deficiency that could affect cognition might be prevented by vitamin supplementation [82].

ONGOING STUDIES AND FUTURE DIRECTIONS

There are several ongoing observational studies and clinical trials that seek to clarify the association of metformin with AD/ADRD and the underlying mechanisms of this association if it exists.

The Diabetes Prevention Program Outcomes Study (DPPOS) AD/ADRD project (National Institutes of Health [NIH] grant U19AG078558) is conducting comprehensive phenotyping of cognitive syndromes (MCI, dementia) using the National Alzheimer’s Coordinating Center Uniform Dataset version 3 and AD pathology using plasma biomarkers of amyloid, tau, and neurodegeneration in a cohort of over 1800 persons with pre-diabetes and T2D. In addition, a sub-sample of this cohort is undergoing amyloid PET and brain MRI. Although the DPPOS AD/ADRD project is an observational study it will overcome some of the caveats mentioned before because it will have detailed ascertainment of metformin exposures, comorbidities, other medications, and state of the art AD/ADRD phenotyping. The DPPOS has over 20 years of detailed data on metformin exposure. Randomized trials of metformin versus placebo in persons with T2D are not feasible since use of metformin in T2D as first line therapy is standard of care.

There are several ongoing or planned clinical trials. Metformin in Alzheimer’s dementia Prevention (MAP, NIH grant R01AG062624, clinicaltrials.gov ID NCT04098666) is an ongoing multisite 18 month 1:1 randomized placebo controlled clinical trial of extended-release metformin 2000 mg in 326 persons with amnestic MCI without T2D in the United States. It includes cognitive outcomes and biomarker outcomes, including measures of neurodegeneration and cerebrovascular disease on brain MRI, amyloid and tau in brain PET, and plasma biomarkers of amyloid, tau, and neurodegeneration. MAP is planned for completion in 2026. Preventing Cognitive Decline with Metformin (MetMemory Study, clinicaltrials.gov ID NCT04511416) is a 3-year randomized clinical trial of extended release metformin versus placebo in 242 persons with mild cognitive impairment with a hemoglobin A1C <6.5% with cognitive and biomarker outcomes based currently under way in Australia. METformin and Finger Intervention to Prevent Cognitive Impairment and Disability in Older Adults at Risk for Dementia (MET-FINGER, NCT05109169) is a 24 month 1:1:1 randomized trial of metformin 2000 mg/day versus 1000 mg/day versus placebo to be conducted in the United Kingdom, Finland, and Sweden [83]. Six hundred persons at risk for dementia will be randomized 1:1 to the FINGER 2.0 intervention versus comparator intervention; those in the FINGER 2.0 group at increased risk for diabetes will be randomized to the metformin arms.

These studies will provide important data on the cognitive safety of metformin and its effects on cognitive outcomes, brain structure, and AD biomarkers both in persons with and without T2D. If metformin is shown to have cognitive benefits, it will be necessary to examine if they it can be used in the treatment or prevention of AD complementing amyloid targeting treatments such as lecanemab [84] and donanemab [85].

There is a need for a precision medicine approach in these studies to identify the subpopulations that are more likely to benefit from metformin. Characteristics that could be considered include APOE ɛ4 genotype, sex, body composition measures, and insulin resistance.

CONCLUSION

Metformin is a safe and effective treatment for T2D, also used for the prevention of T2D, that has multiple metabolic benefits that have been hypothesized to ameliorate diseases such as cancer and diseases related to aging in general. Observational studies suggest that metformin is beneficial for dementia prevention, but this is countered by studies that suggest that metformin could be harmful. A few small randomized clinical trials in persons without T2D suggest that metformin could be beneficial in preventing cognitive impairment in persons with prodromal dementia or early dementia. It is necessary to conduct observational and mechanistic studies in persons with T2D with appropriate ascertainment of metformin and covariates, and state of the art phenotyping of AD/ADRD. Moreover, it is necessary to conduct placebo-controlled randomized clinical trials of metformin in large samples of persons without T2D with relatively long duration and state of the art AD/ADRD phenotyping. Metformin could also be tested in combination with other strategies.

AUTHOR CONTRIBUTIONS

Mouna Tahmi (Data curation; Writing – original draft); Richard Benitez (Conceptualization; Data curation; Writing – original draft); Jose Luchsinger (Conceptualization; Supervision; Writing – original draft).

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

This work was supported by NIH grants R01AG062624, U19AG078558, and K24AG045334.

CONFLICT OF INTEREST

JA Luchsinger is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review.

JA Luchsinger receives a stipend from Wolters Kluwer, N.V. as Editor in Chief of the journal Alzheimer’s Disease and Associated Disorders and has served as a paid consultant to Merck KGaA. The other authors have no interests to declare.

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