Exploration of Neuroscience

Table 3. Summary of select studies on the impact of antidiabetic interventions on cognitive impairment/decline or Alzheimer’s disease/dementia risk.

Study	Region and timeline*	Study participants and design	Study tools and interventions	Study findings
Glucagon-like peptide-1 receptor agonists (GLP-1RAs)
Lin et al. [162]	USA, 2017–2024	Obese T2D participants on GLP-1RA (n = 30,430) propensity score-matched to other antidiabetic medication users (n = 30,430); real-world, longitudinal, retrospective cohort	TriNetX US collaborative network. GLP-1RA use included semaglutide, tirzepatide. Primary outcomes: incidence of neurodegenerative and cerebrovascular disease. Secondary outcome: all-cause mortality. Propensity score-matched for age, sex, ethnicity, race, HbA1c, BMI, estimated glomerular filtration rate, comorbidities, medications, lifestyle, health care use, socioeconomic status.	At least 1 year follow-up; GLP-1RA vs. other antidiabetic medication users at lower dementia (HR 0.63, 95% CI 0.50, 0.81) and all-cause mortality (HR 0.70, 95% CI 0.63, 0.78) risk but not MCI (HR 1.13, 95% CI 0.87, 1.46). By dementia subtype, GLP-1RA users not at lower AD or VaD risk. By GLP-1RA subgroup, semaglutide may be more protective against dementia, tirzepatide against stroke.
Nassar et al. [163]	Worldwide	T2D participants on GLP-1RA (n = 854,197) propensity score-matched to without GLP-1RA (n = 854,197); real-world, longitudinal, retrospective cohort	Global Collaborative Network via TriNetX analytics platform. Participants treated with or without GLP-1RAs. Diagnoses by ICD codes for incidence and risk differences in dementia, AD, and various other illnesses. Propensity score-matched for demographics and clinical characteristics.	At least a 5-year follow-up; GLP-1RA users at lower dementia (risk difference –0.010, 95% CI –0.010, –0.009, p < 0.001) and AD (risk difference –0.003, 95% CI –0.003, –0.003, p < 0.001) risk.
Siddeeque et al. [164]	Worldwide, 2010–2023	Obese participants on GLP-1RA (n = 102,935) propensity score-matched to without GLP-1RA (n = 102,935); real-world, longitudinal, retrospective cohort	Global Collaborative Network via TriNetX analytics platform. GLP-1RA use included semaglutide, liraglutide, dulaglutide. Diagnoses by ICD codes for primary outcomes: incidence of AD, VaD, other. Secondary outcomes: all-cause mortality and incidence of other neurodegenerative diseases. Propensity score-matched for demographics and comorbidities.	Variable follow-up (shorter in GLP-1RA users); diabetes prevalence 54.1% after matching; GLP-1RA users at lower AD (RR 0.627, 95% CI 0.481, 0.817, p < 0.001) and VaD (RR 0.438, 95% CI 0.327, 0.588, p < 0.001) risk. By GLP-1RA subgroup, semaglutide but not liraglutide or dulaglutide users at lower AD and VaD risk.
Sodium-glucose cotransporter 2 inhibitors (SGLT2is)
Youn et al. [168]	Worldwide, 2018–2023	Systematic review, meta-analysis registered in PROSPERO (CRD42023461758)	Population: adults aged ≥ 18 years at enrollment; intervention: SGLT2i use; comparison: no SGLT2i and/or other antidiabetic medication use; outcomes: dementia incidence as adjusted HRs or ORs and/or cognitive function score changes; study design: longitudinal comparative studies. 11 included studies.	Vs. non-users, SGLT2i use linked to significantly lower dementia risk (HR 0.68, 95% CI 0.50, 0.92). SGLT2i use significantly linked to improved cognitive function (standardized mean difference 0.88, 95% CI 0.32, 1.44), particularly in MCI or dementia.
Zhang et al. [169]	Worldwide, 2005–2025	T2D participants initiating SGLT2i propensity score-matched to without SGLT2i; real-world, longitudinal, retrospective cohort	Global Collaborative Network (> 150 health systems worldwide). Applied a 456-day washout to reduce protopathic and immortal time bias. Participants stratified by baseline HbA1c (< 7.0%, 7.0–8.9%, ≥ 9.0%). Primary outcome: incident all-cause dementia. Secondary outcomes: dementia subtypes, major adverse cardiovascular events, major adverse kidney events, osteoporotic fracture as a negative control. Propensity score-matched for demographics, comorbidities, and medication use.	Median 4.2 years follow-up; vs. Hb1Ac < 7.0%, higher baseline HbA1c (HR 1.32 for HbA1c 7.0–8.9%; HR 1.68 for HbA1c ≥ 9.0%) significantly linked to higher dementia risk. Associations consistent but attenuated in propensity score-matched models (HR 1.08 and 1.28). Associations strongest for VaD.
GLP-1RA, SGLT2is, versus other antidiabetic medications
Li et al. [171]	Worldwide	Systematic review, network meta-analysis registered in PROSPERO (CRD42022379082)	Population: adults with T2D; intervention: antidiabetic vs. other antidiabetic agents or placebo; comparison: interchangeable with intervention; outcomes: dementia events; study design: observational studies (cohort, case-control, and cross-sectional) or RCTs. 41 observational studies (3,307,483 participants), 23 RCTs (155,443 participants) included. Follow-up period was not restricted.	In network meta-analysis of observational studies, vs. non-users, use of SGLT2i (OR 0.56, 95% CI 0.45, 0.69), GLP-1RA (OR 0.58, 95% CI 0.46, 0.73), TZD (OR 0.68, 95% CI 0.57, 0.81), metformin (OR 0.89, 95% CI 0.80, 0.99) significantly linked to lower dementia risk. Rank order SGLT2i > GLP-1RA > TZD > DPP-4i > metformin > AGI > GKA > sulfonylureas > glinides > insulin on cognitive benefits. Vs. non-users, use of SGLT2i (OR 0.43, 95% CI 0.30, 0.62), GLP-1RA (OR 0.54, 95% CI 0.30, 0.96), DPP-4i (OR 0.73, 95% CI 0.57, 0.93) significantly linked to lower AD risk, while SGLT2i (OR 0.42, 95% CI 0.22, 0.80), TZD (OR 0.52, 95% CI 0.36, 0.75) linked to lower VaD risk. In network meta-analysis of RCTs, dementia risks comparable among antidiabetic agents and placebo.
Schechter et al. [177]	Worldwide, 2010–2021	T2D participants on GLP-1RA (n = 107,221) propensity score-matched to DPP-4i users (n = 107,221); real-world, longitudinal, retrospective cohort	TriNetX platform of EHRs of > 170 million people worldwide. GLP-1RA use included semaglutide, liraglutide, dulaglutide. Diagnoses by ICD codes for dementia, AD, VaD, and other. Propensity score-matching used 40 baseline characteristics of demographic variables, medical diagnoses, laboratory measurements, medication use.	Mean 4.0 years follow-up; GLP-1RAs vs. DPP-4i users at lower dementia (HR 0.76, 95% CI 0.72, 0.81), AD (HR 0.77, 95% CI 0.68, 0.87), VaD (HR 0.75, 95% CI 0.67, 0.85) risk, unadjusted for multiple comparisons. Results in the same direction GLP-1RAs vs. basal insulin users.
Seminer et al. [179]	Worldwide, 2015–2023	Systematic review, meta-analysis registered in PROSPERO (CRD42024557562)	Population: adults aged ≥ 18 years; intervention: SGLT2is, GLP-1RAs, metformin, pioglitazone use; comparison: RCT control arm; outcomes: dementia, CI, and/or change in cognitive score; study design: RCTs with minimum 6-mo follow-up. Total 26 RCTs included 164,531 participants. 12 (SGLT2i), 10 (GLP-1RA) RCTs included in meta-analysis for all-cause dementia.	Overall, glucose-lowering therapy was not significantly linked to lower CI or dementia risk (OR 0.83, 95% CI 0.60, 1.14). By class, GLP-1RAs were significantly linked to lower dementia risk (OR 0.55, 95% CI 0.35, 0.86) but not SGLT2is (OR 1.20, 95% CI 0.67, 2.17).
Song et al. [175]	Worldwide, 2010–2022	Systematic review, meta-analysis registered in PROSPERO (CRD420251037959)	Population: T2D adults aged ≥ 18 years; intervention: SGLT2is, GLP-1RAs, DPP-4i; comparison: interchangeable with intervention; primary outcome: incidence of all-cause dementia; secondary outcomes: AD, VaD, all-cause mortality. 9 included studies.	SGLT2i use significantly linked to lower all-cause dementia risk vs. DPP-4i (HR 0.67, 95% CI 0.59, 0.77) and GLP-1RA (HR 0.93, 95% CI 0.86, 1.00) use. SGLT2i use significantly linked to lower AD risk vs. DPP-4i (HR 0.49, 95% CI 0.35, 0.70) and GLP-1RA (HR 0.68, 95% CI 0.52, 0.88) use. Empagliflozin consistently most protective among SGLT2i agents. Subgroup analyses reveal more benefits for patients aged > 65 years.
Tang et al. [174]	Sweden, 2010–2020	T2D participants (n = 88,381); incident dementia cases (n = 4,607) at follow-up; retrospective, emulated trial study	Various Swedish national registers. T2D by ICD codes or with any non-insulin antidiabetic medication prescription; medication initiation by Anatomical Therapeutic Chemical codes; dementia by ICD codes. Inverse-probability weighting by propensity scores balanced baseline characteristics between groups.	In intention-to-treat analysis, GLP-1RA initiation was significantly linked to lower dementia risk vs. sulfonylureas (HR 0.69, 95% CI 0.60, 0.79, p < 0.0001) and DPP-4i (HR 0.77, 95% CI 0.68, 0.88, p < 0.0001), adjusted for age, sex, enrollment year, health conditions, past medication use, socioeconomic status. Findings consistent in several sensitivity analyses, including a per-protocol analysis.
Wu et al. [176]	United Kingdom, 2007–2022	T2D participants (n = 13,965 pairs of GLP1-RA vs. DPP-4i; n = 25,533 pairs SGLT2i vs. DPP-4i; n = 14,214 pairs GLP1-RA vs. SGLT2i); population-based, emulated trial study	UK Clinical Practice Research Datalink. Participants with HbA1c ≥ 6.5% or T2D diagnosis; GLP1-RA, SGLT2i, DPP-4i medication initiators; dementia by ICD and other codes. Propensity scores overlap weighting for various covariates.	In intention-to-treat analysis, dementia risk did not differ in GLP1-RA vs. DPP-4i initiators (HR 0.95, 95% CI 0.87, 1.04; 6.54 years mean follow-up); continuous GLP1-RA vs. DPP-4i use linked to 21% lower risk (HR 0.79, 95% CI 0.64, 0.97; 2.71 years mean follow-up). In intention-to-treat analysis, dementia risk lower by 14% in SGLT2i vs. DPP-4i initiators (HR 0.86, 95% CI 0.79, 0.94; 4.91 years mean follow-up); continuous SGLT2i vs. DPP-4i uses linked 30% lower risk (HR 0.70, 95% CI 0.60, 0.82; 2.43 years mean follow-up). Dementia risk similar in GLP1-RA vs. SGLT2i initiators and continuous users.
Zhang et al. [178]	USA, 2005–2023	Participants initiating GLP-1RA, SGLT2i, DPP-4i; real-world, longitudinal, retrospective cohort	Optum Clinformatics data, Northwestern Medicine Enterprise Data Warehouse. GLP-1RA use included albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide; SGLT2i use included canagliflozin, dapagliflozin, empagliflozin, ertugliflozin; DPP-4i use included alogliptin, linagliptin, saxagliptin, sitagliptin; use of insulin, metformin, sulfonylureas, TZD, other non-insulin blood glucose-lowering agents also collected. AD by ICD codes.	Vs. DPP-4i, GLP-1RA use (HR ≤ 0.69, p < 0.001) and SGLT2i use (HR ≤ 0.6, p < 0.001) linked to lower AD risk.
Bariatric surgery
Alosco et al. [189]	USA	Obese participants with/without family history of AD (n = 94); prospective, multi-center	Longitudinal Assessment of Bariatric Surgery (LABS) study. Most participants underwent RYGB. Cognition assessed by WebNeuro in attention/executive function, memory, language.	12-week follow-up; 26.6% had diabetes. In overall sample and participants without family AD history, memory and attention/executive function improved 12 weeks post-surgery. In participants with family AD history, only attention/executive function improved 12 weeks post-surgery. Family history of AD linked to higher post-surgery CI rates.
Chen et al. [188]	USA, 2000–2023	Obese participants (n = 5,303) with bariatric surgery, propensity score-matched to obese participants (10,606) without bariatric surgery; retrospective, longitudinal, single-center	Participants underwent RYGB or SG. ADRD via EHR review with ICD-9/10 codes for AD, VaD, Lewy body dementia, frontotemporal dementia, primary progressive aphasia. MCI via EHR review with ICD-9/10 codes.	At baseline, 20.3% of participants overall had T2D. Bariatric surgery was significantly linked to reduced ADRD (SHR 0.37, 95% CI 0.15, 0.89, p = 0.03) and reduced MCI incidence (SHR 0.57, 95% CI 0.39, 0.85, p = 0.01), adjusted for demographics, medical history, and socioeconomic status. Bariatric surgery significantly delayed MCI development by 2.01 years (95% CI 0.70, 3.50, p = 0.004).
Custers et al. [185]	Netherlands, 2018–2020	Obese participants (n = 133); longitudinal, single-center	See Custers et al. [184]. Additionally, MRI for brain volume, cortical thickness, white matter hyperintensities, cerebral blood flow (CBF), spatial coefficient of variation (sCOV).	2 years post bariatric surgery, global cognition > 20% higher in 42.9% (n = 52) of participants; brain structure and perfusion lower in most brain regions; hippocampal and white matter volume stable; no change in CBF and sCOV in nucleus accumbens and parietal cortex; higher temporal cortex thickness and lower sCOV.
Custers et al. [184]	Netherlands, 2018–2020	Obese participants (n = 107); longitudinal, single-center	BARICO study (BAriatric surgery Rijnstate and Radboudumc neuroImaging and Cognition in Obesity). Participants underwent RYGB. General cognition, working memory, episodic memory, shift attention, verbal fluency. Education level.	3 years post bariatric surgery, global cognition > 20% higher in 38.6% (n = 39) of participants; inflammatory factors, leptin, matrix metalloproteinase-9, and apolipoprotein A1 levels remained lower, whereas adiponectin and angiopoietin-1 levels remained higher; depressive symptoms remained lower, whereas physical activity returned to baseline.
Ghanim et al. [190]	USA	Obese participants (n = 15) with T2D; longitudinal	Participants underwent RYGB. AD biomarkers and AD-related gene expression in peripheral blood mononuclear cells.	6-month follow-up; post RYGB, significantly lower plasma glucose and insulin levels, lower homeostasis model of assessment for insulin resistance, lower APP mRNA and protein, lower presenilin-2, ADAM-9, GSK-3β, PICALM, SORL-1, and clusterin levels, lower C-reactive protein and monocyte chemoattractant protein-1 levels.
Reynolds et al. [182]	USA, 2015–2018	Obese participants (n = 87); longitudinal, single-center	Most participants underwent SG. Cognition assessed by NIH toolbox cognitive battery (NIHTB-CB) and Rey Auditory Verbal Learning Test (AVLT). Primary outcome: Change in NIHTB-CB fluid composite score.	2-year follow-up; 24 (27.6%) participants had diabetes, 25 (28.7%) on anti-hyperglycemic medications. Post bariatric surgery, no change in NIHTB-CB composite score [mean change (SD) –0.4 (13.9), p = 0.81, n = 66], significantly higher NIHTB-CB executive function [+6.5 (19.9), p = 0.01, n = 66], significantly lower Rey AVLT memory [−0.24 (0.83), p = 0.01, n = 87]. Improved cognition did not correlate with improved metabolic risk factors and diabetes complications.
Smith et al. [183]	USA, 2016–2019	Obese participants (n = 35); longitudinal, single-center	Participants split between RYGB or SG. A cognitive battery spanning 4 cognitive domains: auditory attention, processing speed, auditory-verbal memory, executive function. Overall composite scores.	RYGB improved weight loss at 1 year follow-up to a greater extent vs. SG. Post SG and RYGB, significantly higher processing speed, auditory attention measures, executive function measures. Only post RYGB, significantly higher executive function. Baseline auditory attention and memory predicted 1 year weight loss post RYGB but not SG. Adjusted for baseline cognition, % total weight loss predicted 1 year auditory attention post RYGB but not SG.

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Entries arranged alphabetically by the first author’s name. *: incomplete years of study enrollment and duration rounded to the indicated year. 95% CI: 95% confidence interval; AD: Alzheimer’s disease; ADRD: Alzheimer’s disease-related dementia; AGI: α-glucosidase inhibitor; BMI: body mass index; CI: cognitive impairment; DPP-4i: dipeptidyl peptidase 4 inhibitors; EHRs: electronic health record; GKA: glucokinase activator; HbA1c: glycated hemoglobin; HR: hazard ratio; ICD: International Classification of Diseases; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; OR: odds ratio; RCT: randomized clinical trial; RR: relative risk; RYGB: Roux-en-Y gastric bypass; SD: standard deviation; SG: sleeve gastrectomy; SHR: subdistribution hazard ratio; T2D: type 2 diabetes; TZD: thiazolidinedione; VaD: vascular dementia.

Supplementary materials

The supplementary table for this article is available at: https://www.explorationpub.com/uploads/Article/file/1006139_sup_1.pdf.

Declarations

Acknowledgments

The authors thank Emily J. Koubek, PhD, for general assistance.

Author contributions

ZGV: Writing—original draft, Writing—review & editing, Visualization. MGS: Conceptualization, Writing—original draft, Writing—review & editing, Visualization. Both authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

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