Diabetes Research: Open Access

Diabetes Research: Open Access

Hiroshi Bando^1,2iD*, Hirohisa Urasaki², Masahiro Bando¹, Akiyo Yoshioka^1
1Medical Research/Tokushima University, Tokushima, Japan
²Yoshinogawa Hospital, Tokushima, Japan

Corresponding Author: Hiroshi Bando ^{ORCID iD}
Address: Tokushima University /Medical Research, Nakashowa 1-61, Tokushima 770-0943, Japan.
Received date: 23 January 2026; Accepted date: 26 February 2026; Published date: 06 March 2026

Citation: Bando H, Urasaki H, Bando M, Yoshioka A. Larger Relationship Between Diabetes and Alzheimer Disease and Related Dementias (ADRD). Diab Res Open Access. 2026 Mar 06;7(1):01-04.

Copyright © 2026 Bando H, Urasaki H, Bando M, Yoshioka A. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium provided the original work is properly cited.

Keywords: Alzheimer Disease and Related Dementias, Alzheimer’s Disease, Glucose-Lowering Drug, Advanced Glycation End Products, Odds Ratio

Abbreviations: ADRD: Alzheimer Disease and Related Dementias; AD: Alzheimer’s Disease; GLD: Glucose-Lowering Drug; AGEs: Advanced Glycation End Products; OR: Odds Ratio

Abstract

Patients with Alzheimer disease and related dementias (ADRD) tend to develop diabetes more than those without diabetes. Diabetic treatments mainly include DPP4-i, GLP-1RAs, and SGLT2-i. They are reported to decrease neuroinflammation, amyloid beta accumulation, and hyperphosphorylation of tau protein, and to prevent neuronal loss and enhance neurogenesis. Anti-diabetic agents may decrease dementia risk in T2D based on large research data of 4 million individuals. As a result, the odds ratios (OR) for reducing dementia showed SGLT2-i 0.69, GLP-1RA 0.70, DPP4-i 0.86, metformin 0.92, sulfonylurea 1.02, α-GI 1.14, and insulin 1.26. From some studies, GLP-1RAs and SGLT2-i show a similar degree of clinical effect.

Commentary

Patients with Alzheimer disease and related dementias (ADRD) tend to develop diabetes more frequently than those without diabetes [1]. This is possibly related to metabolic and neurodegenerative impairments [2]. The presence of hypoglycemia and hyperglycemia is involved in cognitive decline [3], and a longer history of diabetes leads to exacerbation of cognitive dysfunction. By a systematic review and meta-analysis, GLP-1RAs may show a statistically significant decrease in all types of dementia, although cardioprotective glucose-lowering treatment was not associated with a decrease in all-cause dementia [4]. Diabetic patients probably have 1.5 times higher risk of Alzheimer’s disease (AD) and 2.5 times higher risk of vascular dementia according to statistics in Japan. They are also prone to cognitive dysfunction, including impairment of executive function, information processing ability, attention, verbal memory, and visual memory. This situation highlights the importance of taking measures to address this issue, especially in the elderly.

There are various hypothesized mechanisms and risk factors for dementia in diabetes. These include oxidative stress, advanced glycation end products (AGEs), inflammation, malnutrition, depression, hyperglycemia or severe hypoglycemia, postprandial hyperglycemia, large blood glucose fluctuations, systolic hypertension, insulin resistance, and dyslipidemia. Diabetic treatments mainly include DPP4-i, GLP-1RAs, and SGLT2-i. They are reported to decrease neuroinflammation, amyloid beta accumulation, and hyperphosphorylation of tau protein, and to prevent neuronal loss and enhance neurogenesis [5]. We can expect potential preventive and therapeutic effects in clinical practice. During 2025-2026, the number of papers presenting links between diabetes medications and dementia has increased dramatically. Among them, representative reports are introduced with some perspectives.

From a recent study, the relative efficacy of anti-diabetic agents was evaluated for decreasing dementia risk in T2D patients. The methods included 4 million cases from 67 trials as real-world database studies. As a result, the odds ratios (OR) for reducing dementia were SGLT2-i 0.69, GLP1-RA 0.70, DPP4-i 0.86, metformin 0.92, sulfonylurea 1.02, α-GI 1.14, and insulin 1.26. The lowest OR was observed for SGLT2-i, and insulin administration showed an increased risk of dementia [6].

As medications for adult T2D patients, up-to-date evidence on key benefits, harms, and uncertainties was studied [7]. The protocol included 869 trials with 493 thousand participants. The data showed 63 drugs and 26 outcomes of interest. The most effective anti-diabetic drugs for weight reduction were tirzepatide -8.63 kg and orforglipron -7.87 kg, followed by eight GLP-1RAs. For adverse effects, SGLT2-i showed genital infections (OR 3.29), ketoacidosis (OR 2.08), and amputations (OR 1.27). Furthermore, tirzepatide and GLP-1RAs showed gastrointestinal adverse effects (GI-AE) (OR 4.21), and finerenone showed hyperkalemia (OR 5.92). On the other hand, GLP-1RAs may show reduction of dementia risk (OR 0.92) with low certainty.

To study the risk of ADRD, comparative analyses were performed for GLP-1RAs and SGLT2-i versus other glucose-lowering drugs (GLDs) in cohort studies [8]. A total of 396,963 eligible T2D patients were included, and a target trial emulation study was conducted. The hazard ratios (HR) were 0.67 for GLP-1RA versus others, 0.57 for SGLT2-i versus others, and 0.97 for GLP-1RA versus SGLT2-i. Thus, GLP-1RA and SGLT2-i showed statistically significant lower risk of ADRD compared with other GLDs, with no difference between the two agents.

Three agents – GLP-1RA, SGLT2-i, and DPP4-I – show potential beneficial efficacy in AD. Two large real-world databases were analyzed to compare AD risk values [9]. Compared with initiation of DPP4-i, the HR was 0.69 for GLP-1RA and 0.67 for SGLT2-i, both associated with significant risk reduction (p < 0.001). Two GLP-1RAs (semaglutide and liraglutide) and three SGLT2-i (empagliflozin, canagliflozin, and dapagliflozin) showed reduced AD risk in drug-specific sensitivity analyses.

From metformin (Met)-based combined treatment, the risk of developing dementia in new-onset T2D was investigated [10]. A retrospective cohort study including 2 million cases over 18 years was performed. The HRs were Met-thiazolidinedione (TZD) 0.73, Met-DPP4i 0.64, and Met-glinides 1.14. The Met-DPP4i group showed the lowest risk, followed by the Met-TZD group. Metformin has been known as the first-line medication for T2D and is thought to decrease dementia risk. The study aimed to determine whether metformin reduces long-term incidence of dementia [11]. Matched cohorts included BMI groups of 25–, 30–, 35–, and ≥40. The HRs for dementia were 0.875, 0.917, 0.878, and 0.891, respectively. Metformin showed reduced dementia risk and reduced all-cause mortality in obese cases. This protective effect was observed across all BMI groups.

The decreased risk of dementia was also studied for GLP-1RA and DPP4-i using the Clinical Practice Research Datalink in the UK [12]. The protocol compared these agents versus sulfonylurea (SU) between 2007 and 2021. Among 275,144 cases followed for 750,847 person-years, HR was 0.77 for DPP4-i versus SU and 0.74 for GLP-1RA versus SU. Both incretin agents showed similar reduction effects.

A recent study compared GLP-1RA versus SGLT2-i, DPP4-i, and SU for dementia risk reduction using a targeted learning causal inference approach [13]. A cohort study was conducted among T2D patients over 60 years, estimating cumulative risk differences at 2.5 years. GLP-1RA showed reduced dementia diagnosis risk compared with DPP4-i and SU (-0.013 and -0.016, respectively).

The comparison of SGLT2-i and DPP4-i for incident dementia risk in T2D was also performed [14]. In a population-based retrospective cohort study including 118,006 individuals, the incident rate (IR) of dementia was 0.56 per 1000 person-years for SGLT2-i users and 2.67 per 1000 person-years for DPP4-i users. The adjusted HR for SGLT2-i compared with DPP4-i was 0.78 for dementia and 0.86 for mild cognitive impairment (MCI).

In summary, the recent discussion on the relationship between diabetes and ADRD has been described. Both conditions have a strong mutual relationship supported by previous reports. However, further research is required to obtain more precise evidence. This report may provide a useful reference from both diabetes and dementia perspectives.

Conflict of Interest

The authors have read and approved the final version of the manuscript. The authors have no conflicts of interest to declare.

Funding

There was no funding received for this paper.

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