Relationships between memory decline and the use of metformin or DPP4 inhibitors in people with type 2 diabetes with normal cognition or Alzheimer's disease, and the role <i>APOE</i> carrier status

Wu, Che‐Yuan; Ouk, Michael; Wong, YW; Anita, Natasha Z.; Edwards, Jodi D.; Yang, Pearl; Shah, Baiju R.; Herrmann, Nathan; Lanctôt, Krista L.; Kapral, Moira K.; MacIntosh, Bradley J.; Rabin, Jennifer S.; Black, Sandra E.; Swardfager, Walter

doi:10.1002/alz.12161

Cited by 64 publications

(58 citation statements)

References 52 publications

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“…Specifically, we observed that before starting the MedDiet intervention, individuals with type 2 diabetes from a group presenting good glycemic control (S1) treated with metformin presented a higher performance in memory, executive functions and global cognition than those not treated with metformin. These results agree with previous observational studies showing better memory performance (14) or greater maintenance of executive functions and global cognition (34) in cognitively normal subjects with diabetes type 2 treated with metformin, compared to those not treated with metformin. Metformin use has also been associated with lower dementia risk (35,36) and better cognitive function (37), but results are still highly variable across studies (15).…”

Section: Metformin Use and Cognition In Individuals With Diabetessupporting

confidence: 92%

“…This approach allows to account for systematic differences in comorbidities between groups and is used to limit confounding by indication. We also had no information about the APOE genotype of participants, which could influence the association between metformin use and cognitive decline, as reported in previous studies (14).…”

Section: Limitationsmentioning

confidence: 99%

“…Previous studies have shown that metformin use for more than 6 years was associated with lower risk of cognitive impairment (13) and with better performance in some cognitive domains over time in cognitively normal subjects with type 2 diabetes (14). However, there is currently considerable controversy about the effect of metformin on cognition (15).…”

Section: Introductionmentioning

confidence: 99%

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Metformin Use and Cognitive Function in Older Adults With Type 2 Diabetes Following a Mediterranean Diet Intervention

et al. 2021

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Background and Purpose: Both adherence to the Mediterranean diet (MedDiet) and the use of metformin could benefit the cognitive performance of individuals with type 2 diabetes, but evidence is still controversial. We examined the association between metformin use and cognition in older adults with type 2 diabetes following a MedDiet intervention.Methods: Prospective cohort study framed in the PREDIMED-Plus-Cognition sub-study. The PREDIMED-Plus clinical trial aims to compare the cardiovascular effect of two MedDiet interventions, with and without energy restriction, in individuals with overweight/obesity and metabolic syndrome. The present sub-study included 487 cognitively normal subjects (50.5% women, mean ± SD age of 65.2 ± 4.7 years), 30.4% of them (N = 148) with type 2 diabetes. A comprehensive battery of neurocognitive tests was administered at baseline and after 1 and 3 years. Individuals with type 2 diabetes that exhibited a good glycemic control trajectory, either using or not using metformin, were compared to one another and to individuals without diabetes using mixed-effects models with inverse probability of treatment weights.Results: Most subjects with type 2 diabetes (83.1%) presented a good and stable glycemic control trajectory. Before engaging in the MedDiet intervention, subjects using metformin scored higher in executive functions (Cohen's d = 0.51), memory (Cohen's d = 0.38) and global cognition (Cohen's d = 0.48) than those not using metformin. However, these differences were not sustained during the 3 years of follow-up, as individuals not using metformin experienced greater improvements in memory (β = 0.38 vs. β = 0.10, P = 0.036), executive functions (β = 0.36 vs. β = 0.02, P = 0.005) and global cognition (β = 0.29 vs. β = −0.02, P = 0.001) that combined with a higher MedDiet adherence (12.6 vs. 11.5 points, P = 0.031). Finally, subjects without diabetes presented greater improvements in memory than subjects with diabetes irrespective of their exposure to metformin (β = 0.55 vs. β = 0.10, P < 0.001). However, subjects with diabetes not using metformin, compared to subjects without diabetes, presented greater improvements in executive functions (β = 0.33 vs. β = 0.08, P = 0.032) and displayed a higher MedDiet adherence (12.6 points vs. 11.6 points, P = 0.046).Conclusions: Although both metformin and MedDiet interventions are good candidates for future cognitive decline preventive studies, a higher adherence to the MedDiet could even outweigh the potential neuroprotective effects of metformin in subjects with diabetes.

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Section: Metformin Use and Cognition In Individuals With Diabetessupporting

confidence: 92%

Section: Limitationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metformin Use and Cognitive Function in Older Adults With Type 2 Diabetes Following a Mediterranean Diet Intervention

et al. 2021

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“…The cohort data from National Alzheimer's Coordinating Center suggests that the association between metformin use and better memory performance overtime is only observed in diabetic patients with normal cognition (n 1192). By comparison, in patients with AD (n 807), dipeptidyl peptidase-4 inhibitor treatment is associated with a slower memory decline (Wu et al, 2020). In a pooled study including five population-based cohorts (3,590 individuals with diabetes), no significant associations are found between metformin use and brain function and structure outcomes (Weinstein et al, 2019).…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

Metformin: A Novel Weapon Against Inflammation

Bai

Chen

2021

Front. Pharmacol.

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It has become widely accepted that inflammation is a driving force behind a variety of chronic diseases, such as cardiovascular disease, diabetes, kidney disease, cancer, neurodegenerative disorders, etc. However, the existing nonsteroidal anti-inflammatory drugs show a limited utility in clinical patients. Therefore, the novel agents with different inflammation-inhibitory mechanisms are worth pursuing. Metformin, a synthetic derivative of guanidine, has a history of more than 50 years of clinical experience in treating patients with type 2 diabetes. Intense research efforts have been dedicated to proving metformin’s inflammation-inhibitory effects in cells, animal models, patient records, and randomized clinical trials. The emerging evidence also indicates its therapeutic potential in clinical domains other than type 2 diabetes. Herein, this article appraises current pre-clinical and clinical findings, emphasizing metformin’s anti-inflammatory properties under individual pathophysiological scenarios. In summary, the anti-inflammatory effects of metformin are evident in pre-clinical models. By comparison, there are still clinical perplexities to be addressed in repurposing metformin to inflammation-driven chronic diseases. Future randomized controlled trials, incorporating better stratification/targeting, would establish metformin’s utility in this clinical setting.

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“…It was confirmed in a more recent study that type-2 diabetes did not correlate with the amyloid plaque or neurofibrillary tangle load, but it was commented on that both diseases are associated at early stages with a significant cerebrovascular disease that can affect the development of AD pathology [ 27 ]. Much interest in this topic has been on whether patients treated with the insulin sensitizer metformin have a reduced risk of dementia [ 137 , 138 , 139 ]. Metformin, which activates AMPK leading to inhibition of TXNIP expression, has significant activity in inhibiting the activation of the NLRP3 inflammasome complex [ 140 , 141 , 142 ].…”

Section: Txnip Expression In the Brainmentioning

confidence: 99%

Thioredoxin-Interacting Protein (TXNIP) with Focus on Brain and Neurodegenerative Diseases

Tsubaki

Tooyama

Walker

2020

IJMS

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The development of new therapeutic approaches to diseases relies on the identification of key molecular targets involved in amplifying disease processes. One such molecule is thioredoxin-interacting protein (TXNIP), also designated thioredoxin-binding protein-2 (TBP-2), a member of the α-arrestin family of proteins and a central regulator of glucose and lipid metabolism, involved in diabetes-associated vascular endothelial dysfunction and inflammation. TXNIP sequesters reduced thioredoxin (TRX), inhibiting its function, resulting in increased oxidative stress. Many different cellular stress factors regulate TXNIP expression, including high glucose, endoplasmic reticulum stress, free radicals, hypoxia, nitric oxide, insulin, and adenosine-containing molecules. TXNIP is also directly involved in inflammatory activation through its interaction with the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome complex. Neurodegenerative diseases such as Alzheimer’s disease have significant pathologies associated with increased oxidative stress, inflammation, and vascular dysfunctions. In addition, as dysfunctions in glucose and cellular metabolism have been associated with such brain diseases, a role for TXNIP in neurodegeneration has actively been investigated. In this review, we will focus on the current state of the understanding of possible normal and pathological functions of TXNIP in the central nervous system from studies of in vitro neural cells and the brains of humans and experimental animals with reference to other studies. As TXNIP can be expressed by neurons, microglia, astrocytes, and endothelial cells, a complex pattern of regulation and function in the brain is suggested. We will examine data suggesting TXNIP as a therapeutic target for neurodegenerative diseases where further research is needed.

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Relationships between memory decline and the use of metformin or DPP4 inhibitors in people with type 2 diabetes with normal cognition or Alzheimer's disease, and the role APOE carrier status

Cited by 64 publications

References 52 publications

Metformin Use and Cognitive Function in Older Adults With Type 2 Diabetes Following a Mediterranean Diet Intervention

Metformin Use and Cognitive Function in Older Adults With Type 2 Diabetes Following a Mediterranean Diet Intervention

Metformin: A Novel Weapon Against Inflammation

Thioredoxin-Interacting Protein (TXNIP) with Focus on Brain and Neurodegenerative Diseases

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