Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study

Abstract

We evaluated the effect of the antidiabetic drug metformin on patients enrolled in the ADNI study considering patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Employing data from this observational study, we performed a principal component analysis focusing on the cognitive sphere by evaluating data from neuropsychological tests included in a modified version of the Alzheimer's Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite (ADCS-PACC). Second, we included the levels of amyloid-β, tau, and phosphorylated tau in CSF. We found that MCI metformin-treated patients were globally characterized as subjects with a better cognitive performance and CSF biomarkers profile than the mean population of MCI patients. On the other hand, control subjects and type 2 diabetes patients (T2D) were paired by age, gender, ApoE allele, and years of education, defining three groups: MCI, MCI + T2D, and MCI + T2D + metformin. We evaluated the effect of T2D and metformin treatment employing the PACC score and composites defined from standardized ADNI variables to evaluate the memory and learning function. We found that MCI + T2D patients had a worse cognitive performance than MCI patients, but this deleterious effect was not observed in MCI + T2D + metformin patients. These cognitive variations were associated with changes in cortical thickness and hippocampal volume. Finally, no differences were found in metabolic plasmatic parameters (glycemia, cholesterol, triglycerides). Our study-employing different strategies for data analysis from the global study ADNI-shows a beneficial effect of metformin treatment on cognitive performance, CSF biomarkers profile, and neuroanatomical measures in MCI due to AD patients.

Keywords: Alzheimer’s disease; Metformin; Type 2 diabetes.

Fig. 1

Metformin use was associated with a lesser cognitive decline in patients with prodromal Alzheimer’s disease. A Biplot obtained from a principal component analysis performed on 810 MCI^AD subjects. Black dots represent patients receiving metformin. B Box plots indicating the mean value of principal component 1 and principal component 2 for MCIAD-metformin patients (n = 55). *p < 0.05; ns, non-significant differences (one-sample t-test compared with a theoretical mean of zero). C Standardized coefficient obtained for each variable included in the principal component analysis. Note that the values from the Trail Making Test A used for this analysis were inverted

Fig. 2

Treatment with metformin is associated with a healthier biomarker profile in patients with prodromal Alzheimer’s disease. A Biplot obtained from a principal component analysis performed on 455 MCIAD subjects. Black dots represent patients receiving metformin. B Box plots indicating the mean value of principal components 1 and 2 for MCI^AD-metformin patients (n = 31). *p < 0.05; ns, non-significant differences (one-sample t-test compared with a theoretical mean of zero). C Standardized coefficients obtained for each variable included in the principal component analysis

Fig. 3

Metformin ameliorated the cognitive impairment caused by diabetes in patients with Alzheimer’s disease. Mean PACC score (A), mean Memory Composite score (B), and mean Learning Composite score (C) are expressed in relation to cognitively normal subjects. (D) Rey Auditory Verbal Learning Test (AVTOT) score in consecutive trials (T1–T5). Data are presented as mean ± SEM. *p < 0.05, **p < 0.01, and ***p < 0.001 (one-way ANOVA with pairwise comparisons)

Fig. 4

Metformin treatment diminished the neuroanatomical alterations exhibited by diabetic patients with prodromal Alzheimer’s disease. A Cortical thickness of the AD signature (expressed as the sum of the thickness for each area measured in mm). B Total hippocampal volume (expressed as the sum of both left and right hippocampal volume in cm³). *p < 0.05 and ***p < 0.001 (one-way ANOVA)

Fig. 5

Metformin-receiving patients exhibited a metabolic profile that was similar to non-diabetic MCI patients. Levels of plasmatic glucose (A), triglycerides (B), and total cholesterol (C) measured in mg/100 ml. Data are presented as mean ± SEM. **p < 0.01 (one-way ANOVA with pairwise comparisons)