Can Dipeptidyl Peptidase-4 Inhibitors Slow Alzheimer’s Progression in Diabetes Patients?

DPP-4i may lower the amyloid burden in Alzheimer’s patients and improve cognitive impairment. 

Alzheimer’s disease and diabetes mellitus have been closely associated due to the toxic aggregates of amylin that can reduce beta-cell function and progressive loss of mass in patients living with diabetes. Alzheimer’s disease and diabetes mellitus have common mechanisms such as insulin resistance, inflammatory response, insulin growth factor signaling, neurofibrillary tangle formation, oxidative stress, and amyloid-beta (Aβ) formation. 

Dipeptidyl peptidase-4 inhibitors (DPP-4i) treat hyperglycemia by inhibiting the degradation of glucagon-like peptide-1. Studies show that the DPP-4i are associated with favorable cognitive outcomes in the elderly and patients with mild cognitive impairment or Alzheimer’s disease. DPP-4i provide neuroprotective properties by modulating prosurvival and anti-apoptotic signaling, inhibiting phosphorylation of toxic proteins, inhibiting neuroinflammation, and enhancing synaptic plasticity in experimental Alzheimer’s disease models. When Amyloid beta (Aβ) forms plaques on the brain, it interferes with cell-cell communication and activates an immune response. Amyloid beta (Aβ) plaques have been seen in the brains of patients with Alzheimer’s disease and are one of the main characteristics of the disease. This study wants to determine if DPP-4i has protective effects on Aβ aggregation. This study also intends to assess the longitudinal cognitive outcomes in diabetic Alzheimer’s disease-related cognitive impairment (ADCI) patients. 

The study was a retrospective study that enrolled 282 patients; of the 282 patients, 141 patients were non-diabetic patients with ADCI. Patients were assessed for cognitive impairment, the presence of Amyloid-beta (Aβ), and diabetes mellitus. To identify Aβ aggregation, researchers used an F-FBB PET scan, which is widely used as an Aβ imaging biomarker. In addition, standard uptake ratios (SUVR) were calculated from cerebral cortical areas to assess Aβ retention. 

 In this study, patients were divided into three groups. These groups consisted of diabetes patients treated with DPP-4i (ADCI-DPP-4i+), diabetes patients not treated with a DPP-4i (ADCI-DPP-4i–), and patients without diabetes. 

Statistical analyses used in this study were one-way ANOVA with post-hoc false discovery rate to compare baseline demographic, Pearson’s X2 tests or Fisher test for categorical variables. To compare continuous variables between the diabetic groups, the researchers used an independent t-test. Linear regression analysis was used to determine independent effects after adjusting for other variables.  

The patients all had similar baseline characteristics except for APOEε4 carrier, hypertension, HbA1c. Hypertension was present more in the ADCI-DPP-4i+ and ADCI-DPP-4i– groups. HbA1c in the ADCI-DPP-4i+ was significantly higher than patients in the ADCI-DPP-4i–. Global SUVRs values for the ADCI-DPP-4i+ group were substantially lower than in the other groups. The ADCI-DPP-4i+ also had lower composite, lateral temporal SUVRs, and lower global Aβ burden in all four regional cortices. Patients were assessed using the MMSE score, and the results indicate a yearly decrease of 0.77 in the ADCI-DPP-4i+ patients than in the ADCI-DPP-4i-.group. 

This study reported that diabetes patients with ADCI treated with DPP-4i had significantly lower Aβ burdens than patients not treated with DPP-4i and those without diabetes. After the follow-up period of 30 months, the ADCI-DPP-4i+ group had a slower decline in cognitive performance than ADCI-DPP-4i–. This finding may suggest that DPP-4i may have protective effects on cognitive outcomes. This study reported that ADCI-DPP-4i+ patients had a lower global Aβ burden than the non-diabetic ADCI group; this finding opens up the possibility that DPP-4i medication may also benefit patients with non-diabetic ADCI.  Other studies have demonstrated DPP-4i possible benefit for Alzheimer’s patients by increasing the levels of GLP-1 in the peripheral blood. DPP-4i medications such as saxagliptin or linagliptin have been shown to decrease Aβ levels in the hippocampus and improve cognitive performance by suppressing neuroinflammation. Aβ accumulation starts in the presymptomatic stages of Alzheimer’s disease from the cingulate and frontal cortices. This study suggests that because DPP-4i lowers the Aβ load in all four regions, it may modulate Aβ accumulation in Alzheimer’s disease. There are differing theories about the effect that diabetes mellitus has on the Aβ burden. This study’s result shows that the Aβ burden at baseline was similar in patients with ADCI regardless of diabetes. DPP-4i did reduce the Aβ burden and improve the cognitive function of patients. 

Practice Pearls: 

• Alzheimer’s patients taking DPP-4i medication had a lower global amyloid burden than Alzheimer’s patients not taking a DPP-4i. 
• Alzheimer’s patients taking DPP-4i had a slower decline in MMSE score and memory recall. 
• Diabetes mellitus has no significant impact on Aβ burden in patients with Alzheimer’s. 

Jeong, Seong Ho et al. “Association of Dipeptidyl Peptidase-4 Inhibitor Use and Amyloid Burden in Diabetic Patients With AD-Related Cognitive Impairment.” Neurology, Aug 2021   

Jerrine Fletcher, Fourth Year Doctor of Pharmacy Candidate, Florida A&M University College of Pharmacy