Biomarkers

Preclinical studies suggest that dipeptidyl peptidase-4 (DPP-4) inhibitors reduce brain β-amyloid (Aβ) deposition, tau phosphorylation, and neuroinflammation. However, human data remain limited. This post-hoc analysis of the Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT) examined the association between DPP-4 inhibitor use and changes in dementia-related plasma biomarkers-phosphorylated tau 181 (p-tau₁₈₁), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)-in older adults with type 2 diabetes.

This study analyzed 43 participants with type 2 diabetes who completed plasma biomarker assessments at baseline and 18-month follow-up. Biomarkers (p-tau₁₈₁, NfL, GFAP) were measured using the single-molecule array (Simoa™) platform. At baseline, the Aβ composite biomarker-calculated from APP669-711/Aβ_1-42 and Aβ_1-40/Aβ_1-42-was measured using an immunoprecipitation-mass spectrometry assay at Shimadzu Techno Research. To examine associations between DPP-4 inhibitor use and biomarker changes, multiple linear regression analyses were performed. Model 1 was unadjusted; Model 2 included demographic variables (age, sex, education, intervention allocation) and baseline values; Model 3 added terms for glycemic control, glycemic variability (glycoalbumin/HbA1c), and sulfonylurea and biguanide use; Model 4 further adjusted for hypertension, dyslipidemia, presence of ≥1 APOE ε4 allele, Aβ composite biomarker, and estimated glomerular filtration rate.

Among 43 participants, 28 were DPP-4 inhibitor users. At baseline, users had lower Aβ composite biomarker levels than non-users (-0.5 ± 0.7 vs. 0.0 ± 0.7, P = 0.02, Table 1). Over 18 months, users showed smaller increases in p-tau₁₈₁ (0.1 ± 0.5 pg/mL vs 0.6 ± 0.9 pg/mL, P = 0.03, Figure 1). Multiple regression analyses revealed a significant negative association between DPP-4 inhibitor use and p-tau₁₈₁ changes across all models (Model 1, β = -0.35; Model 2, β = -0.35; Model 3, β = -0.42; Model 4, β = -0.39; all P < 0.05). No significant associations were observed for NfL or GFAP.

Our findings align with preclinical evidence that DPP-4 inhibitors may attenuate Alzheimer's disease pathology progression in individuals with type 2 diabetes. Further studies with larger sample sizes are needed to confirm these results.