Impaired peptide amidation and risk of incident dementia in the Malmoe preventive project cohort.

Abstract

Background: Peptidylglycine α-amidating monooxygenase (PAM) is the key enzyme responsible for the C-terminal amidation of multiple vasoactive and neuroactive peptide hormones. Among these, amidated bioactive adrenomedullin (bio-ADM) is a critical regulator of endothelial- and blood-brain barrier (BBB) integrity and vascular homeostasis. Impaired peptide amidation may contribute to endothelial dysfunction and neurovascular dysregulation, mechanisms implicated in the pathogenesis of Alzheimer's disease (AD).

Methods: In 4543 dementia-free participants from the Malmö preventive project (MPP), plasma levels of mid-regional pro-adrenomedullin (MR-proADM), bio-ADM, and PAM activity (PAM-AMA) were measured at baseline, and incident dementia was ascertained through national registry data during follow-up. Associations were evaluated using Cox proportional hazards models with multivariable adjustment for common risk factors, false discovery rate correction, BMI-stratified analyses, and sensitivity analyses.

Results: During a mean follow-up of 4.75 ± 1.3 years, 205 participants developed incident AD and 93 developed vascular dementia (VD). Lower PAM-AMA was associated with increased risk of incident AD (adjusted hazard ratio per 1 standard deviation decrease (aHR): 2.30; 95% confidence interval (CI): 1.31-4.02; q = 0.01). Lower bio-ADM levels were also associated with increased Alzheimer's risk (aHR: 1.62; 95% CI: 1.13-2.33; q = 0.01). A reduced bio-ADM/MR-proADM ratio and its interaction with PAM-AMA further strengthened AD risk estimates. Associations were independent of APOE ε4 carrier status, more pronounced among individuals with BMI < 30 and remained directionally consistent in sensitivity analyses. No consistent associations were observed for VD after multivariable adjustment.

Conclusions: Reduced PAM-AMA and lower bio-ADM levels were associated with increased risk of incident AD, but not VD. A reduced ADM-ratio further indicates precursor peptide accumulation. These findings suggest that impaired peptide hormone amidation may represent an early systemic marker of neurovascular vulnerability and support further investigation of C-terminal peptide amidation pathways in translational AD research, including studies with a longer follow-up period and biomarker-confirmed dementia diagnoses.