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

Authors

Paul Kaufmann, Yulia Ilina, Alice Giontella, Michaela Press, Katarina Nägga, Oskar Hansson, Harald Hampel, Andreas Bergmann, Olle Melander

Published in

Alzheimer's research & therapy. Volume 18. Issue 1. Sep 28, 2026. Epub Sep 28, 2026.

Abstract

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).
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.
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.
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.

PMID:
42811373
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

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