Brain agingHumans

Reduced peptide amidation links to higher Alzheimer's risk

In 4,543 adults, each standard deviation drop in amidation enzyme activity raised incident Alzheimer's risk with an adjusted hazard ratio of 2.30.

Alzheimer's Research & Therapy4 Oct 2026, 08:20 BST

In 4,543 dementia-free adults from the Swedish Malmö Preventive Project, researchers tracked incident dementia over an average follow-up of 4.75 years. They measured baseline plasma levels of mid-regional pro-adrenomedullin, bioactive adrenomedullin (bio-ADM), and the amidating activity of peptidylglycine α-amidating monooxygenase (PAM), the key enzyme responsible for activating these peptide hormones.

During follow-up, 205 participants developed Alzheimer's disease and 93 developed vascular dementia. A one standard deviation decrease in PAM activity was associated with increased risk of incident Alzheimer's disease (adjusted hazard ratio 2.30). Lower bio-ADM levels were also associated with higher Alzheimer's risk (adjusted hazard ratio 1.62). These associations remained independent of APOE ε4 status but showed no significant link to vascular dementia in fully adjusted models.

Why it matters

Peptide amidation by PAM activates hormones that maintain endothelial and blood-brain barrier integrity. The findings suggest that defects in post-translational peptide maturation may represent an early systemic marker of neurovascular vulnerability in Alzheimer's disease.

Caveats

The study was observational and relied on national patient registry codes rather than biological or neuroimaging biomarkers to diagnose dementia. Follow-up was relatively short at under five years, and several peptide associations were substantially confounded by body mass index.