Brain Peptides in Alzheimer's: From Disease Drivers to Therapeutic Targets

The review identifies peptides' central role in AD at both pathological and therapeutic levels: Pathogenic peptides (Aβ oligomers, hyperphosphorylated tau fragments) drive synaptic failure, mitochondrial dysfunction, and neuroinflammation. Endogenous neuropeptides provide compensatory neuroprotective, trophic, and homeostatic effects. Therapeutic advances include aggregation inhibitors, receptor-selective neuropeptide analogues, cell-penetrating peptide conjugates, and approaches targeting proteostasis, insulin/incretin signaling, neurotrophic support, and microglial activation. Critical barriers include blood-brain barrier penetration, metabolic stability, off-target effects, and need for biomarker-guided patient stratification.

Comprehensive narrative review integrating evidence on brain peptides in AD pathophysiology, peptide-based therapeutic strategies, and delivery platform advances.

Alzheimer's disease affects over 55 million people worldwide with limited treatment options. The recognition that peptides are both central to disease pathology and offer unique therapeutic advantages (high specificity, natural brain signaling) positions peptide-based approaches as a promising frontier. The inclusion of incretin/GLP-1 signaling as a therapeutic target also connects to the broader GLP-1 drug revolution.

This review captures an inflection point in Alzheimer's therapeutics: the first disease-modifying antibodies (lecanemab, donanemab) have been approved, and next-generation peptide-based approaches may offer advantages in specificity, delivery, and combination therapy. The connection between incretin/GLP-1 signaling and neurodegeneration reflects the growing recognition that metabolic peptide pathways influence brain health — a concept now being tested in large clinical trials of semaglutide for Alzheimer's.

As a narrative review, this paper provides a broad overview without systematic methodology or quantitative analysis. The field is rapidly evolving, and some discussed therapeutic approaches are at very early stages with limited clinical validation. The challenge of translating peptide therapeutics across the blood-brain barrier remains a fundamental barrier that no review can fully resolve.