Work

Beyond Amyloid: Targeting Co-Aggregating Proteins and Targeted Degradation Strategies in Alzheimer’s Disease

Year: 2026

Type: article

Abstract: Alzheimer's disease (AD) involves a constellation of molecular processes that extend well beyond amyloid-β (Aβ) accumulation. Recent anti-amyloid antibodies provide limited clinical benefits, highlighting the need for additional strategies due to their modest efficacy and safety concerns. Increasing proteomic evidence reveals that proteins such as midkine (MDK), pleiotrophin (PTN) and clusterin (CLU) accumulate within amyloid plaques and may shape disease progression, although their precise contributions-protective, pathogenic, or both-remain unknown. In this Perspective, we examine how emerging targeted protein degradation (TPD) technologies, including Proteolysis-Targeting Chimeras (PROTACs), Lysosome-Targeting Chimeras (LYTACs) and molecular glues (MGs), could provide a means to selectively eliminate these co-aggregating proteins. We also discuss advances in degrader design, artificial intelligence (AI)-assisted screening, and strategies aimed at enhancing Central Nervous System (CNS) delivery. We finally outline how integrating TPD modalities with antibody-based and multi-target therapeutic approaches may promote more effective, systems-level interventions for AD.

Source: Biomedicines

DOI: 10.3390/biomedicines14010216

Authors: Martina Monaco, Alessandra Pinto, Massimo Grilli

Institutions: University of Genoa, Ospedale Policlinico San Martino

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,137