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

## TL;DR

This paper explores new strategies to treat Alzheimer’s disease by targeting proteins that accumulate with amyloid plaques, using advanced drug technologies.

## Contribution

The paper introduces the potential of targeted protein degradation technologies to selectively eliminate co-aggregating proteins in Alzheimer’s disease.

## Key findings

- Proteins like midkine, pleiotrophin, and clusterin co-accumulate with amyloid plaques and may influence disease progression.
- Emerging technologies like PROTACs, LYTACs, and molecular glues offer a way to selectively degrade these co-aggregating proteins.
- Combining targeted protein degradation with antibody-based therapies could lead to more effective Alzheimer’s treatments.

## 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.