# Therapeutic and preventive strategies based on the maladaptive plasticity hypothesis for Alzheimer’s disease

## TL;DR

This paper explores new strategies to prevent and treat Alzheimer's by targeting harmful changes in brain plasticity while preserving healthy brain function.

## Contribution

It introduces a hypothesis-driven framework focusing on maladaptive synaptic plasticity as a key target for Alzheimer's interventions.

## Key findings

- Maladaptive plasticity driven by amyloid-β precursor protein may underlie Alzheimer's pathophysiology.
- Strategies to preserve adaptive plasticity could lead to new prevention and treatment approaches.
- The framework connects molecular, circuit, and cognitive dysfunction in Alzheimer's.

## Abstract

Alzheimer’s disease (AD), the most common form of dementia, is characterized by two hallmark pathologies, amyloid plaques (APs) and neurofibrillary tangles (NFTs). Amyloid-β and tau, key components of APs and NFTs, respectively, are widely considered primary drivers of neurodegeneration in AD. In contrast, an alternative view proposes that network failure, arising from amyloid-β precursor protein-driven excessive/aberrant and maladaptive synaptic plasticity, underlies AD pathophysiology. Synaptic plasticity is indispensable for cognitive functions such as learning and memory; however, when dysregulated, it may lead to cognitive decline and accelerate the trajectory toward AD. This paper, based on this hypothesis, examines strategies to mitigate maladaptive plasticity while preserving adaptive plasticity, and proposes the potential of novel approaches for the prevention and treatment of mild cognitive impairment and AD, encompassing both activity-based interventions and pharmacological treatments. This hypothesis-driven framework offers a coherent perspective linking molecular, circuit, and cognitive levels of dysfunction in AD, and may guide more integrative, multi-level approaches to future preventive and therapeutic strategies, a direction increasingly emphasized in current experimental and clinical AD research.