# Gene-Exercise Interactions in Amyloid Metabolism and Clearance: Implications for Alzheimer’s Disease

## TL;DR

This paper reviews how physical exercise interacts with genes to affect amyloid metabolism, offering new insights into preventing or slowing Alzheimer’s disease.

## Contribution

The paper provides a novel synthesis of how aerobic exercise modulates amyloid-β metabolism and gene expression in Alzheimer’s disease.

## Key findings

- Exercise influences amyloid-β clearance and modulates APP processing through secretases and neprilysin.
- Transcriptomic data reveal gene–exercise interactions in the entorhinal cortex, an early site of amyloid deposition.
- Exercise modulates pathways like mitochondrial function and neuroinflammation, potentially enhancing cognitive resilience.

## Abstract

Alzheimer’s disease (AD), the most prevalent form of dementia, poses a critical global health challenge as its incidence rises with aging populations. Despite extensive research into its genetic and molecular underpinnings, effective therapeutic strategies remain limited. Growing evidence suggests that physical exercise may offer neuroprotective benefits, potentially mitigating AD progression through multifactorial mechanisms. This review synthesizes current findings on the interplay between aerobic exercise and AD pathophysiology, with a focus on amyloid-β (Aβ) metabolism, gene expression, and neuroinflammation. We explore how exercise influences Aβ clearance, modulates amyloid precursor protein (APP) processing, and impacts the activity of key enzymes such as secretases and neprilysin. Further, we highlight the gene–exercise crosstalk identified through transcriptomic data, particularly in the entorhinal cortex—an early site of Aβ deposition. Our analysis also discusses how exercise-induced modulation of molecular pathways—including mitochondrial function, oxidative stress responses, and neuroinflammatory cascades—may confer cognitive resilience. By integrating molecular, genetic, and systems biology data, this review underscores the potential of structured physical activity as a non-pharmacological intervention to delay or attenuate AD pathology. These insights support a precision medicine approach, which combines lifestyle interventions with molecular profiling, to improve prevention strategies and therapeutic outcomes in AD.