# Molecular mechanisms of exercise-induced improvements in Alzheimer’s disease: a focus on lipid homeostasis

## TL;DR

This paper reviews how exercise can improve Alzheimer’s disease by modulating lipid metabolism, offering a non-drug approach with fewer side effects.

## Contribution

The paper proposes a novel hypothesis that lipids mediate peripheral-central crosstalk between exercise and AD, and explores apolipoprotein E genotype effects.

## Key findings

- Exercise modulates multiple lipids simultaneously, slowing AD progression with minimal side effects.
- Lipids like fatty acids and cholesterol are altered in AD and may serve as early diagnostic and intervention targets.
- Apolipoprotein E genotypes may influence how individuals with AD respond to exercise.

## Abstract

Alzheimer’s disease (AD) is the most prevalent type of dementia, and its pathophysiological mechanisms involve multiple factors, including genomic factors, metabolomic factors, and environmental factors. Lipid dysregulation occurs both centrally and peripherally in patients with AD, and the severity is closely associated with disease progression. Applied studies based on genome-wide association studies, genomic analyses, lipidomic analyses, mass spectrometry, and machine learning, have identified lipids as a key potential target for early diagnosis and intervention in AD. However, due to the complexity of AD pathogenesis and the considerable structural and functional diversities of lipids, pharmacological therapies that target lipid homeostasis have shown limited effectiveness in ameliorating AD pathology and are often accompanied by side effects. In contrast, exercise, a holistic intervention with multitarget effects, can modulate the levels of multiple lipids simultaneously and slow the progression of AD with minimal side effects. However, the mechanisms require further clarification. This review summarizes alterations and mechanisms of action of lipids—including fatty acids, triglycerides, glycerophospholipids, sphingolipids, and cholesterol—in AD and further outlines the possible molecular mechanisms through which exercise influences AD through modulation of lipid metabolism. We also review the recent clinical research on lipid-targeting drugs for AD, and propose a hypothesis that lipids may act as a mediator of the peripheral–central crosstalk between exercise and AD. Additionally, how different apolipoprotein E genotypes may affect the response to exercise in AD is explored. These insights provide a theoretical basis for nonpharmacological interventions for AD and offer an important reference for the development of lipid-related therapeutic targets.