Jade Lin

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid plaque accumulation, tau neurofibrillary tangles, and cognitive decline.^1,2 As life expectancy increases, the prevalence of AD is also rising, with most treatments only helping to slow the progression of symptoms.³ Research increasingly supports the role of lifestyle interventions, particularly exercise, in slowing cognitive decline.^2,3,4 However, the molecular mechanisms underlying exercise’s protective effects on AD are not fully understood.^2,3,4 Recent studies identify several key mechanisms, including the role of brain-derived neurotrophic factor (BDNF), adult hippocampal neurogenesis (AHN), amyloid precursor protein (APP) processing, and the lactate-sirtuin 1 (SIRT1) pathway.^1,2,4 These findings address the current knowledge gap in defining biological pathways by which exercise may delay or prevent AD onset.

Objective: In this narrative review, we explore how exercise influences the progression of Alzheimer’s disease and the molecular pathways involved, particularly focusing on its impact on BDNF expression, AHN stimulation, and amyloid-β (Aβ) production and clearance.

Search Methods: An online literature search was conducted using PubMed, prioritizing articles published between 2017 and 2025. Search terms included “Alzheimer’s Disease,” “exercise,” “BDNF,” “amyloid,” and “physical activity”.

Results: One study identified that clinically normal older adults with high Aβ burden benefited from higher activity.³ Additionally, higher levels of physical activity were linked to slower gray matter loss and better cognition, suggesting physical activity as non-invasive early interventions for individuals at risk of AD.³ Further evidence showed that exercise-induced AHN was proven to show improved cognition, increase levels of BDNF, and reduce Aβ load.¹ Moreover, treadmill exercise in rats significantly decreased hippocampal APP and BACE1 levels, key enzymes involved in Aβ production, supporting the molecular basis for exercise’s neuroprotection.² In an exercise trial, researchers collected plasma from Alzheimer’s disease patients and examined neuron-derived extracellular vesicles (NDEVs) for proBDNF, BDNF, and humanin.⁵ Results showed that exercise significantly boosted levels of all three markers in the NDEVs and that notably, individuals with the APOE ε4 allele who are linked to a higher risk of Alzheimer’s, showed an even greater response.⁵ Lastly, lactate, a byproduct of exercise, was shown to activate the SIRT1-PGC1α-FNDC5-BDNF signaling pathway, boosting BDNF production and enhancing neuroprotection.⁴

Conclusion: This literature review identifies the various molecular benefits of exercise in AD prevention and management. BDNF signaling, AHN stimulation, reduction in APP/BACE1 expression, and lactate-mediated SIRT1 activation emerge as key pathways. Understanding these mechanisms opens the door to exciting new possibilities for AD treatment and lays the groundwork for developing targeted physical therapy programs or pharmacological interventions that replicate the benefits of exercise. Clinical trials incorporating NDEV biomarkers could further validate exercise as a viable, non-invasive intervention for reducing the risk of Alzheimer’s disease. Together, these findings not only support exercise as a powerful therapeutic tool but also pave the way for innovative approaches to Alzheimer’s care.

Work Cited:

1. Choi SH, Bylykbashi E, Chatila ZK, et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science. 2018;361(6406):eaan8821. doi:10.1126/science.aan8821
2. Alkadhi KA, Dao AT. Exercise decreases BACE and APP levels in the hippocampus of a rat model of Alzheimer’s disease.Molecular and Cellular Neuroscience. 2018;86:25–29. doi:10.1016/j.mcn.2017.11.008
3. Rabin JS, Klein H, Kirn DR, et al. Associations of Physical Activity and β-Amyloid With Longitudinal Cognition and Neurodegeneration in Clinically Normal Older Adults. JAMA Neurol.2019;76(10):1203–1210. doi:10.1001/jamaneurol.2019.1879
4. El Hayek L, Khalifeh M, Zibara V, et al. Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF). J Neurosci. 2019;39(13):2369-2382. doi:10.1523/JNEUROSCI.1661-18.2019.
5. Delgado-Peraza F, Nogueras-Ortiz C, Simonsen AH, et al. Neuron-derived extracellular vesicles in blood reveal effects of exercise in Alzheimer’s disease [published correction appears in Alzheimers Res Ther. 2024 Jan 23;16(1):18. doi: 10.1186/s13195-023-01371-x.]. Alzheimers Res Ther. 2023;15(1):156. Published 2023 Sep 20. doi:10.1186/s13195-023-01303-9