Ryan Sledge

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia, characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tau tangles that damage key brain structures, resulting in memory loss and cognitive decline.¹ Despite affecting millions worldwide and the prevalence nearly doubling between 1990 and 2016, no cure currently exists. Available treatments remain limited to symptomatic management. Emerging research has identified two proteins, aquaporin-4 (AQP4) and brain-derived neurotrophic factor (BDNF), as important mediators of brain health that are dysregulated in AD. ^2,3 AQP4 is a water channel on astrocytes that facilitates cerebrospinal fluid flow through the glymphatic system, enabling waste clearance. BDNF promotes neuronal survival and synaptic plasticity. Both AQP4 and BDNF are linked to Alzheimer’s pathology, and physical exercise has been proposed as a mechanism to upregulate them; however, the precise biological pathways that explain the benefits of exercise remain incompletely understood.

Objective: This literature review investigated whether exercise slows Alzheimer’s progression, along with the mechanistic pathways through which these effects may occur.

Methods: A targeted review of the literature was conducted using PubMed and Google Scholar. Search terms included: Alzheimer’s disease, aquaporin-4, glymphatic system, BDNF, TrkB signaling, exercise and neurodegeneration, HIIT and Alzheimer’s, and physical activity cognitive decline. Studies selected included human cohort studies, animal model experiments, and postmortem tissue analyses published between 2020 and 2025.

Results: The results indicated that loss of perivascular AQP4 polarization in both postmortem human brain tissue and mouse models impaired glymphatic exchange and promotes Aβ plaque accumulation.² Also, cognitively impaired individuals exhibited significantly lower platelet-poor plasma BDNF levels compared to healthy controls, and higher BDNF levels were associated with reduced tau pathology. However, exercise had an interesting effect on both AQP4 and BDNF. One study demonstrated that high-intensity interval training (HIIT) in AD animal models restored AQP4 polarization in astrocytes, enhancing glymphatic clearance and reducing Aβ and tau accumulation. ⁴ In a separate study, treadmill exercise in 3xTg-AD mice upregulated BDNF-TrkB-PI3K-Akt signaling, reduced hippocampal Aβ, and lowered hyperphosphorylated tau via decreased GSK3β activity (which is associated with reduced AD progression/pathogenesis). ⁵ Finally, a 14-year human trial confirmed that higher physical activity was significantly associated with slower tau accumulation and cognitive decline in individuals with preclinical AD. ⁶

Conclusions: The reviewed literature revealed that exercise benefits individuals with or at risk for Alzheimer’s disease through two complementary mechanisms, restoring AQP4 polarization to enhance glymphatic waste clearance and increasing BDNF to promote neuronal survival. These findings suggest that exercise is a promising non-pharmacological therapeutic strategy for AD. However, most of the mechanistic evidence is limited to animal models. Future human trials are needed to confirm these pathways, determine optimal exercise protocols, and evaluate long-term outcomes across diverse populations.

Work Cited:

1.  Patterson C, Feightner JW, Garcia A, Hsiung GY, MacKnight C, Sadovnick AD. Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. CMAJ. 2008;178(5):548-556. doi:10.1503/cmaj.070796
2. Simon M, Wang MX, Ismail O, et al. Loss of perivascular aquaporin-4 localization impairs glymphatic exchange and promotes amyloid β plaque formation in mice. Alzheimer’s Res Ther. 2022;14(1):59. Published 2022 Apr 26. doi:10.1186/s13195-022-00999-5
3. Kueck PJ, Honea RA, Kemna RE, Burns JM, Morris JK. Brain-derived neurotrophic factor and its relationship to known biomarkers of Alzheimer’s disease. J Alzheimers Dis. 2025;107(2):798-805. doi:10.1177/13872877251362487
4. Feng S, Wu C, Zou P, et al. High-intensity interval training ameliorates Alzheimer’s disease-like pathology by regulating astrocyte phenotype-associated AQP4 polarization. Theranostics. 2023;13(10):3434-3450. Published 2023 Jun 4. doi:10.7150/thno.81951
5. Kim T, Cho J, Kang H. Exercise training-induced benefits for Alzheimer’s disease are associated with modulation of the BDNF-TrkB signaling complex. Sci Rep. 2025;15(1):45130. Published 2025 Dec 22. doi:10.1038/s41598-025-33262-6
6. Yau WW, Kirn DR, Rabin JS, et al. Physical activity as a modifiable risk factor in preclinical Alzheimer’s disease. Nat Med. 2025;31(12):4075-4083. doi:10.1038/s41591-025-03955-6