Physical Activity as a Primary Prevention Strategy for Alzheimer's Disease: A Comprehensive Review of Neurobiological Mechanisms and Clinical Evidence

Alzheimer's disease (AD) represents an important public health crisis, as current treatment interventions have shown limited effects in altering disease progression after the onset of clinical symptoms. Neurodegeneration begins approximately 2 decades before clinical manifestation, providing a considerable window for preventive measures. This detailed review synthesises evidence from longitudinal epidemiological studies, randomised controlled trials and preclinical models to explain the neurobiological mechanisms underlying exercise-induced neuroprotection. Analysis of data from over 200,000 participants across multiple cohorts shows that structured physical activity reduces AD risk by 38-51%, with dose-dependent relationships found across intensity levels. Mechanistically, exercise targets multiple pathways involved in AD pathogenesis, including enhancing amyloid-β clearance via activation of the glymphatic system, upregulating neurotrophic cascades such as BDNF/TrkB signalling, improving cerebrovascular function through endothelial nitric oxide synthase activation, and regulating neuroinflammatory responses through microglial phenotype switching. Significant gaps remain in the current literature. Most evidence is derived from observational studies involving cognitively normal populations and there is limited data regarding optimal exercise prescriptions for individuals with preclinical AD pathology. Additionally, sex-specific responses and genetic modifiers, such as APOE ε4 status, require more investigation to inform personalised prevention strategies. The evidence indicates the need for a fundamental change in clinical practice: physical activity should be prescribed in the same way as pharmacological interventions, with careful choice of timing, intensity, and duration. Exercise should be recognised as a medical intervention, not simply a lifestyle recommendation, especially for the ageing population. To convert evidence into practice, an organised approach to exercise prescription is recommended. This includes assessing physical activity levels and individual risk factors, developing a detailed exercise plan specifying frequency, intensity, type and duration, and providing guidance on safe progression. Scheduled follow-up visits are important for monitoring the outcomes, adjusting prescriptions as needed and removing barriers. This stepwise approach supports the integration of exercise into routine clinical care, ensuring that preventive methods for cognitive health are both evidence-based and actionable.