Reproducible Generalized Thermal Sensation Triggered by Levodopa in a Patient With Parkinson's Disease.

Physical inactivity has been estimated, based largely on epidemiological models, to contribute to approximately 13% of Alzheimer’s disease (AD) cases worldwide (). However, the precise contribution of physical activity (PA) to dementia prevention or treatment remains elusive due to inconsistent research findings. Observational studies suggest that PA is associated with reduced AD risk and markers of neurometabolic health, including greater hippocampal regional volumes, lower neuro-inflammatory markers, and more favorable lipid metabolism regulation (; ). Evidence from randomized controlled trials (RCTs) assessing the relationship between PA and cognitive function shows predominantly null results (; ; ). This discrepancy makes it difficult to determine whether PA has a true disease-modifying role, whether its benefits depend on the disease stage at which it is introduced, or whether the current evidence base is not well aligned with the populations and outcomes most likely to show response. Presence of the apolipoprotein ε4 ( ε4) allele, the strongest genetic risk factor for late-onset sporadic AD, may modulate the effect of PA on cognitive function and brain structure. Although 40% of AD cases consist of ε4 carriers, there is a lack of personalized lifestyle interventions for this high-risk group (; ). Previous literature has been conflicting, with several studies reporting potential protective associations of PA with dementia risk in ε4 carriers, while others report such benefits among non-carriers only (). These inconsistencies may reflect differences in study design, baseline cognitive status, age, PA measurement, intervention timing, and outcome selection rather than a single uniform effect of ε4. Yet, differences between genetic status and regional brain activation in response to PA have also been described, with ε4 carriers exhibiting greater activation in memory-related brain regions, such as the hippocampus and posterior cingulate cortex (). Further, PA has been proposed as a possible modulatory factor on AD pathology (e.g., neuroinflammation, lipid metabolism, neurotrophic factors) in ε4 carriers, with potential to modify AD-related pathological processes, (). These findings suggest that PA may be most informative to study earlier in the disease continuum, before substantial neurodegeneration has occurred. Several systematic reviews have evaluated the association between PA, cognition, and ε4 status; however, no umbrella review has synthesized -specific primary studies while explicitly accounting for baseline cognitive status. To address this gap, the present umbrella review examines primary studies extracted from systematic reviews to evaluate whether cognitive, fluid biomarker, neuroimaging, and vascular/metabolic associations and effects of PA differ by ε4 genotype across stages of cognitive aging. We focus on whether apparent ε4-specific findings vary by baseline cognitive status and study design, and whether the current evidence is aligned with the disease stage at which PA may be most informative.