The Relationship Between Physical Activity and Non-Modifiable Risk Factors on Alzheimer’s Disease and Brain Health Markers: A UK Biobank Study

Background:Modifiable (physical activity) and non-modifiable (sex and genotype) risk factors interact to affect Alzheimer's disease (AD) risk. Further investigation is necessary to understand if these factors influence brain volume and cognition. Objective:The study aimed to assess the effect of physical activity, APOE genotype, and sex on AD risk, brain volume, and cognition. Methods:UK Biobank data from 2006 to 2023 was accessed. Physical activity was measured by accelerometers, and International Physical Activity Questionnaire. Outcomes were AD incidence; brain volume (ventricular cerebrospinal fluid and total brain); and cognition (executive function, memory, visuospatial ability, processing speed, and reaction time). Logistic and linear regression models were conducted. Results:69,060 participants met inclusion criteria (mean age: 62.28 years, SD: 7.84; 54.64% female). Higher self-reported (OR = 0.63, 95% CI [0.40, 1.00], p = 0.047) and accelerometer-assessed (OR = 0.96 [0.93, 0.98], p = 0.002) physical activity was associated with lower disease incidence. Smaller ventricular cerebrospinal fluid volume (β= - 65.43 [- 109.68, - 17.40], p = 0.007), and larger total brain volume (β= 4398.46 [165.11, 8631.82], p <  0.001) was associated with increased accelerometer-assessed and self-reported physical activity respectively. Both brain volume analyses were moderated by sex. Increased accelerometer-assessed physical activity levels were associated with faster reaction time (β= - 0.43 [- 0.68, - 0.18], p = 0.001); though poorer visuospatial ability (β= - 0.06 [- 0.09, - 0.03], p <  0.001), and executive function (β= 0.49 [0.31, 0.66], p <  0.001; β= 0.27 [0.10, 0.45], p = 0.002) was related to self-reported physical activity levels. Conclusions:Higher levels of physical activity reduce AD risk independently of non-modifiable risk factors. Moderation of sex on brain volume highlighted the importance of incorporating non-modifiable risk factors in analysis.