Background: Without effective therapies, the number of persons living with Alzheimer's disease (AD) is projected to increase exponentially owing to the rapid growth in the elderly segment of the United States' population. To thwart this public health epidemic that AD is poised to become, there is a critical need to uncover preventative approaches capable of curbing the progression of the underlying disease process and thereby delaying the onset of overt symptoms. This study examined whether engagement in physical activity might favorably alter the age-dependent evolution of AD-related brain and cognitive changes in a cohort of at-risk, late-middle-aged adults.
      Methods: Three hundred and seventeen enrollees in the Wisconsin Registry for Alzheimer's Prevention (age= 60.29±6.29 years, 68% women, 40% APOE4 carriers, and 74% with family history of AD) underwent T1 MRI; and a subset also underwent PiB-PET (n=186) and FDG-PET (n=152) imaging. Their responses on a self-report measure of current physical activity were used to compute MET-hours/week scores. These scores were then used to classify the participants as either Physically Active or Physically Inactive based on American Heart Association guidelines. The participants also completed a comprehensive neuropsychological battery that assessed 6 domains: Immediate Memory, Verbal Learning & Memory, Working Memory, Speed & Flexibility, Visuospatial Ability, and Verbal Ability. Regression analyses were used to test whether the known effect of age on AD biomarkers and cognition was modified by physical activity, after controlling for relevant covariates.
      Results: There were significant age–physical activity interactions for hippocampal volume (p=.025), amyloid burden (p=.015), and glucose metabolism (p=.015) such that, with advancing age, Physically Active individuals had reduced hippocampal degeneration, slower accumulation of amyloid, and attenuated glucose hypometabolism compared with the Physically Inactive. Similar age–physical activity interactions were also observed on cognitive domains of Immediate Memory, Visuospatial Ability, and Verbal Ability.
      Conclusions: In a middle-aged, at-risk cohort, engagement in physical activity is associated with an attenuation of the deleterious influence of age on key AD biomarkers. Randomized controlled trials in such risk-enriched cohorts, with longitudinal follow up, would help clarify the extent to which midlife participation in structured physical exercise protects against the development of AD and related disorders in later life.
      Figure thumbnail fx1
      Age-associated glucose hypometabolism (a), amyloid deposition (b), hippocampal shrinkage (c), and memory decline (d) are attenuated in physically-active subjects but pronounced in inactive subjects. P values for interaction are .025, .015, .015, .042 respectively.