O5‐04‐05: Aerobic exercise reduces phosphorylated tau protein in cerebrospinal fluid in older adults with mild cognitive impairment

We have shown that in older adults with mild cognitive impairment, aerobic exercise has favorable effects on executive function and plasma beta amyloid, a biomarker linked to Alzheimer's disease pathology. These and similar findings by other investigators suggest that aerobic exercise may be a disease-modifying intervention for adults in the earliest stages of the disease. High tau protein levels in the brain predict rate of progression to Alzheimer's dementia; thus, identifying interventions that can successfully reduce tau levels is a priority in clinical treatment trials. We enrolled 65 sedentary older adults (age: 55-89yrs) with amnestic MCI and prediabetes, as per American Diabetes Association hemoglobin A1c criteria given the added dementia risk conferred by early glucometabolic disease. Participants were randomized to an aerobic training or a stretching control group, and completed structured exercise under the supervision of a trainer for 45-60 min, 4 times/week for 6 months using community facilities. The aerobic group exercised at 70-80% of heart rate reserve (HRR), while the stretching group exercised at an intensity below 35% HRR. At baseline and month 6, participants completed cognitive testing (verbal recall, tests of executive function), a 400m timed walk test, glucose tolerance test, body fat assessment, and blood and cerebrospinal fluid (CSF) collection. Forty participants also received structural and functional brain MRI. ANCOVA models were used with adjustments for age and education. Adherence to the intervention protocols was 92%, and aerobic exercise improved walk times and glucose tolerance relative to the control group (p<0.05). Six months of structured moderate-to-high intensity aerobic exercise reduced CSF levels of phosphorylated and total tau protein, particularly for adults over the age of 70 years (p<0.05). We also report exercise-induced increases in blood flow in the right anteromedial temporal lobe region (p<0.05), and favorable effects on a composite measure of executive function (p<0.05). Six months of aerobic exercise is sufficient to favorably move tau protein levels in older adults at high risk of progression to dementia. These findings provide important evidence to support a disease-modifying effect and thus high therapeutic relevance of a readily accessible nonpharmacological intervention for adults with MCI.