Feasibility and preliminary effects of exercise interventions on plasma biomarkers of Alzheimer’s disease in the FIT-AD trial: a randomized pilot study in older adults with Alzheimer’s dementia

Abstract

Background Alzheimer’s disease (AD) biomarkers have provided a unique opportunity to understand AD pathogenesis and monitor treatment responses. However, exercise trials show mixed effects on imagining and cerebrospinal fluid biomarkers of AD. The feasibility and effects of exercise on plasma biomarkers remain unknown. The primary objective of this study was to examine the feasibility of recruitment, retention, and blood sample collection in community-dwelling older adults with mild-to-moderate AD dementia. Secondarily, it estimated the preliminary effects of 6-month aerobic and stretching exercise on plasma amyloid-β42 and Aβ40 (Aβ42/40) ratio, phosphorylated tau (p-tau) 181, and total tau (t-tau). Methods This pilot study was implemented in year 2 of the 2-parallel group FIT-AD trial that randomized 96 participants on a 2:1 allocation ratio to moderate-intensity cycling or low-intensity stretching for 20–50 min, 3 times/week for 6 months with 6-month follow-up. Investigators (except for the statistician) and data collectors were blinded to group assignment. Fasting blood samples were collected from 26 participants at baseline and 3 and 6 months. Plasma Aβ42, Aβ40, p-tau181, and t-tau were measured using Simoa™ assays. Data were analyzed using intention-to-treat, Cohen’s d, and linear mixed models. Resultss The sample averaged 77.6±6.99 years old and 15.4±3.00 years of education with 65% being male and 96.2% being apolipoprotein epsilon 4 gene carriers. The recruitment rate was 76.5%. The retention rate was 100% at 3 months and 96.2% at 6 months. The rate of blood collection was 88.5% at 3 months and 96.2% at 6 months. Means (standard deviation) of within-group 6-month difference in the stretching and cycling group were 0.001 (0.012) and −0.001 (0.010) for Aβ42/40 ratio, 0.609 (1.417) pg/mL and 0.101(1.579) pg/mL for p-tau181, and −0.020 (0.279) pg/mL and −0.075 (0.215) pg/mL for t-tau. Effect sizes for within-group 6-month difference were observed for p-tau181 in stretching (d=0.43 [−0.33, 1.19]) and t-tau in cycling (−0.35 [−0.87, 0.17]). Conclusions Blood collections with fasting were well received by participants and feasible with high recruitment and retention rates. Plasma biomarkers of AD may be modifiable by exercise intervention. Important design considerations are provided for future Phase III trials. Trials registration ClinicalTrials.gov Identifier: NCT01954550 and posted on October 1, 2013

Does Physical Exercise Modify the Pathophysiology of Alzheimer’s Disease in Older Persons?

“…Studies conducted on Aβ species, including middleaged and older men and women with normal cognitive status, mild cognitive impairment or AD indicated no significant effect of exercise interventions, lasting from 8 weeks to 1 year and including 3 to 5 sessions of 45 to 60 min weekly, on either blood (14)(15)(16)(17)(18), CSF (19) or brain (20)(21)(22) amyloid levels, compared to control groups. However, subgroup analyses demonstrated that in APOE-ε4 allele carriers with AD, an increase in CSF Aβ40 was observed in inactive controls after 16 weeks of follow-up while the carriers from the exercise group maintained their baseline concentrations (19).…”

“…Likewise, 6 months of cycling exercise had no impact on the blood levels of phosphorylated tau 181 in cognitively healthy older adults ( 18 ). Furthermore, in older adults with AD, neither 16 ( 19 ) or 24 weeks ( 17 ) of aerobic exercise impacted the concentrations of total and phosphorylated tau proteins measured in the CSF or in the blood.…”

Editorial: The impact of physical activity on white matter during healthy aging

“…The modifiable effects of physical activity are not only restricted to physiological aging, but also continue in people with dementia, as it is shown recently in people with Alzheimer's disease, via regulating some of the disease biomarkers. That is, amyloid and total and phosphorylated (p181) tau protein in plasma (Yu et al, 2022 ). The findings of the studies in this collection collectively suggest that regular exercise is associated with improved white matter microstructural integrity, regardless of the exercise type, age, gender.…”