Mechanistic Effects of Aerobic Exercise in Alzheimer's Disease: Imaging Findings From the Pilot FIT-AD Trial

Abstract

Despite strong evidence from animal models of Alzheimer's disease (AD) supporting aerobic exercise as a disease-modifying treatment for AD, human mechanistic studies are limited with mixed findings. The objective of this pilot randomized controlled trial was to examine the effects of 6-month aerobic exercise on hippocampal volume, temporal meta-regions of interest (ROI) cortical thickness, white matter hyperintensity (WMH) volume, and network failure quotient (NFQ), measured with MRI, in community-dwelling older adults with AD dementia. Additionally, the relationships between 6- and 12-month changes in MRI biomarkers and the AD Assessment Scale-Cognition (ADAS-Cog) were examined. Sixty participants were randomized, but one was excluded because baseline MRI failed quality control: 38 randomized to cycling and 21 to stretching. The intervention was moderate-intensity cycling for 20–50 mins, three times a week for 6 months. Control was low-intensity stretching. The study outcomes include hippocampal volume, temporal meta-ROI cortical thickness, WMH volume, and NFQ. Outcomes were measured at baseline, 6 months, and 12 months. The sample averaged 77.3 ± 6.3 years old with 15.6 ± 2.9 years of education and 53% men. Both groups experienced significant declines over 6 months in hippocampal volume (2.64% in cycling vs. 2.89% in stretching) and temporal meta-ROI cortical thickness (0.94 vs. 1.54%), and over 12 months in hippocampal volume (4.47 vs. 3.84%) and temporal meta-ROI cortical thickness (2.27 vs. 1.79%). These declines did not differ between groups. WMH volume increased significantly with the cycling group increasing less (10.9%) than stretching (24.5%) over 6 months (f = 4.47, p = 0.04) and over 12 months (12.1 vs. 27.6%, f = 5.88, p = 0.02). NFQ did not change significantly over time. Pairwise correlational analyses showed a significant negative correlation between 6-month changes in hippocampal volume and ADAS-Cog (r = −0.34, p < 0.05). To conclude, aerobic exercise may reduce the decline in hippocampal volume and temporal meta-ROI cortical thickness during the intervention period, but the effect sizes are likely to be very small and dose-dependent and reverse once the intervention stops. Aerobic exercise is effective on slowing down WMH progression but has no effect on NFQ. Hippocampal atrophy was associated with cognitive decline during the intervention period.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT01954550.

Understanding How Physical Exercise Improves Alzheimer’s Disease: Cholinergic and Monoaminergic Systems

“…Nowadays, physical activity and exercise have been widely acknowledged as effective strategies for improving AD pathology and AD-associated cognitive impairment ( Northey et al, 2018 ; Jia et al, 2019 ; de Farias et al, 2021 ). From a mechanistic perspective, macroscopically, regular exercise has been shown to alleviate some abnormalities of brain structure and function and to increase cerebral blood flow in subjects with mild cognitive impairment (MCI) and AD ( Broadhouse et al, 2020 ; Tomoto et al, 2021 ; Yu et al, 2021 ); microscopically, exercise training not only increases levels of exerkines (e.g., irisin, Lourenco et al, 2019 ; Islam et al, 2021 ) and metabolic factors (e.g., lactate, El Hayek et al, 2019 ) in the peripheral circulation, which act on the AD brain indirectly, but also exert direct neuroprotective effects by increasing levels of brain-derived neurotrophic factor (BDNF) ( Wang and Holsinger, 2018 ) and promoting adult hippocampal neurogenesis ( Choi et al, 2018 ), enhancing synaptic plasticity ( Mu et al, 2022 ), reducing neuroinflammation and oxidative stress ( Zhang et al, 2019 ), and ameliorating Aβ deposition and tau hyperphosphorylation ( Brown et al, 2019 ). Strikingly, the activity of central neurotransmitter systems seems to be strongly modulated by exercise.…”

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

“…In Danish older adults with mild-to-moderate AD dementia, a 16-week aerobic exercise did not change CSF Aβ 42 [30], CSF tau [31], and PET amyloid [32]. In the USA, a 6-month aerobic exercise showed a trend of reduced hippocampal atrophy and significantly decreased white matter hyperintensity in comparison to stretching exercise in older adults with mild-to-moderate AD dementia [33]. However, no studies have examined the feasibility of blood biomarkers in older adults with Alzheimer's dementia or the effects of aerobic exercise on plasma AD biomarkers in older adults with AD dementia.…”

“…The randomization schedule was concealed in opaque envelopes from all investigators (except for the statistician) and data collectors. The details of the FIT-AD trial protocol and its main cognitive and imaging biomarker findings were published previously [33,35,36]. Procedures involving experiments on human subjects were done in accordance with the ethical standards of the Committee on Human Experimentation of the institution in which the experiments were done or in accord with the Helsinki Declaration of 1975.…”

Meta analysis of aerobic exercise improving intelligence and cognitive function in patients with Alzheimer’s disease

“…[33] Therefore, researchers suspect that Aβ amyloid plaques are only an accompanying phenomenon in the process of AD, rather than the cause of AD. Therefore, researchers started from the perspectives of Tau protein, ferroptosis and exercise [34][35][36][37] in order to find the original target for the treatment of AD.…”