Changes in Motor Activity May Predict Alzheimer's in Cognitively Normal People, Particularly Women

BrightFocus is funding early science behind a promising new technology– a wearable device that provides a very early prediction of Alzheimer’s onset.

What: Disruption of unconscious movement is associated with preclinical Alzheimer’s disease (AD) in cognitively normal women and can be tracked with a digital watch as an early predictor of disease.

Where: Gao L, Li P, Gaba A, et al. Fractal motor activity regulation and sex differences in preclinical Alzheimer’s disease pathology. Alzheimer’s and Dementia, 2021.

BrightFocus Connection: Co-first author Peng Li, PhD, of Brigham and Women’s Hospital and Harvard Medical School, has a BrightFocus Alzheimer’s Disease Research (ADR) grant to investigate whether changes in circadian regulation (the “biological clock”) and autonomic nerve function (ie, involuntary or unconscious motor responses controlled by the nervous system) can be used to predict Alzheimer’s disease.

Why It Is Important: An ideal scenario would make it possible to prevent a disease before it develops. However, to prevent disease, we need indicators that can predict who is at risk, and these predictive biomarkers are still being found for Alzheimer’s. Currently, the gold standard involves measuring toxic proteins in the cerebrospinal fluid, or with neuroimaging. This study demonstrates, for the first time, that disruptions in unconscious daytime motor activity correlate with the presence of these gold standard biomarkers in cognitively normal individuals. Results were most convincingly shown in female, but not male, participants. Monitoring was with a digital watch worn over 14 days.

The autonomic motor activity measured as a biomarker in this study is called fractal motor activity regulation, or FMAR. Human (and other species’) motor activity, like many physiological processes, has predictable patterns over time. Disruption in daytime FMAR has been associated with increased disability, frailty, and mortality in the elderly. Degradation of FMAR accelerates with aging, after AD diagnosis, and correlates with cognitive decline. Previous work by Dr. Li showed that FMAR disruptions could predict early-stage AD and clinical AD an average of five years prior to diagnosis, independent of other AD risk factors. Those results gave rise to the current study, looking for signs of impending AD even further in advance.

The researchers assessed FMAR in 178 cognitively normal people who were at least 45 years old by having them wear a monitor around their wrists for 14 days. They also assessed amyloid plaque and tau pathology using standard techniques (ie, PET imaging and cerebrospinal fluid testing). These molecular markers can be detected 10 to 20 years prior to cognitive impairment, but the necessary imaging and tests are invasive, expensive, and not readily accessible.

This study showed that degradation in FMAR was significantly correlated with amyloid plaque pathology and increased tau – but results only reached statistical significance in women, and were not tied to other influencing factors, including age, race, education, daily activity, and apolipoprotein E ε4 status. These findings suggest that daytime FMAR imparts new information, particularly in women, about AD pathogenesis at the early stage of the disease prior to the onset of cognitive symptoms.

If replicated, these results help position FMAR changes as a uniquely valuable biomarker of AD, since they can be detected early, before cognitive symptoms manifest, and gathered non-invasively and remotely through a wearable monitoring device. Going forward, Dr. Li hopes to conduct larger studies in men to confirm whether the sex-linked differences observed here are replicated. Future studies also are needed to determine the underlying cause of these associations, test the relationship between FMAR alterations and other types of dementia, and explore whether it might be possible not only to use FMAR as a biomarker, but as a treatment approach through modulating motor output to delay the onset of AD.