Linking dementia pathology and alteration in brain activation to complex daily functional decline during the preclinical dementia stage

Abstract: Progressive difficulty in performing everyday functional activities is a key diagnostic feature of dementia syndromes. However, not much is known about the neural signature of functional decline, particularly during the very early stages of dementia. Early intervention before overt impairment is observed offers the best hope of reducing the burdens of Alzheimer’s disease and other dementias. But to justify early intervention, those at risk need to be detected earlier and more accurately. Decline in complex daily function (CdF) such as managing medications has been reported to precede impairment in basic activities of daily living (e.g., eating, dressing). Our goal is to establish the neural signature of decline in CdF during the preclinical dementia period. Gait is central to many CdF and community-based activities.2,3 Hence, to elucidate the neural signature of CdF, we validated a novel electroencephalographic (EEG) approach to measure gait-related brain activation while participants perform complex gait based functional tasks. Our hypothesis is that dementia-related pathology during the preclinical period activates a unique gait-related EEG pattern that predicts subsequent decline in CdF. We provide preliminary findings showing that older adults endorsing CdF limitations can be characterized by a unique gait-related neural signature: weaker sensorimotor and stronger motor control activation. This subsample also had smaller brain volume and WMH in regions affected early by dementia and engaged in less physical exercise. We propose a prospective observational cohort study in cognitively unimpaired older adults with and without subclinical Alzheimer’s disease (plasma amyloid-β [Aβ]) and vascular (white matter hyperintensities [WMH]) pathologies. Our aims are to 1) establish the unique gait-related EEG activation as the neural signature and predictor of decline in CdF during the preclinical dementia period; 2) determine associations between dementia-related pathologies and incidence of neural signature of CdF; 3) establish associations between a dementia risk factor, physical inactivity, and the neural signature of CdF. By establishing the clinical relevance and biological basis of the neural signature of CdF decline, we aim to improve prediction during the preclinical stages of Alzheimer’s diseases and other dementias. Our approach has important research and translational implications because gait-related EEG protocols are relatively inexpensive and portable, and predicting CdF decline may have real world benefits. 1