Neurophysiological and Brain Structural Markers of Cognitive Frailty Differ from Alzheimer's Disease

With increasing life span and prevalence of dementia, it is important to understand the mechanisms of cognitive aging. Here, we focus on a subgroup of the population we term “cognitively frail,” defined by reduced cognitive function in the absence of subjective memory complaints, or a clinical diagnosis of dementia. Cognitive frailty is distinct from cognitive impairment caused by physical frailty. It has been proposed to be a precursor to Alzheimer's disease, but may alternatively represent one end of a nonpathologic spectrum of cognitive aging. We test these hypotheses in humans of both sexes, by comparing the structural and neurophysiological properties of a community-based cohort of cognitive frail adults, to people presenting clinically with diagnoses of Alzheimer's disease or mild cognitive impairment, and community-based cognitively typical older adults. Cognitive performance of the cognitively frail was similar to those with mild cognitive impairment. We used a novel cross-modal paired-associates task that presented images followed by sounds, to induce physiological responses of novelty and associative mismatch, recorded by EEG/MEG. Both controls and cognitively frail showed stronger mismatch responses and larger temporal gray matter volume, compared with people with mild cognitive impairment and Alzheimer's disease. Our results suggest that community-based cognitively frail represents a spectrum of normal aging rather than incipient Alzheimer's disease, despite similar cognitive function. Lower lifelong cognitive reserve, hearing impairment, and cardiovascular comorbidities might contribute to the etiology of the cognitive frailty. Critically, community-based cohorts of older adults with low cognitive performance should not be interpreted as representing undiagnosed Alzheimer's disease. SIGNIFICANCE STATEMENT The current study investigates the neural signatures of cognitive frailty in relation to healthy aging and Alzheimer's disease. We focus on the cognitive aspect of frailty and show that, despite performing similarly to the patients with mild cognitive impairment, a cohort of community-based adults with poor cognitive performance do not show structural atrophy or neurophysiological signatures of Alzheimer's disease. Our results call for caution before assuming that cognitive frailty represents latent Alzheimer's disease. Instead, the cognitive underperformance of cognitively frail adults could result in cumulative effects of multiple psychosocial risk factors over the lifespan, and medical comorbidities.