Frailty and the brain: a narrative review of functional and pathological correlates

: Frailty influences the risk, phenotypic expression, and course of highly prevalent neurological conditions. However, the structural, functional, and pathological changes in the brain associated with frailty remain insufficiently explored. This narrative review examines existing evidence on the functional and pathological brain correlates of frailty in both healthy adults and patients with neurological conditions, encompassing findings from neuropathology, fluid biomarkers, neuroimaging, and neurophysiology. Autopsy studies suggest that individuals experiencing frailty may exhibit decreased resistance and resilience to neuropathological changes, along with heightened cognitive vulnerability, even in the presence of low levels of pathology. The accumulation of brain pathology may, in turn, play a role in accelerating frailty progression. Numerous MRI-based studies have shown that frailty is associated with vascular brain damage, mostly consisting of increased white matter hyperintensity volumes, and with reduced gray matter volumes. Additionally, variations in cerebrospinal fluid and plasma biomarkers of Alzheimer's disease pathology have been documented. Furthermore, frailty-related changes in EEG/MEG signals and brain plasticity suggest potential widespread neural dysfunction. Future research is needed to elucidate the pathophysiological mechanisms underlying the neurological correlates of frailty. This exploration should encompass key aspects of aging, such as inflammation, mitochondrial dysfunction, and impaired proteostasis. Gaining a deeper understanding of the relationship between frailty and brain function and pathology could pave the way for discovering novel biomarkers and intervention targets, ultimately impacting the prevention and management of age-related neurological conditions.