Association of frailty and neuropathology of neurodegenerative and brain vascular diseases

Abstract Background Frailty, characterized by increased physical vulnerability, is associated with a higher incidence and severity of cognitive impairment and also a higher burden of neurodegenerative and cerebrovascular diseases. This study investigates the association between frailty and neurodegenerative and cerebrovascular pathologies. Method Cross‐sectional analysis using clinical and neuropathological data from individuals aged 60 or older, enrolled in the Biobank for Aging Studies between 2004 and 2023. A 42‐item frailty index was constructed. Cognitive impairment was defined as a clinical dementia rating score (CDR) of 0.5 or over and participants were stratified according to cognitive status. Linear regression models, adjusting for age, sex, education and race, explored the association between frailty and neuropathology, including Alzheimer´s disease (AD), argyrophilic grain disease (AGD), Lewy‐type pathology (LBP), hippocampal sclerosis, cerebral amyloid angiopathy (CAA), lacunar infarcts, hyaline arteriosclerosis, TDP‐43 pathology and a neuropathological comorbidity score (NPC). Results We examined data from 1.343 subjects. The group with cognitive impairment was older, predominantly female, had lower education, a higher frailty index, and no race differences (Table 1). This group also exhibited a higher prevalence of all neuropathologies previously described (Table 2). In adjusted analyses, frailty was associated with AD Braak staging (β = 0.022, 95% CI=0.017; 0.028, p<0.001 ), CERAD score (β = 0.021, CI 95% = 0.013; 0.029 p<0.001), CAA (β = 0.065, 95% CI = 0.039; 0.092 p<0.001), LBD (β = 0.051, 95% CI = 0.027; 0.075 p<0.001), hippocampal sclerosis (β= 0.053, CI 95% = 0.008; 0.100 p=0.022), lacunar infarcts (β=0.071, CI 95%= 0.046; 0.097 p<0.001), siderocalcinosis (β=0.033, CI 95%= 0.015; 0.051 p<0.001), hyaline arteriosclerosis (β=0.065, CI 95%= 0.050‐0.081 p<0.001) and NPC score (Table 3) (β=0.032, CI 95%= 0.024; 0.040 p<0.001). Frailty was not associated with AGD and TDP‐43. Conclusion Frailty was associated with several neuropathological markers of neurodegenerative and cerebrovascular diseases. More studies are warranted to investigate how this association relates to relevant outcomes such as cognitive impairment.