Investigating the role of frailty in the expression of dementia

Abstract

Background: Frailty is related to neuropathological features of Alzheimer’s disease (AD) as well as cognitive decline and dementia.

Objectives: 1) determine whether frailty moderates the relationship between neuropathology and dementia status in Alzheimer’s dementia; 2) examine the influence of frailty on the relationship between a neuropathological index and all-cause dementia; 3) examine the influence of frailty on the relationship between a neuropathological index and all-cause dementia in a population-representative dataset; 4) characterize longitudinal change in frailty and how this relates to dementia; and 5) validate a visual frailty tool in a memory clinic.

Methods: I used data from two clinical-pathological cohort studies to address objectives 1-4, and created a frailty index based on the deficit accumulation approach for each clinical evaluation. Cognitive status was ascertained at last evaluation or via clinical consensus post-mortem. Neuropathological assessment was completed post-mortem. I employed regression models to evaluate the relationship between neuropathology, frailty, and dementia status, and mixed-effects models to characterize longitudinal change in frailty. I collected data from patients at a memory clinic to address objective five.

Results: Frailty moderates the relationship between AD-pathology and Alzheimer’s dementia such that as frailty increases, the relationship between AD-pathology and dementia becomes weaker. When I extended this analysis to include mild cognitive impairment and all-cause dementia and a broader conceptualization of neuropathology (10-item index), frailty and neuropathology were additive risk factors for cognitive impairment. I replicated these findings in a population-representative dataset and demonstrated that if severe frailty (FI>0.4) were prevented, 1/8 dementia cases could be avoided. People with more rapidly increasing frailty were more likely to develop dementia, even after controlling for neuropathology. I found the Pictorial Fit-Frail Scale to be feasible, reliable, and valid in a memory clinic setting among geriatricians, nurses, caregivers, and patients.

Conclusions: Frailty, as quantified by deficit accumulation, plays a key role in the clinical expression of dementia. Frailty intervention appears to be a promising avenue to mitigate the cognitive and functional consequences of neuropathology, and may suggest a resilience mechanism. Future research examining mechanisms of age-related disease should account for frailty to better understand risk and impact of treatment.