Relationship Between Neuropathology and Cognitive Impairment: Exploring the Interacting Roles of Frailty and Sex

Neuropathologic burden explains part of the clinical expression of dementia. Frailty and sex have been involved in the individual vulnerability to cognitive impairment, yet it remains unclear how they jointly modify the relationship between neuropathology and cognition. This study investigated whether frailty and sex modify the associations of neurodegenerative and cerebrovascular pathologies with cognitive abilities.

In a cross-sectional study with participants 60 years or older from the Biobank for Aging Studies, frailty was assessed using a 31-item index, and cognitive abilities were evaluated using the Clinical Dementia Rating sum of boxes (CDR-SB). Neuropathologies, including neurofibrillary tangles (NFT), neuritic plaques (NP), Lewy body disease (LBD), hippocampal sclerosis, and vascular pathologies, were evaluated individually and combined into a neuropathologic comorbidity score (NPC). Multivariable linear regression models were used to investigate the associations between neuropathology and cognitive function, including interaction terms for frailty and sex.

We analyzed data from 1,531 participants (mean age 78 ± 9 years; 53% female; 65% White participants). The associations between neuropathology and poor cognitive abilities were stronger in frail participants for NFT (β = 1.84; 95% CI 1.54-2.15; p < 0.001), NP (β = 2.58; 95% CI 2.16-2.99; p < 0.001), transactive DNA-binding protein 43 (β = 3.29; 95% CI 2.32-4.26; p < 0.001), cerebral amyloid angiopathy (β = 3.48; 95% CI 1.94-5.01; p < 0.001), hippocampal sclerosis (β = 4.92; 95% CI 2.66-7.17; p < 0.001), and hyaline arteriolosclerosis (β = 2.20; 95% CI 1.15-3.25; p < 0.001). Frailty and sex modified the associations of Alzheimer disease (AD) pathology and the NPC with cognition. Frail women showed higher predicted CDR-SB scores than frail men at Braak NFT stages III-IV (8.07; 95% CI 7.37-8.78 vs 5.89; 95% CI 5.08-6.71), moderate (11.15; 95% CI 10.19-12.10 vs 8.23; 95% CI 6.92-9.54), and severe Consortium to Establish a Registry for Alzheimer's Disease (CERAD) NP scores (14.34; 95% CI 13.49-15.18 vs 11.95; 95% CI 10.57-13.33).

The relationship between neuropathology and cognition was stronger in frail individuals, especially women, who showed more vulnerability to AD pathology. These findings suggest that frailty and sex jointly shape susceptibility to cognitive impairment. As a potentially modifiable clinical condition, frailty represents a meaningful target for interventions aimed at mitigating the cognitive expression of neuropathology, particularly among women. Limitations include informant-based assessments and the cross-sectional design.