Associations between frailty, biomarkers of cerebral pathology, cognitive and neuropsychiatric symptoms: a memory clinic study

J Frailty Aging. 2026 Mar 23;15(3):100148. doi: 10.1016/j.tjfa.2026.100148. Online ahead of print.

ABSTRACT

BACKGROUND: Frailty is a prevalent condition among older adults with neurocognitive disorders.

OBJECTIVES: To ascertain whether frailty contributes to the severity of cognitive impairment and neuropsychiatric symptoms, and its association with cerebral pathology measured in vivo by fluid and imaging biomarkers.

DESIGN: We conducted cross-sectional and longitudinal analyses based on CLEM Study, a multicentre memory-clinic cohort that recruited participants between 2014 and 2018.

SETTING: CLEM Study occurred in eight memory centres in France (Lyon, Paris, Strasbourg, Poitiers, Tours, Grenoble) and Monaco.

PARTICIPANTS: A total of 168 participants (mean age 80.5 ± 4.8 years) with mild to moderate dementia due to at least one aetiological diagnosis between Alzheimer’s disease, dementia with Lewy bodies or vascular dementia were included in the study.

MEASUREMENTS: The participants were evaluated at baseline and followed up for two years. The concept of frailty was operationalised using a 45-item Frailty Index. Cognition was assessed using the ADAS-cog scale, while neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory. The cerebral pathological score, a proxy for brain pathologies, was a composite score based on the presence of several in vivo biomarkers: presynaptic dopaminergic denervation on ¹²³I-FP-CIT SPECT (DaTscan®), vascular lesions on MRI, elevated blood-based pTau181, neurofilaments light-chain or glial fibrillary acid protein. Linear and mixed regression analyses were conducted to model the relationships between cognitive or neuropsychiatric symptoms, frailty and cerebral pathologic score, adjusted for age, sex and education.

RESULTS: The findings indicate an impact of both frailty (β = 0.28, 95 % CI [0.14-0.43], p < 0.001) and cerebral pathological score (β = 0.30, 95 % CI [0.13-0.47], p = 0.002) on cognitive impairment. However, only frailty was associated with neuropsychiatric symptoms (β = 0.28, 95 % CI [0.14-0.43], p < 0.001), particularly with apathy (β = 0.40, 95 % CI [0.26-0.53], p < 0.001). We found an association between cerebral pathological score and longitudinal cognitive decline (β = 0.36, 95 % CI [0.19-0.53], p < 0.001) in exploratory analyses with available longitudinal data at 24 months (n = 74).

CONCLUSIONS: Neurocognitive disorders are complex entities, where cognitive and neuropsychiatric symptoms are not fully influenced by the same factors. When cognitive symptoms seem more driven by cerebral pathology than frailty, neuropsychiatric symptoms appear to be more influenced by general state of frailty. Measuring and treating frailty might be a key factor in dealing with neuropsychiatric symptoms and their consequences.

PMID:41880327 | DOI:10.1016/j.tjfa.2026.100148