Clinical Impact and Prognostic Value of Alzheimer Disease Biomarkers in the Very Old.

Abstract (English)

BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) is increasingly viewed as a clinical-biological continuum, but the utility of biomarkers in individuals aged ≥80 years, the so-called "very old," remains uncertain, because of concerns about its clinical usefulness. This study aimed to determine the clinical impact and prognostic value of AD biomarkers in very old individuals. METHODS: We performed a retrospective longitudinal cohort study within the Sant Pau Initiative on Neurodegeneration (SPIN, Barcelona, Spain), a memory clinic-based research cohort. Patients were referred from primary care physicians or community neurologists for evaluation within a public universal health care catchment area. We included SPIN participants evaluated between October 2013 and May 2024 who were aged ≥80 years and had mild cognitive impairment (MCI) at the baseline visit. Participants underwent standardized clinical and neuropsychological assessments and had CSF and plasma biomarker measurements available. AD biology was defined by the CSF phosphorylated tau at threonine 181/amyloid-&#x3b2; 42 ratio. Plasma phosphorylated tau at threonine 217 (p-Tau217) was evaluated for (1) diagnostic accuracy for AD biology and (2) prognostic associations with longitudinal cognitive change (Mini-Mental State Examination [MMSE]) and progression to dementia. Analyses used linear mixed-effects models for MMSE trajectories and Cox regression for dementia conversion. RESULTS: A total of 167 participants were included (mean age 82.3 years, 59% women) with a mean follow-up of 35.8 months; the ones with AD biology (n = 116, 69%) had worse baseline cognitive performance, particularly in memory, compared with those without (Cohen <i>d</i> = 0.34, <i>p</i> = 0.03). Plasma p-Tau217 showed excellent diagnostic accuracy for detecting AD biology (0.93, 95% CI 0.88-0.98; cutoff 0.19 pg/mL; sensitivity 94.5%; specificity 84%). Over time, participants with AD biology declined faster on the MMSE than those without (-0.47 vs -0.18 points per year; <i>p</i> < 0.01). Cox models showed an increased risk of progression to a dementia stage among individuals with higher plasma p-Tau217 concentrations (hazard ratio 1.49, 95% CI 1.05-2.13, <i>p</i> = 0.026). DISCUSSION: In very old individuals with MCI, AD biology (CSF) and plasma p-Tau217 identify individuals at higher risk of faster cognitive decline and progression to dementia. Limitations of this study include the single-center design and the modest sample size.