Multimodal biomarker characterization of amnestic objective subtle cognitive decline

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Abstract Background Alzheimer’s disease (AD) diagnostic guidelines acknowledge transitional decline prior to clinical onset, yet the absence of practical recommendations for defining this stage presents a major challenge for early detection and risk stratification. Objectively defined subtle cognitive decline (obj-SCD) is increasingly recognized, yet optimal methods for its definition remain uncertain, and consequently, the pathological and neuronal characteristics of this stage remain largely unexplored. The objective of this study was to provide a multimodal biomarker characterization of amnestic obj-SCD, defined using clinically grounded standardized longitudinal neuropsychological criteria in aging and preclinical AD. Methods This prospective observational study analyzed 3-year longitudinal data from the Alzheimer’s and Families+ (ALFA+) cohort, including cognitively unimpaired participants with available baseline CSF biomarker measurements (normal or AD continuum profiles) and longitudinal neuropsychological assessments (2 time points, 3-year follow-up). The primary study measurement, amnestic obj-SCD, was defined using robust longitudinal neuropsychological references combined with multivariate base rate thresholds of significant cognitive decline (Free and Cued Selective Reminding Test, Memory Binding Test, Wechsler Memory Scale IV: Logical Memory). Study outcomes included plasma p-tau217, NfL, and GFAP; CSF p-tau181/Aβ42, NfL, and GFAP; Aβ and tau PET; and Grey Matter volume (GMv) measurements. The associations of amnestic obj-SCD with fluid (plasma and CSF) and neuroimaging (PET and GMv) biomarkers were evaluated using mixed-effects and voxel-wise linear regression models, respectively. Results A total of 350 CU individuals were included (mean age 61 years; 60% female; mean education, 14 years, 35% CSF Aβ-positive). Applying the criteria defined for clinical staging, amnestic obj-SCD was identified in 10% of the sample. Multimodal biomarker characterization demonstrated significant associations of amnestic obj-SCD with core AD biomarkers, including diagnostic core 1 (higher plasma p-tau217 concentration, higher CSF p-tau181/Aβ42 ratio, and higher global Aβ PET burden) and prognostic core 2 AD biomarkers (higher MTL tau PET burden). Amnestic obj-SCD was also significantly associated with biomarkers of non-specific processes involved in AD pathophysiology, including neurodegeneration (higher plasma and CSF NfL concentrations, reduced GMv in the cingulate cortex, and longitudinal GMv bilateral reductions in the hippocampus) alongside inflammation (higher plasma and CSF GFAP concentrations, and longitudinal GMv increases in neocortical brain regions). Discussion This study suggests that amnestic obj-SCD reflects early AD-related neuropathological changes (Aβ and tau) and key downstream mechanisms involved in AD pathophysiology (neurodegeneration and inflammation). These findings highlight the need for standardized clinical staging criteria to enhance early detection and risk stratification in aging and preclinical AD.

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