Clinical Manifestations.

Background: Objective Subtle Cognitive Decline (obj-SCD) can be identified through standardized neuropsychological tests and may precede the development of Mild Cognitive Impairment (MCI). Nevertheless, current clinical and research criteria lack a standardized protocol for identifying obj-SCD. This study introduces cutting-edge sensitive methods to characterize obj-SCD, defined through Alzheimer's disease (AD) biomarker-based longitudinal cognitive performance in episodic memory. Neurocognitive characterization of obj-SCD is supported by Voxel-Based Morphometry (VBM) analyses, examining longitudinal changes in Grey Matter volume (GMv) at the preclinical stage of the Alzheimer's continuum.

Method: Three hundred cognitively unimpaired (CU) individuals (mean age: 60, SD: 4.76) from the ALFA+ cohort study (three-year follow-up) were included. AT(N) profiles were defined at baseline with Cerebrospinal Fluid (CSF) biomarkers. AD biomarker-based reliable change indices adjusted for practice effect (A-T-[N]- longitudinal performance as reference) were computed for the assessment of episodic memory (Free-Cued Selective Reminding Test, Memory Binding Test, Wechsler Memory Scale-IV). Considering the relationship between the number of neuropsychological measures and the base rate of impaired scores, obj-SCD was defined as longitudinal biomarker-based performance below -1.645 SD (<5 percentile) in at least 3/11 variables. Magnetic Resonance Imaging scans were performed with 3T-scanner and a high-resolution 3D T1-weighted sequence (voxel-size: 0.75mm). Intra-individual changes in GMv were voxel-wise computed using longitudinal scans, smoothed at 8mm. The associations between obj-SCD and GMv changes were analyzed with VBM linear regression models, selecting a voxel-wise statistical threshold of p<0.005 with a cluster-extent correction of 100 voxels.

Result: According to the above-defined criteria 19 (6.33%) participants exhibited episodic memory obj-SCD, with significant differences considering AT profiles (Table-1). Episodic memory obj-SCD was associated with longitudinal reductions of GMv bilaterally in the hippocampus and the left cerebellum, as well as widespread increments of GMv involving AD-vulnerable cortical regions (Table-2, Figure-1).

Conclusion: Episodic memory obj-SCD captured longitudinal changes in GMv indicative of AD-progression (i.e., hippocampus). These results suggested that episodic memory obj-SCD is a consistent marker of AD-related impairment. Characterizing obj-SCD enhances preclinical stage identification, with implications for advancing early detection and intervention strategies in Alzheimer's disease, informing about an elevated risk of AD-dementia in an otherwise CU population.