Memory Self-Awareness Phenotypes are Associated with Alzheimers Disease Biomarker Burden and Clinical Progression in Amnestic Mild Cognitive Impairment

Background: Altered memory self-awareness is common in mild cognitive impairment (MCI), but its relationship to Alzheimer's disease (AD) pathology and progression remains unclear. Methods: Using 590 amnestic MCI ADNI participants, memory self-awareness was derived from participant-informant discrepancies on the memory subdomain of the Everyday Cognition questionnaire. Heightened awareness and unawareness subscores were calculated, and k-means clustering identified four phenotypes. Associations with cerebrospinal fluid (CSF) and positron emission tomography (PET) were examined, and clinical progression was assessed using Cox models. Results: Aware and Unaware groups showed lower CSF amyloid-B, and higher CSF phosphorylated tau and PET amyloid. The Unaware phenotype was associated with increased progression risk (hazard ratio 2.41, 95% CI 1.48-3.92), whereas the Worried Well phenotype showed reduced risk (hazard ratio 0.58, 95% CI 0.34-0.99). Conclusions: Multidimensional assessment of memory self-awareness identifies biologically and prognostically distinct subgroups within MCI and may improve risk stratification in prodromal AD.