Decreased Awareness of Cognitive Decline is Associated with Multimodal Alzheimer’s Disease Biomarkers in Cognitively Unimpaired Individuals

ABSTRACT INTRODUCTION Alzheimer’s disease (AD) diagnostic guidelines emphasize subjective cognitive decline (SCD) preceding mild cognitive impairment (MCI), implicitly assuming awareness of cognitive decline (ACD) is preserved in preclinical AD. This study aimed to evaluate associations of decreased ACD with multimodal core AD biomarkers in cognitively unimpaired (CU) individuals. METHODS We analyzed data from CU individuals with baseline CSF biomarkers and 3-year longitudinal neuropsychological assessment (ALFA+ cohort). Decreased ACD was defined by concurrent decline in episodic memory and awareness using robust longitudinal references (Free and Cued Selective Reminding Test, Memory Binding Test, Wechsler Memory Scale, and Subjective Cognitive Decline Questionnaire). Biomarker outcomes included plasma and CSF p-tau181, p-tau181/Aβ42, p-tau217; Aβ ([¹⁸F]flutemetamol) and tau PET ([¹⁸F]RO948). Associations of ACD with AD biomarkers were evaluated using linear regression models. Sensitivity analyses were restricted to individuals with memory decline. RESULTS 350 CU individuals were included (mean age 61 years; 60% female; mean education 14 years; 35% CSF Aβ-positive). Episodic memory decline was identified in 61 (17%) individuals, of whom 25 (41%) also exhibited awareness decline; meeting criteria for decreased ACD. This group demonstrated greater levels of AD pathology compared to the remaining sample. Among fluid biomarkers, CSF p-tau217 showed the strongest association. Neuroimaging revealed elevated frontoparietal Aβ PET, alongside temporal, insular, and frontal tau PET deposition. Sensitivity analyses showed that, at the same threshold of memory decline, decreased ACD reflects greater AD pathology. DISCUSSION Standardized assessment of cognitive awareness, integrating objective neuropsychological performance with subjective reports, may provide a crucial extension of current clinical frameworks.