Decreased awareness of cognitive decline is associated with multimodal Alzheimer's disease biomarkers in cognitively unimpaired individuals

Neurobiol Aging. 2026 Jun 18;167:76-94. doi: 10.1016/j.neurobiolaging.2026.06.006. Online ahead of print.

ABSTRACT

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 characterize a discrete clinical profile consistent with subtle amnestic anosognosia: decreased ACD, evaluating its association with multimodal core AD biomarkers in cognitively unimpaired (CU) individuals. 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 cognitive 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 p-tau181, p-tau181/Aβ42, p-tau217; CSF p-tau181, Aβ42/40, 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 analysis was restricted to individuals with memory decline. 350 CU individuals were included (mean age 61 years; 60% female; mean education 14 years; 35% CSF Aβ-positive). Memory decline was identified in 61 (17%) individuals, of whom 25 (41%) exhibited concurrent awareness decline; meeting criteria for decreased ACD. This group demonstrated higher 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 analysis confirmed that, although less pronounced, this pattern persists at the same threshold of memory decline. This study suggests that assessment of ACD may provide a crucial extension of current AD clinical frameworks.

PMID:42361729 | DOI:10.1016/j.neurobiolaging.2026.06.006