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Biomarkers / Alzheimer Disease / Alzheimer’s Disease · Journal article
Neurobiology of Aging · June 18, 2026
Encouraging direction, but not yet definitive.
This prospective cohort study characterizes decreased awareness of cognitive decline (ACD)—defined as concurrent decline in episodic memory and cognitive awareness—as a discrete clinical phenotype in cognitively unimpaired older adults. The phenotype is associated with higher AD pathology, particularly on CSF p-tau217 and multimodal neuroimaging, suggesting ACD assessment may identify preclinical AD; however, the small phenotype subgroup (n=25) and single-cohort design limit generalizability and require replication.
Prospective cohort study with multimodal cross-sectional biomarker analysis. Cognitively unimpaired individuals from ALFA+ cohort with baseline CSF biomarkers and 3-year longitudinal neuropsychological follow-up; mean age 61 years, 60% female, mean education 14 years, 35% CSF Aβ-positive.. Intervention: Assessment of awareness of cognitive decline against longitudinal neuropsychological decline (episodic memory) using standardized tests and questionnaires; evaluation of multimodal AD biomarkers (plasma, CSF, PET imaging).. n = 350.
Memory decline identified in 61/350 CU individuals (17%); 25/61 (41%) exhibited concurrent awareness decline meeting criteria for decreased ACD Among fluid biomarkers, CSF p-tau217 showed strongest association with decreased ACD Neuroimaging revealed elevated frontoparietal Aβ PET and temporal, insular, frontal tau PET deposition in decreased ACD group
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The identification of decreased awareness of cognitive decline as a discrete phenotype linked to AD biomarkers could extend current clinical frameworks for preclinical AD detection. Clinicians should consider assessing cognitive awareness in addition to subjective cognitive decline, particularly in cognitively unimpaired older adults with objective memory decline, though independent validation in other cohorts is needed before routine implementation.
A single-centre prospective cohort study with well-defined neuropsychological criteria identifying a discrete clinical phenotype (decreased awareness of cognitive decline) associated with multimodal AD biomarkers in cognitively unimpaired individuals; promising but requires replication and validation in independent populations.
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The identification of decreased awareness of cognitive decline as a discrete phenotype linked to AD biomarkers could extend current clinical frameworks for preclinical AD detection. Clinicians should consider assessing cognitive awareness in addition to subjective cognitive decline, particularly in cognitively unimpaired older adults with objective memory decline, though independent validation in other cohorts is needed before routine implementation.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
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.
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