Multimodal neural correlates of cognitive awareness in aging and Alzheimer's disease

Impaired cognitive awareness-anosognosia-is a core symptom of Alzheimer's disease (AD), yet its neural correlates remain poorly defined. This study examined how cognitive awareness, measured both cross-sectionally and longitudinally via subject-informant discrepancy on the Everyday Cognition (ECog) questionnaire, relates to three AD biomarkers: amyloid burden, glucose hypometabolism, and cortical atrophy. We included 785 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), spanning cognitively normal (CN), mild cognitive impairment (MCI), and AD dementia. All biomarkers were assessed at baseline across the same 86 cortical regions, enabling anatomically harmonized, cross-modality comparisons. Linear mixed models incorporating all three biomarkers revealed no significant associations in CN. In MCI, declining awareness was associated with widespread cortical amyloid deposition (significant in 80/86 regions), sparing some limbic areas. Atrophy in 11 regions-including limbic, lateral temporal, and occipital cortices-also predicted awareness decline (all p < 0.044). In AD, no significant associations were found between amyloid and awareness, suggesting a plateau effect at advanced stages. In both MCI and AD, lower baseline glucose metabolism in the left posterior cingulate cortex (PCC) was associated with poorer awareness (MCI: β ± SE =  - 0.14 ± 0.04, p = 0.006; AD: β ± SE =  - 0.24 ± 0.07, p = 0.042). No significant biomarker-time interactions were found in AD, suggesting relatively stable awareness levels at advanced disease stages. These findings indicate that anosognosia in AD is linked to distinct biomarker and regional profiles that vary by disease phase. Multimodal analysis across harmonized regions reveals the left PCC as a robust metabolic correlate of awareness, underscoring its potential as a key target in understanding and monitoring self-awareness impairment in neurodegenerative disease.