Cognitive variation reflects amyloid, tau, and neurodegenerative biomarkers in Alzheimer's disease

In Alzheimer's disease (AD), the accumulation of neuropathological markers such as amyloid-β plaques, neurofibrillary tangles, and cortical neurodegeneration occurs over many years before overt manifestation of cognitive impairment. There is thus a need for neuropsychological markers that are indicative of pathological changes in the early stages of the disease. Intra-individual cognitive variability (IICV), defined as the variation of an individual's performance across cognitive domains, is a promising neuropsychological marker measuring heterogeneous changes in cognition that may reflect these early pathological changes. In this study, we comprehensively evaluated the global and regional associations of IICV with positron emission tomography (PET) and magnetic resonance imaging (MRI) measures of AD biomarkers in cognitively normal (CN) and mild cognitive impairment (MCI) participants. We found that higher IICV was robustly associated with increased Aβ, increased tau, decreased brain glucose metabolism, and reduced cortical thickness. Higher IICV was also associated with tau (OR = 2.53, P < .001) and fluorodeoxyglucose (OR = 1.34, P < .001) positivity but not Aβ positivity (OR = 1.15, P = .107). In regional analyses, IICV showed widespread associations with AD biomarkers, with the strongest Aβ and tau effects in the frontal and temporal regions, respectively. The strongest regional cortical thickness effects were found in the entorhinal and parahippocampal cortices. Our findings suggest that IICV may be a useful neuropsychological marker for increased Aβ, and especially increased tau and neurodegeneration that are reflective of emerging AD pathology in individuals without dementia.