Global and domain-specific cognitive intraindividual variability associations with neurodegenerative diagnoses and postmortem pathologies.

BACKGROUND: Cognitive intraindividual variability (IIV) or within-person variation in neuropsychological test performance relates to in vivo biomarkers of neurodegeneration and progression to mild cognitive impairment (MCI) and dementia. The current study aimed to explore longitudinal associations between global and domain-specific IIV with cognitive status and neuropathological findings at autopsy, and whether these associations differed by sex. METHODS: The sample included 20,715 older adults from the National Alzheimer’s Coordinating Center (NACC) who completed cognitive testing as part of the Uniform Data Set. Participants were cognitively unimpaired at Visit 1. Baseline neuropsychological data was used to calculate coefficient of variation IIV (intraindividual standard deviation/mean performance) for global, executive, language, and memory domains. Global and domain-specific IIV associations with final visit cognitive status, etiological diagnosis, and progression to MCI/dementia were examined. Associations between each IIV score and neuropathological data were examined for participants with available autopsy data (ns = 1184–1717). Secondary models explored sex by IIV interactions. RESULTS: Greater IIV (i.e., more variability) in global and specific domains related to worse cognitive status at final visit and final etiological diagnosis. Across all IIV domains, higher IIV related to greater risk of progressing to MCI/dementia. Higher global IIV related to greater postmortem burden of amyloid-β plaques, neurofibrillary tangles (NFT), AD neuropathologic change (ADNC) scores, hippocampal atrophy, substantia nigra neuron loss, hypopigmentation in the locus coeruleus, and cerebral amyloid angiopathy (CAA). Domain-specific effects included: higher executive IIV related to greater NFT, neuritic plaques, ADNC scores, and CAA; and higher memory IIV related to greater neuritic plaques and NFT. There were no significant interactions of sex and IIV. CONCLUSIONS: Among cognitively unimpaired older adults, global IIV was a sensitive but non-specific marker associated with cognitive decline and neuropathology at autopsy. Domain-specific IIVs were also associated with cognitive progression but offered more specificity in neuropathologic outcomes. Associations were largely consistent across sexes, indicating IIV is robust to sex-specific effects. Findings highlight IIV as sensitive to long-term cognitive health and neuropathological burden and may improve early risk stratification for dementia.