Micro infarcts are associated with cognitive impairment in neurofibrillary tangle predominant decedents: evidence from the NACC autopsy cohort

Background A subset of older adults develops high neurofibrillary tangle burden with minimal amyloid, a biomarker profile consistent with suspected non-Alzheimer’s pathophysiology or primary age-related tauopathy. Yet its cognitive correlates are unclear, particularly when vascular neuropathologies coexist. We examined whether vascular neuropathologies are linked to cognitive impairment proximate to death and pre-mortem cognitive decline among decedents with intermediate-to‐high Braak stage (III-VI) and absent/low neuritic plaques. Methods In 579 autopsied participants from the National Alzheimer’s Coordinating Center cohort (Braak III–VI; CERAD C0–C1), we evaluated arteriolosclerosis, atherosclerosis of the circle of Willis, cerebral amyloid angiopathy, gross infarcts/lacunes, and microinfarcts effect on harmonized memory, executive function, and language z-scores proximate to death using multivariable linear regression (adjusted for age, sex, education, APOE ε4 status). Linear mixed‐effects models assessed interactions between each vascular neuropathology and years‐to‐death on pre-mortem longitudinal decline. Results At the last assessment, microinfarcts were associated with lower memory (β=–0.28, 95% CI − 0.51 - − 0.05; p = 0.02), executive function (β=–0.24, 95% CI − 0.44 - − 0.04; p = 0.02), and language (β=–0.21, 95% CI − 0.38 - − 0.04; p = 0.02). These associations remained after controlling for cardiovascular risk, neuritic plaques and Braak stage, last assessment and death interval, and co-existing vascular neuropathologies. Microinfarcts were not associated with the rates of pre-mortem cognitive decline. Conclusions Microinfarcts are contributors to domain-specific cognitive deficits in tangle‐predominant, low‐amyloid older adults. These findings underscore a vascular‐neurodegenerative pathway distinct from classic Alzheimer’s disease. Thus, targeting microvascular injury may mitigate impairment in this underrecognized phenotype.