Microinfarcts are Associated with Cognitive Impairment in Neurofibrillary Tangle Predominant Decedents: Evidence from the NACC Autopsy Cohort

Background: A growing number of older adults exhibit neurofibrillary tangle pathology without significant amyloid deposition, a biomarker profile consistent with suspected non-Alzheimer’s pathophysiology or primary age-related tauopathy. The cognitive consequences within this subgroup remain poorly characterized, particularly with respect to vascular comorbidity. This study investigates whether vascular neuropathologies are associated with pre-mortem cognitive decline among individuals with predominately neurofibrillary tangles and low to none neuritic plaque pathology detected post-mortem. Methods: The sample included autopsy-confirmed data from 579 participants in the National Alzheimer’s Coordinating Center (NACC) cohort with intermediate-to-high Braak stage (B2–B3) and absent or minimal neuritic plaques (C0-C1). Vascular neuropathologies included arteriolosclerosis, atherosclerosis of the circle of Willis, gross infarcts/ lacunes, and microinfarcts were assessed for associations with global cognition (Clinical Dementia Rating Sum of Boxes, CDR-SOB) and harmonized cognitive domain specific performance (memory, executive function, and language) using multivariable regression adjusted for age, sex, education, and apolipoprotein ε4 status. Sensitivity analyses further controlled for cardiovascular risk, excluded individuals with any neuritic plaques, and controlling for individual neuritic plaque and Braak staging. Results: Cross-sectionally, microinfarcts were consistently associated with poorer memory (β = − 0.28, p = 0.02), executive function (β = − 0.24, p = 0.02), and language (β = − 0.21, p = 0.02) approximate to death. Gross infarcts were associated with language impairment and higher CDR scores. These associations remained significant after adjusting for cardiovascular risk and were even stronger when restricted to strictly neuritic amyloid negative individuals. Conclusions: Microinfarcts may represent a key driver of cognitive impairment in neurofibrillary tangle predominant individuals. These findings highlight a vascular-neurodegenerative pathway that warrants consideration in non-neuritic plaque models of cognitive decline and may inform targeted prevention strategies.