BACKGROUNDLittle is known about incidence of vascular and Alzheimer’s dementias in American Indians. METHODS We conducted a large, heterogeneous, population-based, longitudinal cohort study of brain aging in community-dwelling American Indians aged 64-95 years from 11 tribes across 3 states, with neurological examinations, 1.5T magnetic resonance imaging (MRI), and extensive cognitive testing. Visit 1 in 2010-2013 (n=817) and Visit 2 in 2017-2019 (n=403) included all willing, surviving participants. Standardized cognitive tests at both visits included Modified Mini Mental Status Examination (3MSE), Wechsler Adult Intelligence Scale digit symbol coding (WAIS), Controlled Oral Word Association fas (COWA), California Verbal Learning Test short form (CVLT). Test materials added at follow-up included Wide Range Achievement (reading) Test (WRAT) and National Alzheimer’s Coordinating Center Uniform Data Set cognitive battery (v3 form C2) , including Montreal Cognitive Assessment (MoCA). MRI neuroradiologists coded infarcts, hemorrhages, white matter hyperintensities, sulcal atrophy, and ventricle enlargement. RESULTS Mean time between exams was 6.7 years (SD 1.1, range 3.8-9.1). Years of formal education had modest correlation with WRAT reading score (r=0.45). Prevalence and incidence of infarcts were (respectively) 32% and 12.8/1000 person-years (PY); hemmorhages 6% and 4.4/1000 PY; worsening sulci 74% and 19.0/1000 PY; wosening ventricle 79% and 30.1/1000 PY; worsening leukoaraiosis 44% and 26.1/1000 PY. Linear losses per year in cognitive scores were 0.6% 3MSE, 1.2% WAIS, 0.6% COWA, 2.2% CVLT. Mean MoCA scores were 18.9 (SD 4.3). DISCUSSION These are the first data on longitudinal cognitive and imaging changes in American Indians, as well as first reports of AD related features. Mean scores in MoCA were similar or lower than standard cutoffs used to diagnose dementia in other racial/ethnic groups, suggesting that standardized cognitive tests may not perform well in this population. Test validation, adaptation, and score adjustment are warranted. Years of education was a poor proxy for premorbid function, suggesting novel methods for cognitive score contextualization is also needed in this population. Evaluation of selective survival suggests attrition from death and frailty should be accounted for in causal analyses. Overall, these data represent a unique opportunity to examine neurology topics of critical importance to an understudied population.

Background: American Indians have high prevalence of risk factors for Alzheimer’s disease and related dementias (ADRD) compared to the general population, yet dementia onset and frequency in this population are understudied. Intraindividual cognitive variability (IICV), a measure of variability in neuropsychological test performance within a person at a single timepoint, may be a novel, noninvasive biomarker of neurodegeneration and early dementia. Objective: To characterize the cross-sectional associations between IICV and hippocampal, total brain volume, and white matter disease measured by magnetic resonance imaging (MRI) among older American Indians. Methods: IICV measures for memory, executive function, and processing speed, and multidomain cognition were calculated for 746 American Indians (aged 64–95) who underwent MRI. Regression models were used to examine the associations of IICV score with hippocampal volume, total brain volume, and graded white matter disease, adjusting for age, sex, education, body mass index, intracranial volume, diabetes, stroke, hypertension, hypercholesterolemia, alcohol use, and smoking. Results: Higher memory IICV measure was associated with lower hippocampal volume (Beta = –0.076; 95% CI –0.499, –0.023; p = 0.031). After adjustment for Bonferroni or IICV mean scores in the same tests, the associations were no longer significant. No IICV measures were associated with white matter disease or total brain volume. Conclusion: These findings suggest that the IICV measures used in this research cannot be robustly associated with cross-sectional neuroimaging features; nonetheless, the results encourage future studies investigating the associations between IICV and other brain regions, as well as its utility in the prediction of neurodegeneration and dementia in American Indians.