Assessment of Demographic, Genetic, and Imaging Variables Associated With Brain Resilience and Cognitive Resilience to Pathological Tau in Patients With Alzheimer Disease

Importance Better understanding is needed of the degree to which individuals tolerate Alzheimer disease (AD)-like pathological tau with respect to brain structure (brain resilience) and cognition (cognitive resilience). Objective To examine the demographic (age, sex, and educational level), genetic (APOE-epsilon 4 status), and neuroimaging (white matter hyperintensities and cortical thickness) factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography (PET) load and to changes in global cognition over time. Design, Setting, an Participants In this cross-sectional, longitudinal study, tau PET was performed from June 1, 2014, to November 30, 2017, and global cognition monitored for a mean [SD] interval of 2.0 [1.8] years at 3 dementia centers in South Korea, Sweden, and the United States. The study included amyloid-beta-positive participants with mild cognitive impairment or AD dementia. Data analysis was performed from October 26, 2018, to December 11, 2019. Exposures Standard dementia screening, cognitive testing, brain magnetic resonance imaging, amyloid-beta PET and cerebrospinal fluid analysis, and flortaucipir (tau) labeled with fluor-18 (F-18) PET. Main Outcomes and Measures Separate linear regression models were performed between whole cortex [F-18]flortaucipir uptake and cortical thickness, and standardized residuals were used to obtain a measure of brain resilience. The same procedure was performed for whole cortex [F-18]flortaucipir uptake vs Mini-Mental State Examination (MMSE) as a measure of cognitive resilience. Bivariate and multivariable linear regression models were conducted with age, sex, educational level, APOE-epsilon 4 status, white matter hyperintensity volumes, and cortical thickness as independent variables and brain and cognitive resilience measures as dependent variables. Linear mixed models were performed to examine whether changes in MMSE scores over time differed as a function of a combined brain and cognitive resilience variable. Results A total of 260 participants (145 [55.8%] female; mean [SD] age, 69.2 [9.5] years; mean [SD] MMSE score, 21.9 [5.5]) were included in the study. In multivariable models, women (standardized beta = -0.15, P = .02) and young patients (standardized beta = -0.20, P = .006) had greater brain resilience to pathological tau. Higher educational level (standardized beta = 0.23, P < .001) and global cortical thickness (standardized beta = 0.23, P < .001) were associated with greater cognitive resilience to pathological tau. Linear mixed models indicated a significant interaction of brain resilience x cognitive resilience x time on MMSE (beta [SE] = -0.235 [0.111], P = .03), with steepest slopes for individuals with both low brain and cognitive resilience. Conclusions and Relevance Results of this study suggest that women and young patients with AD have relative preservation of brain structure when exposed to neocortical pathological tau. Interindividual differences in resilience to pathological tau may be important to disease progression because participants with both low brain and cognitive resilience had the most rapid cognitive decline over time. This cross-sectional, longitudinal study of amyloid-beta-positive individuals with mild cognitive impairment or Alzheimer disease dementia examines the factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography load and to changes in global cognition over time. Question Which demographic, genetic, and neuroimaging factors are associated with cognitive and brain resilience to pathological tau in patients with Alzheimer disease? Findings In this multicenter, cross-sectional, longitudinal study of 260 cognitively impaired amyloid-beta-positive participants, young age and female sex were associated with greater brain resilience, whereas higher educational level and cortical thickness were associated with greater cognitive resilience. Meaning Cognitive and brain resilience may be associated with differential mechanisms, which may help explain interindividual differences in how well patients tolerate pathological tau.