Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults

Abstract

Objective: To assess cross-sectional associations of neurofibrillary tangles, measured by tau-PET, with cognitive performance in cognitively unimpaired (CU) adults.

Methods: Tau- and amyloid-PET were performed in 579 CU participants aged 50-98 from the population-based Mayo Clinic Study of Aging. Associations between tau-PET signal in 43 brain regions and cognitive test scores were assessed using penalized linear regression. In additional models, participants were classified by normal/abnormal global amyloid-PET (A+/A-) and normal/abnormal regional tau-PET (T+/T-). Regional tau-PET cutpoints were defined as standardized uptake value ratio (SUVR) greater than the 95th percentile of tau-PET SUVR in that region among 117 CU participants aged 30-49.

Results: Higher tau-PET signal was associated with poorer memory performance in all medial temporal lobe (MTL) regions and also in the middle temporal pole and frontal olfactory regions. The largest association with tau-PET and memory z scores was seen in the entorhinal cortex; this association was independent of tau-PET signal in other brain regions. Tau-PET in the entorhinal cortex was also associated with poorer global and language performance. In the entorhinal cortex, T+ was associated with lower memory performance among both A- and A+.

Conclusions: Tau deposition in MTL regions, as reflected by tau-PET signal, was associated with poorer performance on memory tests in CU participants. The association with entorhinal cortex tau-PET was independent of tau-PET signal in other brain regions. Longitudinal studies are needed to understand the fate of CU participants with elevated medial temporal tau-PET signal.

Figure 1. Association between regional tau-PET signal and cognition

Mean (95% confidence interval) difference in cognitive z scores for a 10% increase in tau-PET estimated from penalized linear regression models. Significant findings at p < 0.05 are shown with asterisks. These estimates are adjusted for age, sex, education, and the number of previous exposures to cognitive testing. Tau-PET was modeled with a log transformation and the reported estimates are log (1.1) × β to represent the effect on z score of a 10% higher tau PET standardized uptake value ratio. The estimates in this figure are based on penalized maximum likelihood, which stabilizes coefficients and accounts for multiple comparisons.

Figure 2. Scatterplots of association between regional tau-PET signal and cognition

(A) Memory z score by tau-PET standardized uptake value ratio (SUVR) in the entorhinal cortex. (B) Memory z score by tau-PET SUVR in the precentral region. The regression line and 95% confidence interval are from a penalized linear regression model and correspond to the mean memory z assuming a 70-year-old man with 16 years of education and 2 prior exposures to the Mayo Clinic Study of Aging cognitive battery. Due to the large sample size, the 2 participants with entorhinal cortex tau-PET SUVR above 2.0 have little influence on the overall fit.

Figure 3. Association between regional tau-PET signal and cognition stratified by A− and A+ status

Mean (95% confidence interval) difference in cognitive z scores for a 10% increase in tau-PET estimated from penalized linear regression models. Blue squares indicate A− while orange circles indicate A+. p Values are from a test of whether the tau effect differed by a status. These estimates are adjusted for age, sex, education, and the number of previous exposures to cognitive testing. Tau-PET was modeled with a log transformation and the reported estimates are log (1.1) × β to represent the effect on z score of a 10% higher tau PET standardized uptake value ratio. The estimates in this figure are based on penalized maximum likelihood, which stabilizes coefficients and accounts for multiple comparisons.

Figure 4. Pairwise analysis of memory cognition by amyloid-PET and tau-PET abnormality status

Estimated mean (95% confidence interval) memory z score by amyloid-PET and tau-PET groups from a penalized linear regression model adjusting for age, sex, education, and number of previous exposures to cognitive testing. Estimates are shown for a 70-year-old man with 16 years of education and 2 prior exposures to cognitive testing; differences between groups do not depend on these covariates. p Values indicate pairwise test results between individual A and T groups. This figure is limited to regions where memory z varied by AT group at the p ≤ 0.05 level.

Figure 5. Tau-PET image examples in each AT group

Representative amyloid and tau-PET images in each group of A−T−, A−T+, A+T−, and A+T+. Global Pittsburgh compound B (PiB) standardized uptake value ratio (SUVR) and entorhinal cortex (ERC) tau-PET SUVR values are listed for an individual participant in each group.