Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease: A Head-to-Head Comparison Against Amyloid Positron Emission Tomography and Magnetic Resonance Imaging

Abstract

Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear.

Objective: To examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers.

Design, setting, and participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ).

Exposures: [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation.

Main outcomes and measures: Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations.

Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P < .001, bootstrapped for difference) and in the Aβ-positive CU group (R2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P < .001, bootstrapped for difference). These findings were replicated in the [18F]RO948 PET cohort. MRI mediated the association between [18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P = .71). Age (t = -2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline [18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels.

Conclusions and relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.

Figure 1.. Association of Baseline Tau Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI), and Amyloid PET With Change in Mini-Mental State Examination (MMSE)

Graphs represent associations between baseline fluorine 18–labeled flortaucipir (tau) PET uptake in a temporal region of interest (top row), cortical thickness in an Alzheimer disease (AD) signature region defined on MRI (middle row), and amyloid PET (bottom row) with annual slopes of MMSE scores across all participants (A), the amyloid-β (Aβ)-positive AD dementia group (B), the Aβ-positive mild cognitive impairment (MCI) group (C), the Aβ-negative MCI group (D), the Aβ-positive cognitively unimpaired (CU) group (E), and the Aβ-negative CU group (F). Model outputs are derived from a linear regression model between baseline tau PET/MRI/amyloid PET and MMSE slopes, adjusted for age, sex, educational attainment, and cohort. R² values are provided for the full model (including covariates), and t test and P values represent the interaction between the imaging modality and time.

Figure 2.. Mediation Analyses

Path diagrams indicate whether Alzheimer disease (AD)–signature cortical thickness mediates the associations between baseline fluorine 18–labeled flortaucipir standardized uptake value ratio (SUVR) in the temporal meta–region of interest (ROI) and Mini-Mental State Examination (MMSE) slopes, adjusted for age, sex, educational level, cohort, and APOE ε4 status. The direct effect (ie, coefficient c') reflects the extent to which MMSE slopes change when baseline tau positron emission tomography (PET) increases by 1 unit while baseline cortical thickness remains unaltered. The indirect effect (ie, coefficient a₁ × b₁) reflects the extent to which MMSE slopes change when baseline tau PET is held constant and baseline cortical thickness changes by the amount it would have changed had baseline tau PET increased by 1 unit. The coefficient c represents the total effect (ie, direct plus indirect effects). Aβ indicates amyloid-β; CU, cognitively unimpaired; MCI, mild cognitive impairment. ^aP < .001. ^bP < .05.

Figure 3.. Age, Sex, and APOE ε4 Status as Potential Modifiers of the Association Between Baseline Tau Positron Emission Tomography (PET) and Cognitive Change Over Time

Linear mixed-effects models with random intercepts and fixed slopes were performed to examine whether age, sex, and APOE ε4 status moderate the association between baseline fluorine 18–labeled flortaucipir uptake in a temporal region of interest (ROI) and change over time in Mini-Mental State Examination (MMSE) scores while adjusting for age, sex, educational attainment, cohort, and diagnostic group when appropriate. The t tests and P values represent the 3-way interaction of age/sex/APOE ε4 status × time × tau PET. Age was entered as continuous variable in the linear mixed-effects models but was dichotomized at 70 years for visualization purposes.