Frequency and Clinical Outcomes Associated With Tau Positron Emission Tomography Positivity

Abstract

Importance: Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD).

Objective: To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes.

Design, setting, and participants: Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included.

Exposures: Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration- and European Medicines Agency-approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI).

Main outcomes and measures: Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia).

Results: Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET-positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET-positive/tau PET-negative (17% [95% CI, 13%-22%]) and Aβ PET-negative/tau PET-negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET-positive/tau PET-positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%).

Conclusions and relevance: In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Figure 1.

Frequency of tau-PET positivity in cognitively unimpaired individuals, mild cognitive impairment, and patients with a clinical diagnosis of various neurodegenerative disorders. Estimated frequency of tau-PET positivity, established using the approved visual interpretation method for [¹⁸F]flortaucipir, as a function of age in cognitively unimpaired individuals (A), participants with MCI (B), and AD dementia (C). The cognitively unimpaired, MCI, and AD dementia groups were defined based solely on the respective clinical symptoms, independent of Aβ status or other biomarker results. Benchmark estimates of the frequency of Braak stages V-VI (orange lines) in cognitively unimpaired and participants with AD dementia were derived using data from an independent sample of participants from the Neuropathology cohort (n=3178). Panel D shows the overall frequency of tau-PET positivity in other clinically diagnosed (i.e., independent of Aβ status or other biomarker results) neurodegenerative disorders. Whiskers represent 95% confidence intervals. The number of participants with other neurodegenerative disorders were (tau-PET-positive/total): Dementia with Lewy bodies, (29/81); behavioural variant frontotemporal dementia, (23/69); semantic variant primary progressive aphasia, (20/29); nonfluent variant primary progressive aphasia, (9/29); Parkinson disease with cognitive impairment, (9/31); progressive supranuclear palsy, (3/73); corticobasal syndrome, (15/57). Abbreviations: PET, positron emission tomography.

Figure 2.

Frequency of tau-PET positivity among Aβ-PET-positive and Aβ-PET-negative individuals, stratified by clinical diagnosis. Panels A and B show the estimated frequency of tau-PET positivity as a function of age among Aβ-PET-positive and Aβ-PET-negative individuals, separately for cognitively unimpaired (grey), mild cognitive impairment (green), and patients with a clinical diagnosis of Alzheimer disease dementia (red). Whiskers represent 95% confidence intervals. Abbreviations: Aβ, amyloid-β; PET, positron emission tomography.

Figure 3.

Clinical outcomes of tau-PET-positive individuals. Aβ± and vTAU± represent Aβ-PET and tau-PET status (positive/negative), respectively. Panels A and B show Kaplan-Meier-based estimates of the absolute risk (accounting for the competing risk of death during follow-up) of clinical progression, defined as progression to MCI or dementia among initially cognitively unimpaired individuals (A) or progression to dementia among individuals with MCI (B), according to different Aβ-PET/tau-PET biomarker profiles. The inserts show covariate-adjusted cause-specific hazard ratios (HR) of clinical progression (see Statistical Analysis section), using the respective Aβ-PET-negative/tau-PET-negative profile as the reference; quantities between parentheses are 95% confidence intervals. Panels C and D show Kaplan-Meier-based estimates of the absolute risk (accounting for the competing risk of death during follow-up) of progressing CDR-G, defined as any increase in the score, across initially cognitively unimpaired individuals and patients with MCI or AD dementia. The inserts show covariate-adjusted cause-specific hazard ratios (HR) of progressing CDR-G, using the respective Aβ-PET-negative/tau-PET-negative group as the reference; quantities between parentheses are 95% confidence intervals. Crosses on Kaplan Meier curves from panels A-E represent censored time points. Panels E and F show average trajectories of the CDR-SB score (range, 0 to 18, with higher scores indicating worse clinical symptoms) among cognitively unimpaired individuals and patients with MCI or AD dementia, according to Aβ-PET/tau-PET profiles. Dashed and dotted lines represent previously specified CDR-SB scores consistent with MCI (panel E, dashed line), mild AD dementia (panel F, dashed line), or moderate AD dementia (panel F, dotted line) (see Outcomes section). Modelled trajectories are conditional on age (70 years). Shaded areas represent 95% confidence intervals. All the aforementioned analyses in participants with MCI and AD dementia were restricted to individuals with baseline CDR-G of 0.5 or 1. Exploratory analyses of the Aβ-PET-negative/tau-PET-positive group are reported in the Online Supplement (eFigure 9). Abbreviations: Aβ, amyloid-β; AD, Alzheimer disease; CDR-G, Clinical Dementia Rating Global score; CDR-SB, Clinical Dementia Rating Sum of Boxes score; MCI, mild cognitive impairment; PET, positron emission tomography; vTAU, tau-PET status (positive/negative).