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. 2022 Jun 1;79(6):592-603.
doi: 10.1001/jamaneurol.2022.0676.

Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease

Christina B Young  1 , Joseph R Winer  1 , Kyan Younes  1 , Karly A Cody  2   3 , Tobey J Betthauser  2   3 , Sterling C Johnson  2   3   4 , Aaron Schultz  5 , Reisa A Sperling  5   6 , Michael D Greicius  1 , Inma Cobos  7 , Kathleen L Poston  1 , Elizabeth C Mormino  1 ; Alzheimer’s Disease Neuroimaging Initiative and the Harvard Aging Brain Study
Collaborators, Affiliations

Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease

Christina B Young et al. JAMA Neurol. .

Abstract

Importance: Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease.

Objective: To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated β-amyloid (A+).

Design, setting, and participants: This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n = 447; ADNI, n = 433; HABS, n = 190; and Wisconsin, n = 328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022.

Main outcomes and measures: Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined.

Results: The 447 A4 participants (A+ group, 392; and normal β-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867 = -2.597; P = .03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin.

Conclusions and relevance: This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Young reported receiving grants from the Alzheimer’s Association during the conduct of the study. Ms Cody reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Johnson reported receiving grants from the NIH during the conduct of the study; and personal fees from Roche Diagnostics outside the submitted work. Dr Schultz reported receiving grants from the NIH during the conduct of the study; and personal fees from NervGen, Qynapse, Biogen, and Janssen outside the submitted work. Dr Sperling reported receiving grants from the National Institute on Aging and the Alzheimer’s Association during the conduct of the study; and personal fees from AC Immune, Janssen, Genentech, Ionis, NerGen, Shionogi, and Oligmerix outside the submitted work. Dr Greicius reported receiving grants from the NIH during the conduct of the study. Dr Poston reported receiving grants from the NIH/National Institute of Neurological Disorders and Stroke during the conduct of the study; and grants from MJFF, Alzheimer’s Drug Discovery Foundation, and Lewy Body Dementia Association outside the submitted work. Dr Mormino reported receiving grants from the NIH during the conduct of the study; and personal fees from Eli Lilly, Roche, and NeuroTrack; and grants from the Alzheimer’s Association outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Definition of β-Amyloid (A) and Tau (T) Groups and Flortaucipir Signal for the 36 Participants With Preclinical Alzheimer Disease (AD) and Divergent Cortical Tau (A+T Cortical+) Positron Emission Tomography Patterns
A, Criteria for defining A and T groups. B, Horizontal bar graph shows number of participants with extreme cortical residual values or asymmetry indices. Bottom right circles show intersections of various cortical combinations; circles are color coded to show subtype. Vertical bar graph shows number of participants with each intersection combination. C, Mean flortaucipir distribution for each A and T group. A– indicates normal β-amyloid; A+, elevated β-amyloid; A–T MTL–, normal β-amyloid without elevated MTL tau; A–T MTL+, normal β-amyloid and elevated MTL tau; A+T MTL–, preclinical AD without elevated MTL tau; A+T MTL+, preclinical AD and elevated MTL tau; MTL, medial temporal lobe; and SUVR, standardized uptake value ratio.
Figure 2.
Figure 2.. Regional Tau (T) Positron Emission Tomography Standardized Uptake Value Ratios (SUVRs) for Each β-Amyloid (A) and T Group
The circles are individual data points. The boxes and vertical lines are boxplots. A+T cortical+ indicates preclinical Alzheimer disease and divergent cortical tau; A+T MTL+, preclinical Alzheimer disease and elevated MTL tau; A–T MTL+, normal β-amyloid and elevated MTL tau; A–T MTL–, normal β-amyloid without elevated MTL tau; A–T MTL+, normal β-amyloid and elevated MTL tau; MTL, medial temporal lobe; S, subtype. aP < .001. bP < .01.
Figure 3.
Figure 3.. Amyloid, Age, and Cognitive Differences Between β-Amyloid (A) and Tau (T) Groups
The circles are individual data points. The boxes and vertical lines are boxplots. A+T cortical+ indicates preclinical Alzheimer disease and divergent cortical tau; A+T MTL+, preclinical Alzheimer disease and elevated MTL tau; A–T MTL+, normal β-amyloid and elevated MTL tau; A–T MTL–, normal β-amyloid without elevated MTL tau; FCSRT, Free and Cued Selective Reminding Test; LM, logical memory; MTL, medial temporal lobe; S, subtype; and SUVR, standardized uptake value ratio. aP < .001. bP < .05. cP < .01.
Figure 4.
Figure 4.. Association Between Age, Global Amyloid, and Regional Tau
A, Association between age and continuous global amyloid, measured in standardized uptake value ratios (SUVRs). B, Association between age and regional tau using SUVRs. C, Association between age and regional tau using SUVR controlling for global amyloid burden. All plots depict individuals with preclinical Alzheimer disease and medial temporal lobe (MTL) tau (A+T MTL+) and individuals with preclinical Alzheimer disease and divergent cortical tau (A+T cortical+). The orange lines correspond to the A+T cortical+ data points, and the black lines correspond to the A+T MTL+ data points. S indicates subtype.
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