Question  Do cortical tau positron emission tomography (PET) patterns vary across clinically unimpaired individuals with abnormal β-amyloid (ie, preclinical Alzheimer disease [AD])?

Findings  This cross-sectional study found that divergent patterns of cortical tau uptake are present in approximately 10% of individuals with preclinical AD. Three main subtypes were identified: asymmetrical left, precuneus predominant, and asymmetrical right; individuals demonstrating these cortical tau PET patterns were younger and showed worse executive function than individuals with preclinical AD and typical medial temporal lobe uptake.

Meaning  This study suggests that heterogeneous cortical tau PET patterns exist among patients with preclinical AD and are more common than currently appreciated.

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 (t_61.867 = –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.