Characterizing Amyloid-Positive Individuals With Normal Tau PET Levels After 5 Years

Background and Objective Individuals with biomarker evidence of ss-amyloid (A ss) deposition are increasingly being enrolled in clinical treatment trials but there is a need to identify markers to predict which of these individuals will also develop tau deposition. We aimed to determine whether A ss-positive individuals can remain tau-negative for at least 5 years and identify characteristics that could distinguish between these individuals and those who develop high tau within this period. Methods Tau PET positivity was defined using a Gaussian mixture model with log-transformed standard uptake value ratio values from 7 temporal and medial parietal regions using all participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with flortaucipir PET. Tau PET scans were classified as normal if the posterior probability of elevated tau was less than 1%. A ss PET positivity was defined based on ADNI cutpoints. We identified all A ss-positive individuals from ADNI who had normal tau PET more than 5 years after their first abnormal A ss PET (amyloid with low tau [ALT] group) and all A ss-positive individuals with abnormal tau PET within 5 years (biomarker AD). In a case-control design, logistic regression was used to model the odds of biomarker AD vs ALT accounting for sex, age, APOE e4 carriership, A ss Centiloid, and hippocampal volume. Results We identified 45 individuals meeting criteria for ALT and 157 meeting criteria for biomarker AD. The ALT group had a lower proportion of APOE e4 carriers, lower A ss Centiloid, larger hippocampal volumes, and more preserved cognition, and were less likely to develop dementia, than the biomarker AD group. APOE e4, higher A ss Centiloid, and hippocampal atrophy were independently associated with increased odds of abnormal tau within 5 years. A Centiloid value of 50 effectively discriminated biomarker AD and ALT with 80% sensitivity and specificity. The majority of the ALT participants did not develop dementia throughout the 5-year interval. Discussion A ss-positive individuals can remain tau-negative for at least 5 years. Baseline characteristics can help identify these ALT individuals who are less likely to develop dementia. Conservative A ss cutpoints should be utilized for clinical trials to better capture individuals with high risk of developing biomarker AD.