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Background: The 2018 NIA-AA Alzheimer's Disease (AD) Research Framework states that subtle cognitive decline in cognitively unimpaired individuals can be measured by subjective reports or evidence of objective decline on neuropsychological measures. Both subjective memory complaint (SMC) and objective subtle cognitive decline (Obj-SCD) have been shown to be associated with future cognitive decline and AD biomarkers. We examined whether there are differences in tau PET levels between (a) SMC- vs. SMC+ participants, (b) Obj-SCD- vs. Obj-SCD+ participants, and (c) participants with overlapping vs. discrepant SMC and Obj-SCD classifications., Methods: Cognitively unimpaired participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 236) were classified at baseline as positive or negative for SMC (SMC- n = 77; SMC+ n = 159) based on the first 12 items of the Cognitive Change Index and/or classified as positive or negative for Obj-SCD (Obj-SCD- n = 173; Obj-SCD+ n = 63) based on previously defined neuropsychological criteria. Analyses of covariance, adjusting for age, sex, APOE ε4 carrier status, and pulse pressure, examined the group differences in tau PET (AV-1451) using a composite standardized uptake variable ratio (SUVR) for regions consistent with Braak stage III/IV. The chi-squared tests examined the tau positivity rates across the groups., Results: Obj-SCD+ participants had higher tau continuous SUVR levels (p = .035, η p 2 = .019) and higher rates of tau positivity (15.8% Obj-SCD- vs. 30.2% Obj-SCD+) than Obj-SCD- participants. Neither tau levels (p = .381, η p 2 = .003) nor rates of tau positivity (18.2% SMC- and 20.1% SMC+) differed between the SMC groups. There was very little agreement between SMC and Obj-SCD classifications (42%; κ = 0.008, p = .862). Participants who were Obj-SCD+ without SMC had the highest tau PET levels and differed from participants who were SMC+ without Obj-SCD (p = .022). Tau levels in participants with both SMC and Obj-SCD did not differ from those with only Obj-SCD (p = .216). Tau positivity rates across the SMC-/Obj-SCD-, SMC+/Obj-SCD-, SMC-/Obj-SCD+, and SMC+/Obj-SCD+ groups were 10.5%, 18.1%, 40.0%, and 25.6%, respectively., Conclusion: Participants with Obj-SCD had a greater tau PET burden than those without Obj-SCD, but SMC was not associated with higher tau levels. The combination of SMC and Obj-SCD did not have higher tau levels than Obj-SCD alone. Findings add to the evidence that the Obj-SCD classification is associated with AD biomarkers and faster cognitive decline in ADNI participants, but further work is needed to validate this approach in more representative/diverse cohorts., (© 2022. The Author(s).)

Background: Tau positron emission tomography (PET) is increasing in popularity for biomarker characterization of Alzheimer's disease (AD), and recent frameworks rely on tau PET cut-points to stage individuals along the AD continuum. Given the lack of standardization in tau PET thresholding methods, this study sought to systematically canvass and characterize existing studies that have derived tau PET cut-points and then directly assess different methods of tau PET thresholding in terms of their concurrent validity., Methods: First, a literature search was conducted in PubMed to identify studies of AD and related clinical phenotypes that used the Flortaucipir (AV-1451) tau PET tracer to derive a binary cut-point for tau positivity. Of 540 articles screened and 47 full-texts reviewed, 23 cohort studies met inclusion criteria with a total of 6536 participants. Second, we derived and compared tau PET cut-points in a 2 × 2 × 2 design that systematically varied region (temporal meta-ROI and entorhinal cortex), analytic method (receiver operating characteristics and 2 standard deviations above comparison group), and criterion/comparison variable (amyloid-beta negative cognitively unimpaired or cognitively unimpaired only) using a sample of 453 older adults from the Alzheimer's Disease Neuroimaging Initiative., Results: For the systematic review, notable variability in sample characteristics, preprocessing methods, region of interest, and analytic approach were observed, which were accompanied by discrepancy in proposed tau PET cut points. The empirical follow-up indicated the cut-point derived based on 2 standard deviations above a either comparison group in either ROI best differentiated tau positive and negative groups on cerebrospinal fluid phosphorylated tau, Mini-Mental State Examination score, and delayed memory performance., Conclusions: Given the impact of discrepant thresholds on tau positivity rates, biomarker staging, and eligibility for future clinical treatment trials, recommendations are offered to select cut-point derivations based on the unique goals and priorities of different studies., (© 2022. The Author(s).)