Amyloid duration is associated with preclinical cognitive decline and tau PET

Abstract

INTRODUCTION:This study applies a novel algorithm to longitudinal amyloid positron emission tomography (PET) imaging to identify age-heterogeneous amyloid trajectory groups, estimate the age and duration (chronicity) of amyloid positivity, and investigate chronicity in relation to cognitive decline and tau burden. METHODS:Cognitively unimpaired participants (n=257) underwent 1-4 amyloid PET scans. Group-based trajectory modeling was applied to participants with longitudinal scans (n=171) to identify and model amyloid trajectory groups, which were combined with Bayes' theorem to estimate age and chronicity of amyloid positivity. Relationships between chronicity, cognition, clinical progression and tau PET (MK-6240) were investigated using regression models. RESULTS:Chronicity explained more heterogeneity in amyloid binding than age and binary amyloid status. Chronicity was associated with faster cognitive decline, increased risk of abnormal cognition, and higher entorhinal tau. DISCUSSION: Amyloid chronicity provides unique information about cognitive decline and neurofibrillary tangle development and may be useful to investigate preclinical AD. ABBREVIATIONS AD = Alzheimer's disease PET = positron emission tomography A+/-= amyloid positive/negative GBTM = group-based trajectory modeling WRAP = Wisconsin Registry for Alzheimer's Prevention PIB = Pittsburgh Compound B PIB(+/-) = Pittsburgh Compound B positive/negative PACC-3 = three-test preclinical Alzheimer cognitive composite RAVLT = Rey Auditory Verbal Learning MR = magnetic resonance DVR = distribution volume ratio BIC = Bayesian Information Criteria WRAT3 = Wide Range Achievement Test 3 AICc = Akaike Information Criteria sd = standard deviation APOE4 = apolipoprotein ε4 LME = linear mixed effects

Sex differences in off-target binding using tau positron emission tomography

“…All participants had no history of neurological or cognitive disorders and performed normally on cognitive tests. Aβ status (positive/negative) was determined using Aβ PET (BioFINDER-1: [ 18 F]flutemetamol standardized uptake value ratio (SUVR), composite cerebellar, brain stem and white matter reference region; cut-off > 0.693; ADNI: [ 18 F]florbetapir SUVR, whole cerebellum reference region; cut-off > 1.11; WRAP: [ 11 C]PiB global distribution volume ratio > 1.2, whole cerebellum reference region) ( Koscik et al, 2020 ) or the ratio of Aβ42 to Aβ40 in CSF (BioFINDER-2; Mesoscale Discovery Immunoassays, cut-off: <0.752). Written informed consent was obtained from all participants and local institutional review boards for human research ethics approved the studies at each site.…”

Clinical validity of second-generation tau PET tracers as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework

“…Additionally, age-related correlation of 18 F-MK-6240 was small and disappeared when controlled for amyloid status [46]. Further evidence provided from the same cohort underscored the importance of amyloid deposition, showing that amyloid chronicity, a measure of exposure to significant amyloid burden over time, was associated with retention of 18 F-MK-6240 in the entorhinal cortex [47].…”

In-Vivo Staging of Regional Amyloid Progression In Healthy Middle Aged To Older People At Risk of Alzheimer’s Disease

“…A principal limitation of our study is that although the initial sample size was relatively large, the nal number of participants categorized into the different amyloid stages was relatively low, which was also re ected in a low proportion of globally amyloid-positive individuals in the cohort (15%). Previous studies on the WRAP cohort have reported relatively higher rates of amyloid-positivity (approximately 20% depending on the assessed subcohort and study visit), which could be due to the use of different cortical masks for calculating the global average signal (51,52).…”