This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer’s Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I–VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer’s disease during late middle-age. Within the Alzheimer’s disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer’s disease.

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 one to four amyloid PET scans (Pittsburgh Compound B, PiB). 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 burden 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 Alzheimer's disease.

Hydroxylamine metabolites, implicated in dose-dependent and idiosyncratic toxicity from arylamine drugs, and amidoximes, used as pro-drugs, are metabolized by an as yet incompletely characterized NADH-dependent microsomal reductase system. We hypothesized that NADH cytochrome b 5 reductase and cytochrome b 5 were responsible for this enzymatic activity in humans. Purified human soluble NADH cytochrome b 5 reductase and cytochrome b 5 , expressed in Escherichia coli, efficiently catalyzed the reduction of sulfamethoxazole hydroxylamine, dapsone hydroxylamine, and benzamidoxime, with apparent K m values similar to those found in human liver microsomes and specific activities (V max ) 74 to 235 times higher than in microsomes. Minimal activity was seen with either protein alone, and microsomal protein did not enhance activity other than additively. All three reduction activities were significantly correlated with immunoreactivity for cytochrome b 5 in individual human liver microsomes. In addition, polyclonal antibodies to both NADH cytochrome b 5 reductase and cytochrome b 5 significantly inhibited reduction activity for sulfamethoxazole hydroxylamine. Finally, fibroblasts from a patient with type II hereditary methemoglobinemia (deficient in NADH cytochrome b 5 reductase) showed virtually no activity for hydroxylamine reduction, compared with normal fibroblasts. These results indicate a novel direct role for NADH cytochrome b 5 reductase and cytochrome b 5 in xenobiotic metabolism and suggest that pharmacogenetic variability in either of these proteins may effect drug reduction capacity.Hydroxylamine and amidoxime compounds are metabolized in humans by an as yet incompletely characterized NADH-dependent reductase system. Hydroxylamine metabolites have been implicated in dose-dependent and idiosyncratic drug toxicity from sulfamethoxazole, dapsone, procainamide, and other arylamine drugs (Uetrecht, 2002). Amidoximes and other hydroxylated amines have been developed as prodrugs to enhance the absorption of a wide range of antihypertensive, antiprotozoal, and antithrombotic drugs (Weller et al

Introduction: We examined the influence of enrollment factors demonstrated to differ by race on incident mild cognitive impairment and dementia using Alzheimer's Disease Center data. Methods: Differences in rates of incident impairment between non-Latino Whites and Blacks (n 5 12,242) were examined with age-at-progression survival models. Models included race, sex, education, source of recruitment, health factors, and family history of dementia. Results: No significant race differences in progression were observed in cognitively unimpaired participants. In those with mild cognitive impairment at baseline, Whites evidenced greater risk for progression than Blacks. Enrollment factors, for example, referral source, were significantly related to progression. Discussion: The finding that Blacks demonstrated lower rate of progression than Whites is contrary to the extant literature. Nested-regression analyses suggested that selection-related factors, differing by race, may account for these findings and influence our ability to accurately estimate risk for progression. It is potentially problematic to make racial comparisons using Alzheimer's Disease Center data sets. Published by Elsevier Inc. on behalf of the Alzheimer's Association.

Disclosure of personal disease‐related information to asymptomatic adults has been debated over the last century in medicine and research. Recently, Alzheimer's disease (AD) has been conceptualized as a continuum that begins with a “preclinical” stage in which biomarkers are present in the absence of cognitive impairment. Studies have begun assessing the safety, psychological, and behavioral effects of disclosing both AD‐related genetic and biomarker information to cognitively unimpaired older adults. Yet, debate continues over the appropriate circumstances and methods for returning such information. This article outlines concerns with and rationale for AD biomarker disclosure and summarizes findings from prior studies. Overall, this article aims to describe and respond to key questions concerning disclosure of amyloid positron emission tomography scan results to asymptomatic adults in a research setting. Moving forward, such conditions are important to consider as interventions target the preclinical phase of AD and normalize disclosing biomarker information to cognitively unimpaired persons.