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Introduction: While it is generally appreciated that amyloid precedes symptomatic Alzheimer's disease (AD) by decades, a greater understanding of this timeline may increase prognostic accuracy, planning, and care of persons who are on the AD continuum., Methods: We examined trajectories of Clinical Dementia Rating-Sum of Boxes (CDR-SB) relative to estimated years of amyloid positivity (A+) in n  = 123 participants who were all A+ based on [C-11]Pittsburgh compound B positron emission tomography., Results: The average amyloid chronicity at CDR-SB of 2.5 was 20.1 years. The average trajectory of CDR-SB accelerated after 10 years of elevated amyloid and varied greatly between 10 and 30 years. Exploratory analyses suggested that older age and higher volume of white matter hyperintensities shortened the interval between amyloid onset and cognitive impairment., Discussion: The recontextualization of amyloid burden into the time domain will facilitate studies of disease progression, the influence of co-pathology, and factors that hasten or slow cognitive impairment., Competing Interests: Sterling C. Johnson has served on advisory boards for Roche Diagnostics and Eisai. Robert J. Przybelski has served on a speaking panel for Biogen. The remaining authors have no relevant disclosures. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Modifiable health and lifestyle factors increase risk of dementia, but whether modifiable factors, when measured in late-midlife, impact the emergence or progression of Alzheimer's disease (AD) pathophysiologic or cognitive changes remains unresolved., Methods: In initially cognitively unimpaired, late middle-aged participants ( N  = 1215; baseline age, M [standard deviation] = 59.3 [6.7] years) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), we investigated the influence of the Lifestyle for Brain Health (LIBRA) index, a lifestyle-based dementia risk score, on AD-related cognitive trajectories and amyloid beta (Aβ) plaque accumulation., Results: Overall, lower baseline LIBRA, denoting healthier lifestyle and lower dementia risk, was related to better overall cognitive performance, but did not moderate apolipoprotein E ε4 or Aβ-related longitudinal cognitive trajectories. LIBRA was not significantly associated with Aβ accumulation or estimated age of Aβ onset., Discussion: In WRAP, late-midlife LIBRA scores were related to overall cognitive performance, but not AD-related cognitive decline or Aβ accumulation in the preclinical timeframe., Highlights: The Lifestyle for Brain Health (LIBRA) index was associated with cognitive performance in late-midlife.LIBRA did not moderate apolipoprotein E ε4 or amyloid-related cognitive decline.LIBRA was not associated with the onset or accumulation of amyloid plaques., Competing Interests: Dr. Johnson has participated on an advisory panel for and received an equipment grant from Roche Diagnostics, and he has received support (sponsoring of an observational study and provision of precursor for tau imaging) from Cerveau Technologies. No other disclosures were reported. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Disclosure of Alzheimer's disease (AD) biomarkers to cognitively unimpaired adults are currently conducted only in research settings. Yet, US Food and Drug Administration approval of a disease-modifying treatment for symptomatic individuals, improved understanding of the "preclinical" phase of disease, and advancements toward more accessible biomarker tests suggest such disclosure will increase in frequency, eventually becoming routine in clinical practice. The changing landscape in AD research to focus on biomarkers has generated debate on the validity and clinical utility of disclosure to cognitively unimpaired adults. This article explores the broader social implications of more widespread AD biomarker disclosure-that is, of individuals learning their risk for developing dementia caused by AD. We identify 10 challenges and offer preliminary solutions. As the field continues to evolve, it is essential to anticipate and address these broader ethical, legal, and social implications of disclosure., Competing Interests: The authors have no conflicts to disclose. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: This study examined the relationship between cardiorespiratory fitness (CRF) and longitudinal cognitive functioning in a cohort enriched with risk factors for Alzheimer's disease (AD)., Methods: A total of 155 enrollees in the Wisconsin Registry for Alzheimer's Prevention completed repeat comprehensive neuropsychological evaluations that assessed six cognitive domains. Peak oxygen consumption (VO 2 peak) was the primary measure of CRF. Random effects regression was used to investigate the effect of CRF on cognitive trajectories., Results: Higher CRF was associated with slower decline in the cognitive domains of verbal learning and memory ( P  < .01) and visual learning and memory ( P  < .042). Secondary analyses indicated that these effects were stronger among men than women, and for noncarriers of the apolipoprotein E ε4 allele., Discussion: Higher CRF was associated with a slower rate of the decline in episodic memory that occurs as a natural consequence of aging in a cohort enriched with risk factors for AD., Competing Interests: The authors report no conflicts of interest., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: This work investigated the relationship between cerebrovascular disease (CVD) markers and Alzheimer's disease (AD) biomarkers of amyloid beta deposition, and neurofibrillary tau tangles in subjects spanning the AD clinical spectrum., Methods: A total of 136 subjects participated in this study. Four groups were established based on AD biomarker positivity from positron emission tomography (amyloid [A] and tau [T]) and clinical diagnosis (cognitively normal [CN] and impaired [IM]). CVD markers were derived from structural and quantitative magnetic resonance imaging data., Results: Transcapillary pulse wave delay was significantly longer in controls compared to AT biomarker-confirmed groups (A+/T-/CN P  < .001, A+/T+/CN P  < .001, A+/T+/IM P  = .003). Intracranial low-frequency oscillations were diminished in AT biomarker-confirmed groups both CN and impaired (A+/T-/CN P  = .039, A+/T+/CN P  = .007, A+/T+/IM P  = .011). A significantly higher presence of microhemorrhages was measured in A+/T+/CN compared to controls ( P  = .006)., Discussion: Cerebrovascular markers indicate increased vessel stiffness and reduced vasomotion in AT biomarker-positive subjects during preclinical AD., Competing Interests: K.A. Cody, T. Reher, and R.V. Cadman have nothing to disclose. L.A. Rivera‐Rivera's effort on this work was supported by the Alzheimer's Association AARFD‐20‐678095 paid to the institution. L. Eisenmenger's effort on this work was supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR002373 and KL2TR002374, as well as the Wisconsin Alzheimer's Disease Research Center grant P30‐AG062715 paid to the institution. T. Betthauser has also received grant support outside the submitted work from Alzheimer's Association AARF‐19‐614533 paid to the institution. H.A. Rowley has received consulting fees from GE HealthCare, iSchemaView and for accredited lectures and podcasts for Northwest Imaging Forums and the Data Safety Monitoring Board of HL Gore. H.A. Rowley has also received grant support outside the submitted work from the Radiological Society of North America, Fellow Grant paid to the institution. C.M. Carlsson has received payments for her participation in an NIH study at UCLA (D‐CARE) and study drugs from Amarin Corporation (Vascepa and placebo) for VA Merit Study. C.M. Carlsson has also received grant support outside the submitted work from NIH/Lilly, NIH/Esai, VA Merit, and NIH to the institution. N.A. Chin has received payments for being a member of the Med‐Sci committee for the WI Alzheimer's Association and member of the Med‐Sci committee for the Alzheimer's Foundation of America. S.C. Johnson serves on an advisory board for Roche Diagnostics for which he receives an honorarium and is principal investigator of an equipment grant from Roche. He receives research funding from Cerveau Technologies. K.M. Johnson has received royalties for patents licensed by the institution (UW‐Madison) unrelated to this project. K.M. Johnson has also received grant support outside the submitted work from NIH and GE Healthcare as research support to the institution., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: Batch differences in cerebrospinal fluid (CSF) biomarker measurement can introduce bias into analyses for Alzheimer's disease studies. We evaluated and adjusted for batch differences using statistical methods., Methods: A total of 792 CSF samples from 528 participants were assayed in three batches for 12 biomarkers and 3 biomarker ratios. Batch differences were assessed using Bland-Altman plot, paired t test, Pitman-Morgan test, and linear regression. Generalized linear models were applied to convert CSF values between batches., Results: We found statistically significant batch differences for all biomarkers and ratios, except that neurofilament light was comparable between batches 1 and 2. The conversion models generally had high R 2 except for converting P-tau between batches 1 and 3., Discussion: Between-batch conversion allows harmonized CSF values to be used in the same analysis. Such method may be applied to adjust for other sources of variability in measuring CSF or other types of biomarkers., Competing Interests: Dr. Cynthia Carlsson receives grant support from NIH/Lilly, NIH, Veterans Affairs, and Bader Philanthropies. Dr. Sterling Johnson previously served on the advisory board for Roche Diagnostics. Dr. Sanjay Asthana serves as a site PI for pharmaceutical trials funded by Merck Pharmaceuticals, Lundbeck, NIH/UCSD, EISAI, and Genentech Inc. Dr. Richard Chappell serves on data safety monitoring boards for Axsome Pharmaceuticals and TGR Pharmaceuticals and has recently had a speaking engagement at Merck, Inc. Dr. Henrik Zetterberg has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Dr. Kaj Blennow has served as a consultant or on advisory boards for Abcam, Axon, Biogen, Lilly, MagQu, Novartis, and Roche Diagnostics, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of 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., Competing Interests: Dr. Johnson has participated on an advisory panel for and received an equipment grant from Roche Diagnostics, and he has received support (sponsoring of an observational study and provision of precursor for tau imaging) from Cerveau Technologies. No other disclosures were reported., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

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., Competing Interests: [18F]MK‐6240 precursor and reference standard used in this study were provided by Cerveau Technologies. Dr. Sterling C. Johnson is principal investigator for a separate ongoing study using MK‐6240 sponsored by Cerveau Technologies. Dr. Sterling C. Johnson served on an advisory board for Roche Diagnostics in 2018. Dr. Howard Rowley is a consultant for GE HealthCare and has equity interest in ImageMoverMD. None of the other authors has any relevant disclosures., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of the Alzheimer's Association.)