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Biomarkers have been instrumental in population selection and disease monitoring in clinical trials of recently FDA-approved drugs targeting amyloid-β to slow the progression of Alzheimer's disease (AD). As new therapeutic strategies and biomarker techniques emerge, the importance of biomarkers in drug development is growing exponentially. In this emerging landscape, biomarkers are expected to serve a wide range of contexts of use in clinical trials focusing on AD and related dementias. The joint FDA-NIH BEST (Biomarkers, EndpointS, and other Tools) framework provides standardised terminology to facilitate communication among stakeholders in this increasingly complex field. This review explores various applications of biomarkers relevant to AD clinical trials, using the BEST resource as a reference. For simplicity, we predominantly provide contextual characterizations of biomarkers use from the perspective of drugs targeting amyloid-β and tau proteins. However, general definitions and concepts can be extrapolated to other targets., Competing Interests: Declaration of interests TAP received support to attend meetings from the Alzheimer's Association. LC has received support to attend meetings from the Alzheimer's Association and IMPACT-AD. CKS has received support to attend meetings from the Alzheimer's Association and payment for lectures from the Busse Research Award for Biomedical Research. CSA has received support to attend meetings from the Alzheimer's Association. JF reported receiving personal fees for service on the advisory boards, adjudication committees, or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Esteve, Laboratorios Carnot, Ionis, Lilly, LMI, Lundbeck, Perha, Roche, Zambon and, outside the submitted work. JF reports holding a patent for markers of synaptopathy in neurodegenerative disease (licence to Adx, EPI8382175.0). PR-N received payment for lectures and has served on scientific advisory boards and/or as a consultant for Novo Nordisk, and Eisai. ERZ is on the scientific advisory board of Nintx, Novo Nordisk and is on the scientific advisory board and is a co-founder of MASIMA. MASIMA is a Brazilian company that provides brain scan analytical tools to hospitals. ERZ has never received royalties of financial gains from MASIMA. ERZ has received support to attend meetings from Alzheimer's Association, CNPq, and CAPES. PCLF has received support to attend meetings from the Alzheimer's Association. BB has received support to attend meetings from the Alzheimer's Association., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Females represent approximately 70% of the Alzheimer's disease (AD) cases and the literature has proposed a connection between the decreased estrogen levels during menopause and an increased AD risk. Previous investigations have predominantly focused on assessing how hormone therapy (HT) affects the likelihood of AD development and cognitive deterioration. However, as the research framework has shifted toward a biomarker-defined AD and alterations in specific biomarkers could take place years before cognitive decline becomes discernible, it is crucial to examine how HT influences AD biomarkers. The main goal of this study was to evaluate the impact of HT on AD biomarker-informed pathophysiology in both cognitively unimpaired (CU) and cognitively impaired (CI) post-menopausal females across the aging and AD spectrum., Methods: This cross-sectional study included post-menopausal females without HT history (HT-) and with HT (HT+) at the time of PET imaging assessment from two cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants underwent magnetic resonance imaging (MRI), positron emission tomography (PET) and biofluid collection. Voxel-based t-tests were performed to assess the differences in amyloid-β (Aβ) and tau neurofibrillary tangles (NFTs) loads between HT- and HT + females. Linear regression models with interaction terms were also conducted to examine the interactive effects of HT and Aβ-PET on regional tau-PET., Results: HT + females demonstrated significantly lower tau-PET standardized uptake value ratio (SUVR) in Braak I-II ROIs (P < 0.05, Hedges' g = 0.73), Braak III-IV ROIs (P < 0.0001, Hedges' g = 0.74) and Braak V-VI ROIs (P < 0.0001, Hedges' g = 0.69) compared to HT- females. HT + females also showed significantly lower CSF p-tau 181 (P < 0.001) and plasma p-tau 181 (P < 0.0001) concentrations. Additionally, results from multivariate linear regression models indicated that HT interacts with cortical Aβ and is associated with lower regional NFT load., Conclusions: Overall, findings from this observational study suggest that HT is associated with lower tau neuroimaging and fluid biomarkers in postmenopausal females. Due to the close link between tau and cognition, this study highlights the need for large randomized controlled trials designed to systemically study the influences of HT on AD biomarkers and disease progression., (© 2024. The Author(s).)

Introduction: Mild behavioral impairment (MBI) is characterized by the emergence of neuropsychiatric symptoms in elderly persons. Here, we examine the associations between MBI and Alzheimer's disease (AD) biomarkers in asymptomatic elderly individuals., Methods: Ninety-six cognitively normal elderly individuals underwent MRI, [ 18 F]AZD4694 β-amyloid-PET, and [ 18 F]MK6240 tau-PET. MBI was assessed using the MBI Checklist (MBI-C). Pearson's correlations and voxel-based regressions were used to evaluate the relationship between MBI-C score and [ 18 F]AZD4694 retention, [ 18 F]MK6240 retention, and gray matter (GM) volume., Results: Pearson correlations revealed a positive relationship between MBI-C score and global and striatal [ 18 F]AZD4694 standardized uptake value ratios (SUVRs). Voxel-based regression analyses revealed a positive correlation between MBI-C score and [ 18 F]AZD4694 retention. No significant correlations were found between MBI-C score and [ 18 F]MK6240 retention or GM volume., Conclusion: We demonstrate for the first time a link between MBI and early AD pathology in a cognitively intact elderly population, supporting the use of the MBI-C as a metric to enhance clinical trial enrolment., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

ImportanceNeuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms.ObjectiveTo evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum.Design, setting, and participantsThis cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions.Main outcomes and measuresAll individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-β ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET).ResultsOf the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-β PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (β = 7.37; 95% CI, 1.34-13.41; P = .01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (β = 6.86; 95% CI, 1.77-11.95; P = .008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (β = 5.72; 95% CI, 0.33-11.10; P = .03).Conclusions and relevanceIn this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-β- and microglia-targeted therapies could have an impact on relieving these symptoms.

INTRODUCTION: Fluid biomarkers capable of specifically tracking tau tangle pathology in vivo are greatly needed. METHODS: We measured cerebrospinal fluid (CSF) and plasma concentrations of N‐terminal tau fragments (NTA‐tau), using a novel immunoassay (NTA) in the TRIAD cohort, consisting of 272 individuals assessed with amyloid beta (Aβ) positron emission tomography (PET), tau PET, magnetic resonance imaging (MRI) and cognitive assessments. RESULTS: CSF and plasma NTA‐tau concentrations were specifically increased in cognitively impaired Aβ‐positive groups. CSF and plasma NTA‐tau concentrations displayed stronger correlations with tau PET than with Aβ PET and MRI, both in global uptake and at the voxel level. Regression models demonstrated that both CSF and plasma NTA‐tau are preferentially associated with tau pathology. Moreover, plasma NTA‐tau was associated with longitudinal tau PET accumulation across the aging and Alzheimer's disease (AD) spectrum. DISCUSSION: NTA‐tau is a biomarker closely associated with in vivo tau deposition in the AD continuum and has potential as a tau tangle biomarker in clinical settings and trials. Highlights: An assay for detecting N‐terminal tau fragments (NTA‐tau) in plasma and CSF was evaluated.NTA‐tau is more closely associated with tau PET than amyloid PET or neurodegeneration.NTA‐tau can successfully track in vivo tau deposition across the AD continuum.Plasma NTA‐tau increased over time only in cognitively impaired amyloid‐β positive individuals. [ABSTRACT FROM AUTHOR]