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Introduction: This increasing body of literature indicates that menopause hormonal replacement therapy (MHT) may substantially mitigate the risk of developing late-life cognitive decline due to progressive Alzheimer's disease (AD) pathophysiology. For the first time, we investigated the question whether MHT impacts AD biomarker-informed pathophysiological dynamics in de-novo diagnosed menopausal women., Methods: We analyzed baseline and longitudinal differences between MHT-taking and -not women in terms of concentrations of core pathophysiological AD plasma biomarkers, validated in symptomatic and cognitively healthy individuals, including biomarkers of (1) the amyloid-β (Aβ) pathway, (2) tau pathophysiology, (3) neuronal loss, and (4) axonal damage and neurodegeneration., Results: We report a prominent and significant treatment response at the Aβ pathway biomarker level. Women at genetic risk for AD (APOE e4 allele carriers) have particularly shown favorable results from treatment., Discussion: To our knowledge, we present first prospective clinical evidence on effects of MHT on AD pathophysiology during menopause., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Increased β-secretase 1 (BACE1) protein concentration, in body fluids, is a candidate biomarker of Alzheimer's disease (AD).We reported that plasma BACE1 protein concentrations are associated with the levels of brain amyloidβ (Αβ) accumulation in cognitively healthy individuals with subjective memory complaint (SMC)., Methods: In 302 individuals from the same cohort, we investigated the cross-sectional and longitudinal association between plasma BACE1 protein concentrations and AD biomarkers of neurodegeneration (plasma t-tau and Neurofilament light chain (NfL), fluorodeoxyglucose-positron emission tomography (FDG-PET), brain volumes in the basal forebrain [BF], hippocampus, and entorhinal cortex)., Results: We report a positive longitudinal correlation of BACE1 with both NfL and t-tau, as well as a correlation between annual BACE1 changes and bi-annual reduction of BF volume. We show a positive association between BACE1 and FDG-PET signal at baseline., Conclusions: The association between plasma BACE1 protein concentrations and BF atrophy we found in cognitively healthy individuals with SMC corroborates translational studies, suggesting a role of BACE1 in neurodegeneration., (© 2021 the Alzheimer's Association.)

Introduction: Successful development of effective β-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies., Methods: We investigated whether key biological factors such as sex, apolipoprotein E (APOE ε4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-β (Aβ) deposition, using positron emission tomography global standard uptake value ratios., Results: Baseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline Aβ-positron emission tomography global standard uptake value ratios., Discussion: Our results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain Aβ production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood., Methods: In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years., Results: Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E ε4 (APOE ε4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status., Discussion: For the first time, we demonstrated that the pleiotropic biological effect of the APOE ε4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions., (Copyright © 2019. Published by Elsevier Inc.)

Introduction: Blood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management., Methods: We investigated whether plasma concentrations of the Aβ 1-40 /Aβ 1-42 ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain Aβ positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-a-priori hypothesis study using machine learning., Results: The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma Aβ 1-40 /Aβ 1-42 ratio. The accuracy is not affected by the apolipoprotein E (APOE) ε4 allele, sex, or age., Discussion: Our results encourage an independent validation cohort study to confirm the indication that the plasma Aβ 1-40 /Aβ 1-42 ratio, assessed via Simoa, may improve future standard of care and clinical trial design., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: In this multicenter study on subjective cognitive decline (SCD) in community-based and memory clinic settings, we assessed the (1) incidence of Alzheimer's disease (AD) and non-AD dementia and (2) determinants of progression to dementia., Methods: Eleven cohorts provided 2978 participants with SCD and 1391 controls. We estimated dementia incidence and identified risk factors using Cox proportional hazards models., Results: In SCD, incidence of dementia was 17.7 (95% Poisson confidence interval 15.2-20.3)/1000 person-years (AD: 11.5 [9.6-13.7], non-AD: 6.1 [4.7-7.7]), compared with 14.2 (11.3-17.6) in controls (AD: 10.1 [7.7-13.0], non-AD: 4.1 [2.6-6.0]). The risk of dementia was strongly increased in SCD in a memory clinic setting but less so in a community-based setting. In addition, higher age (hazard ratio 1.1 [95% confidence interval 1.1-1.1]), lower Mini-Mental State Examination (0.7 [0.66-0.8]), and apolipoprotein E ε4 (1.8 [1.3-2.5]) increased the risk of dementia., Discussion: SCD can precede both AD and non-AD dementia. Despite their younger age, individuals with SCD in a memory clinic setting have a higher risk of dementia than those in community-based cohorts., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls., Methods: The pathophysiological role of CSF α-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD)., Results: We found a positive association between CSF α-syn concentrations and brain β-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α-syn and both CSF t-tau and p-tau 181 concentrations., Discussion: Animal models presented evidence, indicating that α-syn may synergistically and directly induce fibrillization of both tau and β-amyloid. Our data indicate an association of CSF α-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease., (Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Observational multimodal neuroimaging studies indicate sex differences in Alzheimer's disease pathophysiological markers., Methods: Positron emission tomography brain amyloid load, neurodegeneration (hippocampus and basal forebrain volumes adjusted to total intracranial volume, cortical thickness, and 2-deoxy-2-[fluorine-18]fluoro-D-glucose-positron emission tomography metabolism), and brain resting-state functional connectivity were analyzed in 318 cognitively intact older adults from the INSIGHT-preAD cohort (female n = 201, male n = 117). A linear mixed-effects model was performed to investigate sex effects and sex∗apolipoprotein E genotype interaction on each marker as well as sex∗amyloid group interaction for non-amyloid markers., Results: Men compared with women showed higher anterior cingulate cortex amyloid load (P = .009), glucose hypometabolism in the precuneus (P = .027), posterior cingulate (P < .001) and inferior parietal (P = .043) cortices, and lower resting-state functional connectivity in the default mode network (P = .024). No brain volumetric markers showed differences between men and women. Sex∗apolipoprotein E genotype and sex∗amyloid status interactions were not significant., Discussion: Our findings suggest that cognitively intact older men compared with women have higher resilience to pathophysiological processes of Alzheimer's disease., (Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Cognitive change in people at risk of Alzheimer's disease (AD) such as subjective memory complainers is highly variable across individuals., Methods: We used latent class growth modeling to identify distinct classes of nonlinear trajectories of cognitive change over 2 years follow-up from 265 subjective memory complainers individuals (age 70 years and older) of the INSIGHT-preAD cohort. We determined the effect of cortical amyloid load, hippocampus and basal forebrain volumes, and education on the cognitive trajectory classes., Results: Latent class growth modeling identified distinct nonlinear cognitive trajectories. Education was associated with higher performing trajectories, whereas global amyloid load and basal forebrain atrophy were associated with lower performing trajectories., Discussion: Distinct classes of cognitive trajectories were associated with risk and protective factors of AD. These associations support the notion that the identified cognitive trajectories reflect different risk for AD that may be useful for selecting high-risk individuals for intervention trials., (Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: The diagnostic and classificatory performances of all combinations of three core (amyloid β peptide [i.e., Aβ 1-42 ], total tau [t-tau], and phosphorylated tau) and three novel (neurofilament light chain protein, neurogranin, and YKL-40) cerebrospinal fluid biomarkers of neurodegeneration were compared among individuals with mild cognitive impairment (n = 41), Alzheimer's disease dementia (ADD; n = 35), frontotemporal dementia (FTD; n = 9), and cognitively healthy controls (HC; n = 21), using 10-fold cross-validation., Methods: The combinations ranking in the top 10 according to diagnostic accuracy in differentiating between distinct diagnostic categories were identified., Results: The single biomarkers or biomarker combinations generating the best area under the receiver operating characteristics (AUROCs) were the following: the combination [amyloid β peptide + phosphorylated tau + neurofilament light chain] for distinguishing between ADD patients and HC (AUROC = 0.86), t-tau for distinguishing between ADD and FTD patients (AUROC = 0.82), and t-tau for distinguishing between FTD patients and HC (AUROC = 0.78)., Conclusions: Novel and established cerebrospinal fluid markers perform with at least fair accuracy in the discrimination between ADD and FTD. The classification of mild cognitive impairment individuals was poor., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: We assessed the diagnostic accuracy of cerebrospinal fluid (CSF) YKL-40 in discriminating (1) clinical Alzheimer's disease (AD) from cognitively healthy controls (HCs) and frontotemporal dementia (FTD) (level I) and (2) patients stratified by different pathophysiological profiles from HCs and FTD following a novel unbiased/descriptive categorization based on CSF biomarkers, independent of cognitive impairment severity (level II)., Methods: YKL-40 was compared among HCs (n = 21), mild cognitive impairment (n = 41), AD (n = 35), and FTD (n = 9) (level I) and among HCs (n = 21), AD pathophysiology (tau and amyloid β) negative (n = 15), tau positive (n = 15), amyloid β positive (n = 13), AD pathophysiology positive (n = 33), and FTD (n = 9) (level II)., Results: Level I: YKL-40 discriminated AD from HC and FTD (area under the receiver operating characteristic curves [AUROCs] = 0.69, 0.71). Level II: YKL-40 discriminated tau-positive individuals and AD pathophysiology-positive individuals from HC, AD pathophysiology-positive patients from FTD (AUROCs = 0.76, 0.72, 0.73)., Discussion: YKL-40 demonstrates fair performance in distinguishing tau-positive patients from HCs, suggesting it may aid clinical diagnosis and support a biomarker-guided pathophysiological stratification., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Preclinical Alzheimer's disease (AD) is a relatively recent concept describing an entity characterized by the presence of a pathophysiological biomarker signature characteristic for AD in the absence of specific clinical symptoms. There is rising interest in the scientific community to define such an early target population mainly because of failures of all recent clinical trials despite evidence of biological effects on brain amyloidosis for some compounds. A conceptual framework has recently been proposed for this preclinical phase of AD. However, few data exist on this silent stage of AD. We performed a systematic review to investigate how the concept is defined across studies. The review highlights the substantial heterogeneity concerning the three main determinants of preclinical AD: "normal cognition," "cognitive decline," and "AD pathophysiological signature." We emphasize the need for a harmonized nomenclature of the preclinical AD concept and standardized population-based and case-control studies using unified operationalized criteria., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases., (Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Late-life depression is frequently associated with cognitive impairment. Depressive symptoms are often associated with or even precede a dementia syndrome. Moreover, depressive disorders increase the risk of persistence for mild cognitive impairment and dementia. Here, we present both the current state of evidence and future perspectives regarding the integration and value of clinical assessments, neuropsychological, neurochemical, and neuroimaging biomarkers for the etiological classification of the dementia versus the depression syndrome and for the prognosis of depression relating to dementia risk. Finally, we summarize the existing evidence for both pharmacotherapy and psychotherapy of depression in demented patients. There is an urgent need for large-scale collaborative research to elucidate the role and interplay of clinical and biological features in elderly individuals with depressive disorders who are at elevated risk for developing dementia. To overcome barriers for successful drug development, we propose the introduction of the precision medicine paradigm to this research field., (Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: The corticobasal syndrome (CBS) constitutes a neurodegenerative disease spectrum with substantial phenotypical or biological heterogeneity, requiring large or multimodal studies to identify its clinico-biological signature while disentangling Alzheimer's disease (AD)-related from non-AD-related CBS., Methods: We analyzed a large (N = 45) monocenter expert-clinic CBS cohort, recruited in motor and/or cognitive units to avoid recruitment biases, assessed with standardized motor and/or cognitive-language tests, brain perfusion imaging, and cerebrospinal fluid biomarkers., Results: CBS mainly manifests as a motor and/or language disorder incorporating a "mixed progressive aphasia" phenotype, consistent with left-lateralized damage to frontal-parietal-temporal cortices. Biomarker expression indicates in 18% underlying AD causing predominant parietal-temporal damage and Gerstmann syndrome (sensitivity 75%; specificity 75%), whereas non-AD-CBS presented with predominant prefrontal and lexical-semantic impairment., Discussion: CBS is primarily a "motor-plus-aphasia" disease unfolding into AD-related and non-AD-related variants with distinctive cognitive-anatomic patterns. CBS, and notably its "Gerstmann variant", should be included in the new AD "lexicon" and categorized in the evolving diagnostic spectrum of "atypical AD"d., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: The aim of this study was to test the diagnostic value of cerebrospinal fluid (CSF) beta-amyloid (Aβ1-42), phosphorylated tau, and total tau (tau) to discriminate Alzheimer's disease (AD) dementia from other forms of dementia., Methods: A total of 675 CSF samples collected at eight memory clinics were obtained from healthy controls, AD dementia, subjective memory impairment, mild cognitive impairment, vascular dementia, Lewy body dementia (LBD), fronto-temporal dementia (FTD), depression, or other neurological diseases., Results: CSF Aβ1-42 showed the best diagnostic accuracy among the CSF biomarkers. At a sensitivity of 85%, the specificity to differentiate AD dementia against other diagnoses ranged from 42% (for LBD, 95% confidence interval or CI = 32-62) to 77% (for FTD, 95% CI = 62-90)., Discussion: CSF Aβ1-42 discriminates AD dementia from FTD, but shows significant overlap with other non-AD forms of dementia, possibly reflecting the underlying mixed pathologies., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD)., Methods: A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method., Results: Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = -1.89%) compared with the placebo group (APC = -3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups., Discussion: A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

The lack of readily available biomarkers is a significant hindrance toward progressing to effective therapeutic and preventative strategies for Alzheimer's disease (AD). Blood-based biomarkers have potential to overcome access and cost barriers and greatly facilitate advanced neuroimaging and cerebrospinal fluid biomarker approaches. Despite the fact that preanalytical processing is the largest source of variability in laboratory testing, there are no currently available standardized preanalytical guidelines. The current international working group provides the initial starting point for such guidelines for standardized operating procedures (SOPs). It is anticipated that these guidelines will be updated as additional research findings become available. The statement provides (1) a synopsis of selected preanalytical methods utilized in many international AD cohort studies, (2) initial draft guidelines/SOPs for preanalytical methods, and (3) a list of required methodological information and protocols to be made available for publications in the field to foster cross-validation across cohorts and laboratories., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The development of validated, qualified, and standardized biomarkers for Alzheimer's disease (AD) that allow for an early presymptomatic diagnosis and discrimination (classification) from other types of dementia and neurodegenerative diseases is warranted to accelerate the successful development of novel disease-modifying therapies. Here, we focus on the value of the 42-residue-long amyloid β isoform (Aβ1-42) peptide in the cerebrospinal fluid as the core, feasible neurobiochemical marker for the amyloidogenic mechanisms in early-onset familial and late-onset sporadic AD. We discuss the role and use of Aβ1-42 in combination with evolving neuroimaging biomarkers in AD detection and diagnosis. Multimodal neuroimaging techniques, directly providing structural-functional-metabolic aspects of brain pathophysiology, are supportive to predict and monitor the progression of the disease. Advances in multimodal neuroimaging provide new insights into brain organization and enable the detection of specific proteins and/or protein aggregates associated with AD. The combination of biomarkers from different methodologies is believed to be of incrementally added risk-value to accurately identify asymptomatic and prodromal individuals who will likely progress to dementia and represent rational biomarker candidates for preventive and symptomatic pharmacological intervention trials., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

The aim of this perspective article is to stimulate radical shifts in thinking and foster further discussion on the effective discovery, development, validation, and qualification process of biological markers derived from all available technical modalities that meet the complex conceptual and pathophysiological challenges across all stages of the complex, nonlinear, dynamic, and chronically progressive sporadic Alzheimer's disease (AD). This perspective evaluates the current state of the science regarding a broad spectrum of hypothesis-driven and exploratory technologies and "markers" as candidates for all required biomarker functions, in particular, surrogate indicators of adaptive to maladaptive and compensatory to decompensatory, reversible to irreversible brain "systems failure." We stress the future importance of the systems biology (SB) paradigm (next to the neural network paradigm) for substantial progress in AD research. SB represents an integrated and deeper investigation of interacting biomolecules within cells and organisms. This approach has only recently become feasible as high-throughput technologies and mass spectrometric analyses of proteins and lipids, together with rigorous bioinformatics, have evolved. Existing high-content data derived from clinically and experimentally derived neural tissues point to convergent pathophysiological pathways during the course of AD, transcending traditional descriptive studies to reach a more integrated and comprehensive understanding of AD pathophysiology, derived systems biomarkers, and "druggable" system nodes. The discussion is continued on the premise that the lack of integration of advanced biomarker technologies and transfertilization from more mature translational research fields (e.g., oncology, immunology, cardiovascular), which satisfy regulatory requirements for an accurate, sensitive, and well-validated surrogate marker of specific pathophysiological processes and/or clinical outcomes, is a major rate-limiting factor for the successful development and approval of effective treatments for AD prevention. We consider the conceptual, scientific, and technical challenges for the discovery-development-validation-qualification process of biomarker tools and analytical algorithms for detection of the earliest pathophysiological processes in asymptomatic individuals at elevated risk during preclinical stages of AD. The most critical need for rapid translation of putative markers into validated (performance) and standardized (harmonized standard operating procedures) biomarker tools that fulfill regulatory requirements (qualify for use in treatment trials: e.g., safety, target engagement, mechanism of action, enrichment, stratification, secondary and primary outcome, surrogate outcome) is the availability of a large-scale worldwide comprehensive longitudinal database that includes the following cohorts: (a) healthy aging, (b) people at elevated risks (genetic/epigenetic/lifestyle/comorbid conditions), and (c) asymptomatic-preclinical/prodromal-mild cognitive impairment/syndromal mild, moderate, or severe AD. Our proposal, as initial strategic steps for integrating markers into future development of diagnostic and therapy trial technologies, is to work toward: (a) creating the essential research and development infrastructure as an international shared resource, (b) building the organizational structure for managing such a multinational shared resource, and (c) establishing an integrated transsectoral multidisciplinary global network of collaborating investigators to help build and use the shared research resource., (Copyright © 2012 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)