the transcription factor TFEB, its mRNA transcripts, and their principle autophagy proteins – LC3... more the transcription factor TFEB, its mRNA transcripts, and their principle autophagy proteins – LC3B, p62, and LAMP2 – by immunohistochemistry and computational modeling of ApoE protein-DNA interactions. Results: Levels of the three key TFEB-regulated mRNA transcripts were lower in the brains of Alzheimer patient carriers of APOE ε4,4 than those of APOE ε3,3 carriers, despite similar nuclear levels of TFEB. This was due to specific binding of ApoE4 to TFEB-regulated CLEAR DNA motifs and was dependent on the presence of Arg112 and Arg61 as was shown to be the case by preclusion of such binding by computational substitution of Ala for Arg at 112 and 61. Conclusions: ApoE4-CLEAR motif interactions may account for elevated aggregation in ApoE4 carriers, and this in turn, account for increased risk for disease development. ApoE4 increases risk for development of AD in part by weakening the autophagy response, specifically by direct binding of ApoE4 to the CLEAR motif, which is recognized by the master autophagy regulator TFEB. The close relationship between inflammation and autophagy suggests that therapies targeting both pathways might be beneficial in treating Alzheimer patients.
BackgroundSelective positron emission tomography (PET) tracers to target neurofibrillary tangles ... more BackgroundSelective positron emission tomography (PET) tracers to target neurofibrillary tangles of the second generation have indicated to overcome some of the methodological issues observed with the tau‐tracers of the first generation. How these second‐generation tau tracers may be better suitable for clinical practice was assessed in the context of the Geneva Biomarker Roadmap Initiative during and prior to a two‐day workshop (Geneva, November 2019).MethodGuided by a framework for systematic validation of oncological diagnostic biomarkers adapted for the implementation of biomarker quantifying the pathological hallmarks of Alzheimer’s Disease (AD), we evaluated the performance of the tau‐selective tracers of the second generation. Subsequently we defined research priorities focusing on the advancement of the framework, with the goal for implementation of these PET tracers in clinical practice.ResultAll tracers identified as second generation, have provided evidence for in vitro binding to tau tangles in tissue samples of patients with and without Alzheimer’s disease. Additionally, in vivo pharmacokinetic modeling has been successfully achieved for some (e.g., 18F‐MK‐6240, 18F‐PI‐2620) but not all second‐generation tau tracers (e.g., GTP‐1, 18F‐JNJ‐067). Overall, observational cross‐sectional studies have provided preliminary evidence on the diminished extent of off‐target binding, high discriminatory ability between healthy and diseased populations and sensitivity in clinically diverse samples (e.g., 18F‐RO‐948, 18F‐MK‐6240, 18F‐PI‐2620).ConclusionA readily implementation of the tau tracer of the second‐generation in clinical practice is limited by the scarcity of comprehensive data analysis with bigger samples sizes and by the overall lack of end‐of‐life studies. However, the goal of the second‐generation tau tracers to overcome some of the methodological issues raised by the first generation tau tracers is partially achieved. Finally, the adaptation of the oncological diagnostic framework to the clinical validity of biomarkers measuring AD pathology has proven most useful in formulating new practical research goals to advance the clinical utility of the second generation tau tracer.
BackgroundThe 2017 Alzheimer’s disease (AD) Biomarker Roadmap structures the validation of AD dia... more BackgroundThe 2017 Alzheimer’s disease (AD) Biomarker Roadmap structures the validation of AD diagnostic biomarkers into a systematic sequence of 5 Phases, each encompassing primary and secondary aims assessing analytical validity (Phases 1‐2), clinical validity (Phases 3‐4) and clinical utility (Phase 5). This framework allows us to assess current evidence and identify requirements, gaps, and research priorities towards Phase‐5 validity. While using this methodology to assess the validation status of biomarkers of tau pathology we revised this methodology consistently with progresses in AD research.MethodFirst, we critically appraised the adequacy of the 2017 Biomarker Roadmap to assess tau biomarkers and relative to the current biomedical perspective of AD (e.g., A/T/N framework). Second, we proposed and discussed the adaptations at a workshop (Geneva, November 11‐12, 2019) convening the Alzheimer’s Association and 8 leading AD biomarker research groups, tasked with assessing the validity of CSF‐, plasma‐ and imaging‐tau biomarkers for AD according to the updated Biomarker Roadmap framework.ResultThe 2019 updates apply to tau as well as other biomarkers and include: Phase 3: a greater variety of study designs (e.g., cross‐sectional in addition to longitudinal) and reference standards (e.g., AD biomarker confirmation in addition to clinical progression) deemed appropriate to appraise the evidence on tau biomarkers; Phases 1‐5:evidence appraisal examining quality of evidence in addition to target results. Most urgent research priorities for both tau and other biomarkers are to: Define specific clinically‐ and patient‐relevant outcomes with all pertinent stakeholders (patients, caregivers, clinicians, regulators), to prepare proper studies on clinical utility and implementation; Produce/adapt specific reporting guidelines facilitating methodological compliance, reporting and assessment of the produced evidence.ConclusionWe have revised the Biomarker Roadmap accommodating biomarkers of tau pathology. This revision improves the methodology also for the other AD biomarkers. To further boost their validation up to Phase‐5 studies, the available evidence should be assessed by methodologists not directly involved in the assessed studies, possibly through dynamic data sharing on accessible platforms. Compliance with this methodology is essential to implement tau biomarkers efficiently in clinical research and diagnostics.
BackgroundIn the last decade, the research community focused on defining reliable biomarkers for ... more BackgroundIn the last decade, the research community focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer’s Disease (AD). In 2017, the Geneva AD Biomarker Roadmap Initiative adapted the framework for the systematic validation of oncological diagnostic biomarkers to AD, with the aim to accelerate their development and implementation in clinical practice. With this work we assess the maturity of [18F]flortaucipir and we define the research priorities.MethodIn a two‐day workshop (Geneva, November 2019), we convened a panel of experts in AD biomarkers. The level of maturity of [18F]flortaucipir has been assessed based on the Biomarker Roadmap (Frisoni et al., 2017). Biomarker maturity and research priorities were processed by thematic subgroups before the meeting, and presented and discussed during the workshopResult[18F]flortaucipir binds with high affinity to paired helical filaments of tau and has favorable kinetic properties. It accurately discriminates between AD and patients with non‐AD neurodegenerative disorders as well as healthy controls. Initial studies showed high correlations between ante mortem and post‐mortem tau pathology. Further research is needed to investigate the effects of covariates on tracer binding and its ability to detect tau pathology in the early phase of AD.Conclusion[18F]flortaucipir provide partial evidence for clinical utility. In vivo [18F]flortaucipir PET shows excellent discrimination for AD from controls and non‐AD neurodegenerative disorders and promising results for the validation with autopsy. However, completion of studies on analytical validity is a requirement to investigate clinical utility properly.
p1⁄40.43) as Auc-. There was no significant difference in rate of diagnostic (21% vs. 33%, p1⁄40.... more p1⁄40.43) as Auc-. There was no significant difference in rate of diagnostic (21% vs. 33%, p1⁄40.41) or treatment change (66% vs. 77%, p1⁄40.38) between Auc+ and Auc-. We observed significantly greater rate of diagnostic change in LO compared to EO (43% vs. 13%, p1⁄40.017) but no difference in treatment change (62% vs. 78%, p1⁄40.21). These results remained unchanged in the dementia-expert sample only. Conclusions: In our preliminary retrospective series we found no difference in pre/post-scan diagnosis in Aucvs. Auc+ and treatment changes in both comparisons. Changes in diagnosis were significantly more common in LO relative to EO suggesting that greater emphasis on scanning LO might be appropriate.
BackgroundThough cerebrospinal fluid (CSF) Aβ42, p‐tau181 and t‐tau have been shown to increase d... more BackgroundThough cerebrospinal fluid (CSF) Aβ42, p‐tau181 and t‐tau have been shown to increase diagnostic accuracy for early Alzheimer’s disease (i.e. AD at the MCI stage), several challenges remain with respect to their routine clinical use. In order to address these and related issues, a multidisciplinary task force was formed (Geneva Biomarker Roadmap Initiative). Adapting a five‐phase framework for the development of cancer biomarkers (Pepe et al., 2001), this task force recently convened (2019) to provide an update on earlier publications (2017). We here provide an update for the core CSF AD biomarkers (Aβ42/Aβ40, p‐tau181 and t‐tau) and for the first time provide a review of the same measures in blood in context of the five‐phase framework.MethodIn a two‐day workshop (Geneva, November 2019), we convened a panel of experts in AD biomarkers. The level of maturity of CSF and blood biomarkers was assessed based on the Biomarker Roadmap (Frisoni et al., 2017). Biomarker maturity and research priorities were systemically assessed by subgroups before the meeting, and presented and discussed during the workshop.ResultCSF biomarkers continued to demonstrate the highest level of maturity according to the strategic roadmap. Significant improvements compared to the 2017 summary (Mattsson et al., 2017) included the development of fully‐automated assays and the introduction of standard operating procedures for the preanalytical handling of CSF. Despite being in their infancy, the data presented and discussed for certain blood biomarkers demonstrated promising results. While t‐tau in blood did not satisfy the criteria for phase 2 (diagnostic discrimination), p‐tau181 and Aβ in blood either fully or partially fulfilled the criteria for this phase. It was agreed that only preliminary, albeit encouraging, evidence was available for the ability of blood measures to predict AD dementia in subjects with MCI (phase 3). An overview of novel CSF and blood tau biomarkers will also be discussed.ConclusionThe core CSF AD biomarkers (t‐tau, p‐tau181 and Aβ) have the highest level of maturity for clinical utility. Blood biomarkers for p‐tau18, and to a lesser degree Aβ, show excellent discrimination for AD from controls and non‐AD neurodegenerative disorders.
Alzheimer's & Dementia: Translational Research & Clinical Interventions
IntroductionCoronavirus disease 2019 (COVID‐19) has caused >3.5 million deaths worldwide and a... more IntroductionCoronavirus disease 2019 (COVID‐19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID‐19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID‐19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID‐19 to neurologic illness, both short and long term.MethodsThis article describes what is known so far in ter...
The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sy... more The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias.This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations.Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Allevia...
Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactor... more Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late‐onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World‐Wide FINGERS (WW‐FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW‐FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline—from at‐risk asymptomatic states to early symptomatic stages—in different geographical, cultural, and economic settings. WW‐FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to fa...
Previous studies have evaluated the diagnostic effect of amyloid positron emission tomography (PE... more Previous studies have evaluated the diagnostic effect of amyloid positron emission tomography (PET) in selected research cohorts. However, these research populations do not reflect daily practice, thus hampering clinical implementation of amyloid imaging. To evaluate the association of amyloid PET with changes in diagnosis, diagnostic confidence, treatment, and patients' experiences in an unselected memory clinic cohort. Amyloid PET using fluoride-18 florbetaben was offered to 866 patients who visited the tertiary memory clinic at the VU University Medical Center between January 2015 and December 2016 as part of their routine diagnostic dementia workup. Of these patients, 476 (55%) were included, 32 (4%) were excluded, and 358 (41%) did not participate. To enrich this sample, 31 patients with mild cognitive impairment from the University Medical Center Utrecht memory clinic were included. For each patient, neurologists determined a preamyloid and postamyloid PET diagnosis that e...
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2017
A classification framework for posterior cortical atrophy (PCA) is proposed to improve the unifor... more A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings. Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web-based quantitative survey regarding symptom frequency and the conceptualization of PCA. A three-level classification framework for PCA is described comprising both syndrome- and disease-level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2 (PCA-pure, PCA-plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD [PCA-AD], Lewy body disease [PCA-LBD], corticobasal de...
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2014
Regulatory qualification of a biomarker for a defined context of use provides scientifically robu... more Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development. The Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data. The literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011. We summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.
Cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) are increasingly used in clinic... more Cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) are increasingly used in clinical settings, research and drug trials. However, their broad-scale use on different technology platforms is hampered by the lack of standardization at the level of sample handling, determination of concentrations of analytes and the absence of well-defined performance criteria for in vitro diagnostic or companion diagnostic assays, which influences the apparent concentration of the analytes measured and the subsequent interpretation of the data. There is a need for harmonization of CSF AD biomarker assays that can reliably, across centers, quantitate CSF biomarkers with high analytical precision, selectivity and stability over long time periods. In this position paper, we discuss reference procedures for the measurement of CSF AD biomarkers, especially amyloid β42 and tau. We describe possible technical approaches, focusing on a selected reaction monitoring mass spectrometry assay as a ca...
the transcription factor TFEB, its mRNA transcripts, and their principle autophagy proteins – LC3... more the transcription factor TFEB, its mRNA transcripts, and their principle autophagy proteins – LC3B, p62, and LAMP2 – by immunohistochemistry and computational modeling of ApoE protein-DNA interactions. Results: Levels of the three key TFEB-regulated mRNA transcripts were lower in the brains of Alzheimer patient carriers of APOE ε4,4 than those of APOE ε3,3 carriers, despite similar nuclear levels of TFEB. This was due to specific binding of ApoE4 to TFEB-regulated CLEAR DNA motifs and was dependent on the presence of Arg112 and Arg61 as was shown to be the case by preclusion of such binding by computational substitution of Ala for Arg at 112 and 61. Conclusions: ApoE4-CLEAR motif interactions may account for elevated aggregation in ApoE4 carriers, and this in turn, account for increased risk for disease development. ApoE4 increases risk for development of AD in part by weakening the autophagy response, specifically by direct binding of ApoE4 to the CLEAR motif, which is recognized by the master autophagy regulator TFEB. The close relationship between inflammation and autophagy suggests that therapies targeting both pathways might be beneficial in treating Alzheimer patients.
BackgroundSelective positron emission tomography (PET) tracers to target neurofibrillary tangles ... more BackgroundSelective positron emission tomography (PET) tracers to target neurofibrillary tangles of the second generation have indicated to overcome some of the methodological issues observed with the tau‐tracers of the first generation. How these second‐generation tau tracers may be better suitable for clinical practice was assessed in the context of the Geneva Biomarker Roadmap Initiative during and prior to a two‐day workshop (Geneva, November 2019).MethodGuided by a framework for systematic validation of oncological diagnostic biomarkers adapted for the implementation of biomarker quantifying the pathological hallmarks of Alzheimer’s Disease (AD), we evaluated the performance of the tau‐selective tracers of the second generation. Subsequently we defined research priorities focusing on the advancement of the framework, with the goal for implementation of these PET tracers in clinical practice.ResultAll tracers identified as second generation, have provided evidence for in vitro binding to tau tangles in tissue samples of patients with and without Alzheimer’s disease. Additionally, in vivo pharmacokinetic modeling has been successfully achieved for some (e.g., 18F‐MK‐6240, 18F‐PI‐2620) but not all second‐generation tau tracers (e.g., GTP‐1, 18F‐JNJ‐067). Overall, observational cross‐sectional studies have provided preliminary evidence on the diminished extent of off‐target binding, high discriminatory ability between healthy and diseased populations and sensitivity in clinically diverse samples (e.g., 18F‐RO‐948, 18F‐MK‐6240, 18F‐PI‐2620).ConclusionA readily implementation of the tau tracer of the second‐generation in clinical practice is limited by the scarcity of comprehensive data analysis with bigger samples sizes and by the overall lack of end‐of‐life studies. However, the goal of the second‐generation tau tracers to overcome some of the methodological issues raised by the first generation tau tracers is partially achieved. Finally, the adaptation of the oncological diagnostic framework to the clinical validity of biomarkers measuring AD pathology has proven most useful in formulating new practical research goals to advance the clinical utility of the second generation tau tracer.
BackgroundThe 2017 Alzheimer’s disease (AD) Biomarker Roadmap structures the validation of AD dia... more BackgroundThe 2017 Alzheimer’s disease (AD) Biomarker Roadmap structures the validation of AD diagnostic biomarkers into a systematic sequence of 5 Phases, each encompassing primary and secondary aims assessing analytical validity (Phases 1‐2), clinical validity (Phases 3‐4) and clinical utility (Phase 5). This framework allows us to assess current evidence and identify requirements, gaps, and research priorities towards Phase‐5 validity. While using this methodology to assess the validation status of biomarkers of tau pathology we revised this methodology consistently with progresses in AD research.MethodFirst, we critically appraised the adequacy of the 2017 Biomarker Roadmap to assess tau biomarkers and relative to the current biomedical perspective of AD (e.g., A/T/N framework). Second, we proposed and discussed the adaptations at a workshop (Geneva, November 11‐12, 2019) convening the Alzheimer’s Association and 8 leading AD biomarker research groups, tasked with assessing the validity of CSF‐, plasma‐ and imaging‐tau biomarkers for AD according to the updated Biomarker Roadmap framework.ResultThe 2019 updates apply to tau as well as other biomarkers and include: Phase 3: a greater variety of study designs (e.g., cross‐sectional in addition to longitudinal) and reference standards (e.g., AD biomarker confirmation in addition to clinical progression) deemed appropriate to appraise the evidence on tau biomarkers; Phases 1‐5:evidence appraisal examining quality of evidence in addition to target results. Most urgent research priorities for both tau and other biomarkers are to: Define specific clinically‐ and patient‐relevant outcomes with all pertinent stakeholders (patients, caregivers, clinicians, regulators), to prepare proper studies on clinical utility and implementation; Produce/adapt specific reporting guidelines facilitating methodological compliance, reporting and assessment of the produced evidence.ConclusionWe have revised the Biomarker Roadmap accommodating biomarkers of tau pathology. This revision improves the methodology also for the other AD biomarkers. To further boost their validation up to Phase‐5 studies, the available evidence should be assessed by methodologists not directly involved in the assessed studies, possibly through dynamic data sharing on accessible platforms. Compliance with this methodology is essential to implement tau biomarkers efficiently in clinical research and diagnostics.
BackgroundIn the last decade, the research community focused on defining reliable biomarkers for ... more BackgroundIn the last decade, the research community focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer’s Disease (AD). In 2017, the Geneva AD Biomarker Roadmap Initiative adapted the framework for the systematic validation of oncological diagnostic biomarkers to AD, with the aim to accelerate their development and implementation in clinical practice. With this work we assess the maturity of [18F]flortaucipir and we define the research priorities.MethodIn a two‐day workshop (Geneva, November 2019), we convened a panel of experts in AD biomarkers. The level of maturity of [18F]flortaucipir has been assessed based on the Biomarker Roadmap (Frisoni et al., 2017). Biomarker maturity and research priorities were processed by thematic subgroups before the meeting, and presented and discussed during the workshopResult[18F]flortaucipir binds with high affinity to paired helical filaments of tau and has favorable kinetic properties. It accurately discriminates between AD and patients with non‐AD neurodegenerative disorders as well as healthy controls. Initial studies showed high correlations between ante mortem and post‐mortem tau pathology. Further research is needed to investigate the effects of covariates on tracer binding and its ability to detect tau pathology in the early phase of AD.Conclusion[18F]flortaucipir provide partial evidence for clinical utility. In vivo [18F]flortaucipir PET shows excellent discrimination for AD from controls and non‐AD neurodegenerative disorders and promising results for the validation with autopsy. However, completion of studies on analytical validity is a requirement to investigate clinical utility properly.
p1⁄40.43) as Auc-. There was no significant difference in rate of diagnostic (21% vs. 33%, p1⁄40.... more p1⁄40.43) as Auc-. There was no significant difference in rate of diagnostic (21% vs. 33%, p1⁄40.41) or treatment change (66% vs. 77%, p1⁄40.38) between Auc+ and Auc-. We observed significantly greater rate of diagnostic change in LO compared to EO (43% vs. 13%, p1⁄40.017) but no difference in treatment change (62% vs. 78%, p1⁄40.21). These results remained unchanged in the dementia-expert sample only. Conclusions: In our preliminary retrospective series we found no difference in pre/post-scan diagnosis in Aucvs. Auc+ and treatment changes in both comparisons. Changes in diagnosis were significantly more common in LO relative to EO suggesting that greater emphasis on scanning LO might be appropriate.
BackgroundThough cerebrospinal fluid (CSF) Aβ42, p‐tau181 and t‐tau have been shown to increase d... more BackgroundThough cerebrospinal fluid (CSF) Aβ42, p‐tau181 and t‐tau have been shown to increase diagnostic accuracy for early Alzheimer’s disease (i.e. AD at the MCI stage), several challenges remain with respect to their routine clinical use. In order to address these and related issues, a multidisciplinary task force was formed (Geneva Biomarker Roadmap Initiative). Adapting a five‐phase framework for the development of cancer biomarkers (Pepe et al., 2001), this task force recently convened (2019) to provide an update on earlier publications (2017). We here provide an update for the core CSF AD biomarkers (Aβ42/Aβ40, p‐tau181 and t‐tau) and for the first time provide a review of the same measures in blood in context of the five‐phase framework.MethodIn a two‐day workshop (Geneva, November 2019), we convened a panel of experts in AD biomarkers. The level of maturity of CSF and blood biomarkers was assessed based on the Biomarker Roadmap (Frisoni et al., 2017). Biomarker maturity and research priorities were systemically assessed by subgroups before the meeting, and presented and discussed during the workshop.ResultCSF biomarkers continued to demonstrate the highest level of maturity according to the strategic roadmap. Significant improvements compared to the 2017 summary (Mattsson et al., 2017) included the development of fully‐automated assays and the introduction of standard operating procedures for the preanalytical handling of CSF. Despite being in their infancy, the data presented and discussed for certain blood biomarkers demonstrated promising results. While t‐tau in blood did not satisfy the criteria for phase 2 (diagnostic discrimination), p‐tau181 and Aβ in blood either fully or partially fulfilled the criteria for this phase. It was agreed that only preliminary, albeit encouraging, evidence was available for the ability of blood measures to predict AD dementia in subjects with MCI (phase 3). An overview of novel CSF and blood tau biomarkers will also be discussed.ConclusionThe core CSF AD biomarkers (t‐tau, p‐tau181 and Aβ) have the highest level of maturity for clinical utility. Blood biomarkers for p‐tau18, and to a lesser degree Aβ, show excellent discrimination for AD from controls and non‐AD neurodegenerative disorders.
Alzheimer's & Dementia: Translational Research & Clinical Interventions
IntroductionCoronavirus disease 2019 (COVID‐19) has caused >3.5 million deaths worldwide and a... more IntroductionCoronavirus disease 2019 (COVID‐19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID‐19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID‐19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID‐19 to neurologic illness, both short and long term.MethodsThis article describes what is known so far in ter...
The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sy... more The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias.This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations.Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Allevia...
Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactor... more Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late‐onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World‐Wide FINGERS (WW‐FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW‐FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline—from at‐risk asymptomatic states to early symptomatic stages—in different geographical, cultural, and economic settings. WW‐FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to fa...
Previous studies have evaluated the diagnostic effect of amyloid positron emission tomography (PE... more Previous studies have evaluated the diagnostic effect of amyloid positron emission tomography (PET) in selected research cohorts. However, these research populations do not reflect daily practice, thus hampering clinical implementation of amyloid imaging. To evaluate the association of amyloid PET with changes in diagnosis, diagnostic confidence, treatment, and patients' experiences in an unselected memory clinic cohort. Amyloid PET using fluoride-18 florbetaben was offered to 866 patients who visited the tertiary memory clinic at the VU University Medical Center between January 2015 and December 2016 as part of their routine diagnostic dementia workup. Of these patients, 476 (55%) were included, 32 (4%) were excluded, and 358 (41%) did not participate. To enrich this sample, 31 patients with mild cognitive impairment from the University Medical Center Utrecht memory clinic were included. For each patient, neurologists determined a preamyloid and postamyloid PET diagnosis that e...
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2017
A classification framework for posterior cortical atrophy (PCA) is proposed to improve the unifor... more A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings. Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web-based quantitative survey regarding symptom frequency and the conceptualization of PCA. A three-level classification framework for PCA is described comprising both syndrome- and disease-level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2 (PCA-pure, PCA-plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD [PCA-AD], Lewy body disease [PCA-LBD], corticobasal de...
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2014
Regulatory qualification of a biomarker for a defined context of use provides scientifically robu... more Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development. The Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data. The literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011. We summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.
Cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) are increasingly used in clinic... more Cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) are increasingly used in clinical settings, research and drug trials. However, their broad-scale use on different technology platforms is hampered by the lack of standardization at the level of sample handling, determination of concentrations of analytes and the absence of well-defined performance criteria for in vitro diagnostic or companion diagnostic assays, which influences the apparent concentration of the analytes measured and the subsequent interpretation of the data. There is a need for harmonization of CSF AD biomarker assays that can reliably, across centers, quantitate CSF biomarkers with high analytical precision, selectivity and stability over long time periods. In this position paper, we discuss reference procedures for the measurement of CSF AD biomarkers, especially amyloid β42 and tau. We describe possible technical approaches, focusing on a selected reaction monitoring mass spectrometry assay as a ca...
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