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*Only for medical professionals to read Reference There is a video playback at the end of the article, please click to watch! In 2021, some exciting progress has been made in the field of Alzheimer's disease (AD).
"Medical Neurology Channel" specially invited Professor Chen Xiaochun from Union Hospital Affiliated to Fujian Medical University to share, mainly including pathogenic genes and related mechanisms, Let's take a look at the four aspects of classification diagnosis, risk prediction, and treatment progress~1AD new causative gene discovered Genome-wide association studies (GWAS) have identified many risk loci for AD, but how do these loci lead to AD risk It's not clear
.
Professors Allan Levey and Thomas Wingo of Emory University School of Medicine believe that quantitative analysis of brain protein abundance through proteomic association studies (PWAS) can provide us with a more thorough idea for explaining the impact of AD-related genes on pathogenesis, and Provides a promising target for further mechanistic and therapeutic studies
.
The researchers performed liquid chromatography-mass spectrometry (LC-MS) analysis of postmortem dorsolateral prefrontal cortex samples from 376 participants, and a total of 8,400 proteins were identified and quantified; further compared with the existing 455,200 Gene chip data and sequencing data of multiple cases and controls were compared, and 11 candidate genes were found
.
Thomas Wingo's team finally selected 1 known AD-related gene and 8 newly discovered risk genes to validate in 150 human brain proteomes
.
These risk genes appear to be involved in AD pathogenesis in a manner independent of the association of AD-associated apolipoprotein E isoform APOEε4
.
Table 1: 11 important genes associated with AD identified by AD GWAS analysis 2 Scientists reveal 4 isoforms of AD Tau protein Long-term data were collected from 1612 individuals in 5 independent multicenter studies, and a total of 1143 cognitive Individuals with normal function or with AD at various stages were classified and cross-validated using SuStaln's (subtype and stage inference) algorithm on tau-PET image data from 1143 individuals
.
The researchers found the 4 most representative tau isoforms, and these 4 groups accounted for between 18% and 30% of all Alzheimer's patients, none of which dominated
.
Figure 1: Characteristics of the 4 subtypes Figure 2: Probability of the 4 subtypes In addition, the 4 subtypes have different clinical characteristics and age of onset, which also means that patients with different subtypes may respond differently to different treatments
.
3 Big data study found that AD single cell nucleus chromatin accessibility and transcriptome analysis This study revealed cis-regulatory factors, transcription factors, and high-risk loci closely related to AD late stage, which provided more insights for subsequent AD pathological research.
In many directions, there is also hope to discover new therapeutic targets
.
Figure 3: Details 4IWG Diagnostic Criteria Update In 2018, the National Institute on Aging (NIA) and the AD Association (AA) proposed a biological definition of AD that relies purely on biomarkers, but its use in everyday clinical practice has led to Arguments and challenges
.
Based on this, the International Working Group (IWG) proposed the limitations of biomarkers in AD diagnosis, and proposed more specific recommendations on when to use biomarkers to diagnose AD in a clinical setting
.
The IWG believes that AD diagnosis should combine biomarkers and clinical phenotypes
.
Meanwhile, for patients without cognitive impairment but positive for biomarkers, risk stratification should be performed based on different biomarkers (Table 2)
.
Table 2: Risk Stratification of Asymptomatic Populations Based on Biomarker Results 5 Anti-Aβ Antibodies Obtain FDA Breakthrough Therapy Designation On June 7, 2021, the FDA approved aducanumab through the accelerated approval pathway for the treatment of AD patients
.
On July 8 of the same year, the FDA updated the instructions for Aducanumab, limiting the drug application to patients with AD-derived mild cognitive impairment (MCI) and mild AD
.
Previously, the Phase III EMERGE study met its primary endpoint with significant clinical outcomes
.
The findings of EMERGE were supported by the results of a subset of patients in the Phase III ENGAGE study who received high doses
.
On August 7, 2020, the US FDA announced that the Aducanumab Biologics License Application (BLA) was granted priority review
.
In addition, anti-Aβ antibodies such as Lecanemab, Donanemab and Gantenerumab have been granted breakthrough therapy designation by the FDA and have entered Phase II or Phase III clinical trials
.
Among them, Lecanemab, jointly developed by Eisai and Biogen, is a humanized anti-Aβ fibril monoclonal IgG1 antibody that clears toxic Aβ from brain parenchyma through microglia
.
The results of the phase II clinical study showed that at 12 months, 10mg/kg every two weeks treatment, patients with AD composite score (ADCOMS) showed that 64% of patients achieved clinically significant efficacy (at least 25% better than placebo)
.
And following the conclusion of the Core study, amyloid reduction after lecanemab treatment remained unchanged for an average of approximately two years of drug withdrawal (Figure 4)
.
Figure 4: Detailed Information 6 Protein structure elucidation facilitates development of novel cholinesterase drugs for AD.
Researchers describe the design of the M1-muscarinic acetylcholine receptor agonist HTL9936 by taking a step-by-step transformation approach from atomic structure, based on Cell/tissue testing, preclinical species evaluation, clinical safety testing, and finally establishing activity in the human memory center to alleviate cognitive impairment, a potential drug for the treatment of memory loss in AD
.
Compared to many other nonselective modulators, the M1-selective clinical candidate HTL9936 significantly reduced the incidence of side effects: in a 4-day repeated dose tolerability assessment in dogs, there was only one seizure-like seizure, but this time The drug exposure in plasma was significantly higher than the dose required for cognitive improvement
.
In addition, there was also a dose-dependent relationship between blood pressure and htl9936
.
7 Scientists Reveal miR-132 as a Potential Therapeutic Target for AD Research confirms that miR-132 acts as a signal sensor in the nervous system, contributing to memory formation
.
AD can lead to miR-132 deficiency and ultimately impair adult hippocampal neurogenesis, and functional rescue experiments found that increasing miR-132 levels can significantly improve memory in AD-mimicking mice, providing a new perspective for AD treatment
.
8 Scientists reveal a new AD probability model that divides AD into three types.
The study divides AD into three types based on familial AD genes and APOE genotypes
.
Figure 5: AD probability model In addition, the age of onset varies among the 3 types of AD due to their different genotypes
.
Table 3: AD type combined with age of onset 9 Plasma p-tau protein and other indicators can accurately predict the transition from SCD and MCI to AD Two independent multicenter cohort studies, first conducted around Sweden's BioFINDER, and subsequently validated in ADNI, A predictive model for AD was established (primary endpoint was progression to AD within 4 years, and secondary endpoints were progression to AD within 2 and 6 years), and a data-driven model selection was performed to screen variables including key demographic data, APOE e4 allele Quantities, simple tests from the four cognitive domains, magnetic resonance imaging (MRI) measurements, and plasma biomarkers, meanwhile, examined the performance of the model by removing variables one by one in the procedure
.
The study found that combining phosphorylated tau protein levels in plasma, cognitive tests, and APOE genotypes to construct a simple algorithm can achieve non-invasive and accurate prediction of AD with an accuracy of over 90%
.
Using CSF P-tau, AB42/AB40, and neurofilament light chains instead of plasma biomarkers did not significantly improve accuracy
.
10 Astrocyte IL-3 can program microglia and limit disease progression in Alzheimer's disease Pathological changes and disease severity in human AD patients are closely related to IL-3 signaling and induce microglia Expression of IL-3Rα, loss of astrocyte IL-3 or microglia IL-3Ra exacerbates Aβ deposition and cognitive decline, and replenishment of IL-3 alleviates Aβ deposition and cognitive decline, which may be the cause of AD patients Provide new therapeutic opportunities
.
Summary of Expert Profile Professor Chen Xiaochun, Secretary of the Party Committee of Fujian Medical University, Professor, Chief Physician, Doctoral Supervisor, Department of Neurology, Union Hospital Affiliated to Fujian Medical University, Member, Ministry of Education, New Medical Department Construction Working Group, Vice Chairman of Fujian Association of Science and Technology, and President of Fujian Medical Doctor Association Executive Director of the Association, Vice President of the Neurology Branch of the Chinese Medical Association Neurology Branch of the Chinese Medical Association Dementia and Cognitive Impairment Group Leader Video playback of scientific and technological workers↓↓↓
"Medical Neurology Channel" specially invited Professor Chen Xiaochun from Union Hospital Affiliated to Fujian Medical University to share, mainly including pathogenic genes and related mechanisms, Let's take a look at the four aspects of classification diagnosis, risk prediction, and treatment progress~1AD new causative gene discovered Genome-wide association studies (GWAS) have identified many risk loci for AD, but how do these loci lead to AD risk It's not clear
.
Professors Allan Levey and Thomas Wingo of Emory University School of Medicine believe that quantitative analysis of brain protein abundance through proteomic association studies (PWAS) can provide us with a more thorough idea for explaining the impact of AD-related genes on pathogenesis, and Provides a promising target for further mechanistic and therapeutic studies
.
The researchers performed liquid chromatography-mass spectrometry (LC-MS) analysis of postmortem dorsolateral prefrontal cortex samples from 376 participants, and a total of 8,400 proteins were identified and quantified; further compared with the existing 455,200 Gene chip data and sequencing data of multiple cases and controls were compared, and 11 candidate genes were found
.
Thomas Wingo's team finally selected 1 known AD-related gene and 8 newly discovered risk genes to validate in 150 human brain proteomes
.
These risk genes appear to be involved in AD pathogenesis in a manner independent of the association of AD-associated apolipoprotein E isoform APOEε4
.
Table 1: 11 important genes associated with AD identified by AD GWAS analysis 2 Scientists reveal 4 isoforms of AD Tau protein Long-term data were collected from 1612 individuals in 5 independent multicenter studies, and a total of 1143 cognitive Individuals with normal function or with AD at various stages were classified and cross-validated using SuStaln's (subtype and stage inference) algorithm on tau-PET image data from 1143 individuals
.
The researchers found the 4 most representative tau isoforms, and these 4 groups accounted for between 18% and 30% of all Alzheimer's patients, none of which dominated
.
Figure 1: Characteristics of the 4 subtypes Figure 2: Probability of the 4 subtypes In addition, the 4 subtypes have different clinical characteristics and age of onset, which also means that patients with different subtypes may respond differently to different treatments
.
3 Big data study found that AD single cell nucleus chromatin accessibility and transcriptome analysis This study revealed cis-regulatory factors, transcription factors, and high-risk loci closely related to AD late stage, which provided more insights for subsequent AD pathological research.
In many directions, there is also hope to discover new therapeutic targets
.
Figure 3: Details 4IWG Diagnostic Criteria Update In 2018, the National Institute on Aging (NIA) and the AD Association (AA) proposed a biological definition of AD that relies purely on biomarkers, but its use in everyday clinical practice has led to Arguments and challenges
.
Based on this, the International Working Group (IWG) proposed the limitations of biomarkers in AD diagnosis, and proposed more specific recommendations on when to use biomarkers to diagnose AD in a clinical setting
.
The IWG believes that AD diagnosis should combine biomarkers and clinical phenotypes
.
Meanwhile, for patients without cognitive impairment but positive for biomarkers, risk stratification should be performed based on different biomarkers (Table 2)
.
Table 2: Risk Stratification of Asymptomatic Populations Based on Biomarker Results 5 Anti-Aβ Antibodies Obtain FDA Breakthrough Therapy Designation On June 7, 2021, the FDA approved aducanumab through the accelerated approval pathway for the treatment of AD patients
.
On July 8 of the same year, the FDA updated the instructions for Aducanumab, limiting the drug application to patients with AD-derived mild cognitive impairment (MCI) and mild AD
.
Previously, the Phase III EMERGE study met its primary endpoint with significant clinical outcomes
.
The findings of EMERGE were supported by the results of a subset of patients in the Phase III ENGAGE study who received high doses
.
On August 7, 2020, the US FDA announced that the Aducanumab Biologics License Application (BLA) was granted priority review
.
In addition, anti-Aβ antibodies such as Lecanemab, Donanemab and Gantenerumab have been granted breakthrough therapy designation by the FDA and have entered Phase II or Phase III clinical trials
.
Among them, Lecanemab, jointly developed by Eisai and Biogen, is a humanized anti-Aβ fibril monoclonal IgG1 antibody that clears toxic Aβ from brain parenchyma through microglia
.
The results of the phase II clinical study showed that at 12 months, 10mg/kg every two weeks treatment, patients with AD composite score (ADCOMS) showed that 64% of patients achieved clinically significant efficacy (at least 25% better than placebo)
.
And following the conclusion of the Core study, amyloid reduction after lecanemab treatment remained unchanged for an average of approximately two years of drug withdrawal (Figure 4)
.
Figure 4: Detailed Information 6 Protein structure elucidation facilitates development of novel cholinesterase drugs for AD.
Researchers describe the design of the M1-muscarinic acetylcholine receptor agonist HTL9936 by taking a step-by-step transformation approach from atomic structure, based on Cell/tissue testing, preclinical species evaluation, clinical safety testing, and finally establishing activity in the human memory center to alleviate cognitive impairment, a potential drug for the treatment of memory loss in AD
.
Compared to many other nonselective modulators, the M1-selective clinical candidate HTL9936 significantly reduced the incidence of side effects: in a 4-day repeated dose tolerability assessment in dogs, there was only one seizure-like seizure, but this time The drug exposure in plasma was significantly higher than the dose required for cognitive improvement
.
In addition, there was also a dose-dependent relationship between blood pressure and htl9936
.
7 Scientists Reveal miR-132 as a Potential Therapeutic Target for AD Research confirms that miR-132 acts as a signal sensor in the nervous system, contributing to memory formation
.
AD can lead to miR-132 deficiency and ultimately impair adult hippocampal neurogenesis, and functional rescue experiments found that increasing miR-132 levels can significantly improve memory in AD-mimicking mice, providing a new perspective for AD treatment
.
8 Scientists reveal a new AD probability model that divides AD into three types.
The study divides AD into three types based on familial AD genes and APOE genotypes
.
Figure 5: AD probability model In addition, the age of onset varies among the 3 types of AD due to their different genotypes
.
Table 3: AD type combined with age of onset 9 Plasma p-tau protein and other indicators can accurately predict the transition from SCD and MCI to AD Two independent multicenter cohort studies, first conducted around Sweden's BioFINDER, and subsequently validated in ADNI, A predictive model for AD was established (primary endpoint was progression to AD within 4 years, and secondary endpoints were progression to AD within 2 and 6 years), and a data-driven model selection was performed to screen variables including key demographic data, APOE e4 allele Quantities, simple tests from the four cognitive domains, magnetic resonance imaging (MRI) measurements, and plasma biomarkers, meanwhile, examined the performance of the model by removing variables one by one in the procedure
.
The study found that combining phosphorylated tau protein levels in plasma, cognitive tests, and APOE genotypes to construct a simple algorithm can achieve non-invasive and accurate prediction of AD with an accuracy of over 90%
.
Using CSF P-tau, AB42/AB40, and neurofilament light chains instead of plasma biomarkers did not significantly improve accuracy
.
10 Astrocyte IL-3 can program microglia and limit disease progression in Alzheimer's disease Pathological changes and disease severity in human AD patients are closely related to IL-3 signaling and induce microglia Expression of IL-3Rα, loss of astrocyte IL-3 or microglia IL-3Ra exacerbates Aβ deposition and cognitive decline, and replenishment of IL-3 alleviates Aβ deposition and cognitive decline, which may be the cause of AD patients Provide new therapeutic opportunities
.
Summary of Expert Profile Professor Chen Xiaochun, Secretary of the Party Committee of Fujian Medical University, Professor, Chief Physician, Doctoral Supervisor, Department of Neurology, Union Hospital Affiliated to Fujian Medical University, Member, Ministry of Education, New Medical Department Construction Working Group, Vice Chairman of Fujian Association of Science and Technology, and President of Fujian Medical Doctor Association Executive Director of the Association, Vice President of the Neurology Branch of the Chinese Medical Association Neurology Branch of the Chinese Medical Association Dementia and Cognitive Impairment Group Leader Video playback of scientific and technological workers↓↓↓
