Alzheimer’s disease(AD)is a slow,progressive neurodegenerative disease with clinical symptoms that typically emerge in the elderly,leading to deterioration of cognitive functions over time.Memory loss is the primary ...Alzheimer’s disease(AD)is a slow,progressive neurodegenerative disease with clinical symptoms that typically emerge in the elderly,leading to deterioration of cognitive functions over time.Memory loss is the primary symptom,eventually leading to significant declines in executive and cognitive functions,along with psychiatric and behavioral changes,and alterations in personality.展开更多
Systemic factors confound blood tests for the diagnosis of Alzheimer’s disease(AD).The Delta Method study explored whether blood biomarkers from the vein proximal to the brain perform better in detecting cerebral Alz...Systemic factors confound blood tests for the diagnosis of Alzheimer’s disease(AD).The Delta Method study explored whether blood biomarkers from the vein proximal to the brain perform better in detecting cerebral Alzheimer’s pathologies using PET or cerebrospinal fluid(CSF)biomarkers as reference standards in two independent cohorts(n=463).Blood was collected from the internal jugular vein(IJV)and median cubital vein(MCV),and AD biomarkers were measured with Lumipulse G and Simoa methods.The results showed that the levels of Aβ42,Aβ40,p-tau217,p-tau181,GFAP,and NfL were higher in the IJV than in MCV and were highly correlated between the two sites.IJV-Aβ42/40 had stronger correlations with AβPET Centiloids and tau PET meta-temporal SUVR than MCV-Aβ42/40.In detecting cerebral Aβpositivity,IJV-Aβ42/40 demonstrated a significantly higher accuracy(79.9%–92.9%vs.72.4%–88.8%)and a lower percentage of uncertain individuals(17.8%–54.5%vs.31.3%–70.1%)than MCV-Aβ42/40.Moreover,the diagnostic accuracy of Lumipulse G IJV-Aβ42/40(88.2%–92.9%)was statistically equivalent to that of MCV-p-tau217(90.2%–94.3%),although the intermediate percentage of IJV-Aβ42/40 was higher(17.8%–34.0%vs.0.7%–17.5%).These findings were verified in the validation cohort.This study demonstrated the superior performance of IJV-Aβ42/40 to MCV-Aβ42/40 in detecting cerebral Alzheimer’s pathologies,offering a novel perspective to reduce the impacts of systemic factors and comorbidities on blood tests.展开更多
In the context of global ageing,the prevalence of neurodegenerative diseases and dementia,such as Alzheimer's disease(AD),is increasing.However,the current symptomatic and disease-modifying therapies have achieved...In the context of global ageing,the prevalence of neurodegenerative diseases and dementia,such as Alzheimer's disease(AD),is increasing.However,the current symptomatic and disease-modifying therapies have achieved limited benefits for neurodegenerative diseases in clinical settings.Halting the progress of neurodegeneration and cognitive decline or even improving impaired cognition and function are the clinically meaningful goals of treatments for neurodegenerative diseases.Ageing is the primary risk factor for neurodegenerative diseases and their associated comorbidities,such as vascular pathologies,in elderly individuals.Thus,we aim to elucidate the role of ageing in neurodegenerative diseases from the perspective of a complex system,in which the brain is the core and peripheral organs and tissues form a holistic network to support brain functions.During ageing,the progressive deterioration of the structure and function of the entire body hampers its active and adaptive responses to various stimuli,thereby rendering individuals more vulnerable to neurodegenerative diseases.Consequently,we propose that the prevention and treatment of neurodegenerative diseases should be grounded in holistic antiageing and rejuvenation means complemented by interventions targeting disease-specific pathogenic events.This integrated approach is a promising strategy to effectively prevent,pause or slow down the progression of neurodegenerative diseases.展开更多
The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a s...The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.展开更多
Epigenome-wide association studies(EWAS)are susceptible to widespread confounding caused by population structure and genetic relatedness.Nevertheless,kinship estimation is challenging in EWAS without genotyping data.H...Epigenome-wide association studies(EWAS)are susceptible to widespread confounding caused by population structure and genetic relatedness.Nevertheless,kinship estimation is challenging in EWAS without genotyping data.Here,we proposed MethylGenotyper,a method that for the first time enables accurate genotyping at thousands of single nucleotide polymorphisms(SNPs)directly from commercial DNA methylation microarrays.We modeled the intensities of methylation probes near SNPs with a mixture of three beta distributions corresponding to different genotypes and estimated parameters with an expectation-maximization algorithm.We conducted extensive simulations to demonstrate the performance of the method.When applying MethylGenotyper to the Infinium EPIC array data of 4662 Chinese samples,we obtained genotypes at 4319 SNPs with a concordance rate of 98.26%,enabling the identification of 255 pairs of close relatedness.Furthermore,we showed that MethylGenotyper allows for the estimation of both population structure and cryptic relatedness among 702 Australians of diverse ancestry.We also implemented MethylGenotyper in a publicly available R package(https://github.com/Yi-Jiang/MethylGenotyper)to facilitate future large-scale EWAS.展开更多
基金supported by the National Natural Science Foundation of China(82120108010 and 81930028).
文摘Alzheimer’s disease(AD)is a slow,progressive neurodegenerative disease with clinical symptoms that typically emerge in the elderly,leading to deterioration of cognitive functions over time.Memory loss is the primary symptom,eventually leading to significant declines in executive and cognitive functions,along with psychiatric and behavioral changes,and alterations in personality.
基金supported by the National Key Research and Development Program of China(2023YFC3605400)the Joint Project of the Chongqing Science and Technology Bureau and the Health Commission(2024GGXM003)。
文摘Systemic factors confound blood tests for the diagnosis of Alzheimer’s disease(AD).The Delta Method study explored whether blood biomarkers from the vein proximal to the brain perform better in detecting cerebral Alzheimer’s pathologies using PET or cerebrospinal fluid(CSF)biomarkers as reference standards in two independent cohorts(n=463).Blood was collected from the internal jugular vein(IJV)and median cubital vein(MCV),and AD biomarkers were measured with Lumipulse G and Simoa methods.The results showed that the levels of Aβ42,Aβ40,p-tau217,p-tau181,GFAP,and NfL were higher in the IJV than in MCV and were highly correlated between the two sites.IJV-Aβ42/40 had stronger correlations with AβPET Centiloids and tau PET meta-temporal SUVR than MCV-Aβ42/40.In detecting cerebral Aβpositivity,IJV-Aβ42/40 demonstrated a significantly higher accuracy(79.9%–92.9%vs.72.4%–88.8%)and a lower percentage of uncertain individuals(17.8%–54.5%vs.31.3%–70.1%)than MCV-Aβ42/40.Moreover,the diagnostic accuracy of Lumipulse G IJV-Aβ42/40(88.2%–92.9%)was statistically equivalent to that of MCV-p-tau217(90.2%–94.3%),although the intermediate percentage of IJV-Aβ42/40 was higher(17.8%–34.0%vs.0.7%–17.5%).These findings were verified in the validation cohort.This study demonstrated the superior performance of IJV-Aβ42/40 to MCV-Aβ42/40 in detecting cerebral Alzheimer’s pathologies,offering a novel perspective to reduce the impacts of systemic factors and comorbidities on blood tests.
基金supported by the National Key Research and Development Program Foundation of China(2023YFC3605400)Natural Science Foundation of China(92249305,82171418).
文摘In the context of global ageing,the prevalence of neurodegenerative diseases and dementia,such as Alzheimer's disease(AD),is increasing.However,the current symptomatic and disease-modifying therapies have achieved limited benefits for neurodegenerative diseases in clinical settings.Halting the progress of neurodegeneration and cognitive decline or even improving impaired cognition and function are the clinically meaningful goals of treatments for neurodegenerative diseases.Ageing is the primary risk factor for neurodegenerative diseases and their associated comorbidities,such as vascular pathologies,in elderly individuals.Thus,we aim to elucidate the role of ageing in neurodegenerative diseases from the perspective of a complex system,in which the brain is the core and peripheral organs and tissues form a holistic network to support brain functions.During ageing,the progressive deterioration of the structure and function of the entire body hampers its active and adaptive responses to various stimuli,thereby rendering individuals more vulnerable to neurodegenerative diseases.Consequently,we propose that the prevention and treatment of neurodegenerative diseases should be grounded in holistic antiageing and rejuvenation means complemented by interventions targeting disease-specific pathogenic events.This integrated approach is a promising strategy to effectively prevent,pause or slow down the progression of neurodegenerative diseases.
基金National Natural Science Foundation of China,Grant/Award Numbers:92249305,82120108010,81930028,31921003Academy of Medical Sciences(Newton Advanced Fellowship),Grant/Award Number:NAF/R11/1010National Institutes of Health,Grant/Award Number:R01DA056739。
文摘The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82325044 and 82021005)the China Postdoctoral Science Foundation(Grant No.2021M701318)+2 种基金the Natural Science Fund for Distinguished Young Scholars of Hubei Province,China(Grant No.2022CFA046)the Fundamental Research Funds for the Central Universities,China(Grant Nos.2019kfyXJJS036 and 2023BR030 of HUST)funded by the National Health and Medical Research Council in Australia(Grant Nos.GNT1161706 and GNT1151854).
文摘Epigenome-wide association studies(EWAS)are susceptible to widespread confounding caused by population structure and genetic relatedness.Nevertheless,kinship estimation is challenging in EWAS without genotyping data.Here,we proposed MethylGenotyper,a method that for the first time enables accurate genotyping at thousands of single nucleotide polymorphisms(SNPs)directly from commercial DNA methylation microarrays.We modeled the intensities of methylation probes near SNPs with a mixture of three beta distributions corresponding to different genotypes and estimated parameters with an expectation-maximization algorithm.We conducted extensive simulations to demonstrate the performance of the method.When applying MethylGenotyper to the Infinium EPIC array data of 4662 Chinese samples,we obtained genotypes at 4319 SNPs with a concordance rate of 98.26%,enabling the identification of 255 pairs of close relatedness.Furthermore,we showed that MethylGenotyper allows for the estimation of both population structure and cryptic relatedness among 702 Australians of diverse ancestry.We also implemented MethylGenotyper in a publicly available R package(https://github.com/Yi-Jiang/MethylGenotyper)to facilitate future large-scale EWAS.
