KLOTHO and Resilience to Synaptic Dysfunction in Preclinical AD
KLOTHO 和临床前 AD 中突触功能障碍的恢复力
基本信息
- 批准号:10587987
- 负责人:
- 金额:$ 77.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:AbateAddressAdultAdverse effectsAgeAge-associated memory impairmentAgingAlzheimer disease preventionAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAlzheimer&aposs disease therapyAmyloid beta-42Amyloid beta-ProteinAttenuatedBeliefBiological MarkersBloodBrainCaregiversCentral Nervous SystemCerebrospinal FluidClinicalCognitiveCognitive deficitsDementiaDependenceDeteriorationDiseaseElderlyExhibitsFunctional disorderGenesGenetic RiskGenotypeHealthHealthcare SystemsHeterozygoteHumanImaging ligandsImpaired cognitionIncidenceIndividualIntegral Membrane ProteinInvestigationKineticsLightLongevityMediatingMemoryMemory LossMetabolismMethodologyModificationN-MethylaspartateNerve DegenerationNeurofibrillary TanglesNeuronsOnset of illnessParticipantPathologicPatientsPhenotypePlayPositioning AttributePositron-Emission TomographyProcessPublic HealthRegistriesResearchResearch PriorityResistanceResourcesRiskRisk FactorsSenile PlaquesSocietiesSynapsesSynaptic plasticitySyndromeTsunamiVariantWisconsinWorkabeta accumulationage effectage relatedaging genealpha synucleinanti agingapolipoprotein E-4attenuationbeta amyloid pathologyblood-based biomarkerclinically relevantcognitive performancecohortcurative treatmentsdensitydisabilitydruggable targetexecutive functionfollow-upheuristicshuman old age (65+)in vivoindexingindividual variationinsightlongevity genemiddle agemouse modelmultimodalitynervous system disorderneurofilamentneurograninneuropathologyneurotoxicpre-clinicalpreventresiliencesexsocioeconomicsstemsymptom managementsynaptic functiontau Proteinstau-1translational studyuptakeβ-amyloid burden
项目摘要
PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD), a progressive and debilitating neurological disorder of old age, is
clinically hallmarked by memory loss and neuropathologically by accumulation of Aβ plaques and
neurofibrillary tangles in the brain. Synaptic dysfunction has recently emerged as another early
key feature of AD; evidence suggests that synaptic density decreases up to 30% in preclinical
stages of AD and correlates more closely with cognitive deficits than Aβ pathology. Although age
is the single biggest risk factor for developing AD, the observation that even individuals at genetic
risk for AD or harboring AD neuropathology are able to remain cognitively normal as they age has
refocused research away from risk and underscored the need for investigations of the factors that
confer resilience in hopes of reducing disability and disease incidence. KLOTHO is dubbed an
anti-aging and longevity gene, and plays a key role in cellular metabolism, central nervous system
maturation, and synaptic plasticity. Critical to this proposal is that KLOTHO also seems to
enhance synaptic integrity and protects from neurodegeneration. Thus, this integrative, clinically
relevant project will rigorously investigate whether KLOTHO 1) confers resilience against age-
and AD-related synaptic dysfunction, and 2) modifies the relationship between such dysfunction
and cognitive decline both cross-sectionally and longitudinally. The proposed study will be
embedded within the robust framework of two well-characterized and longitudinally followed
cohorts of ~2,000 at-risk, late-middle-aged adults (the Wisconsin Registry for Alzheimer’s
Prevention [WRAP] and the Wisconsin Alzheimer’s Disease Research Center [WADRC]). All
participants are already genotyped for KLOTHO and have been cognitively phenotyped for up to
20 years under WRAP/WADRC. The R01 will provide resources for a subset of these participants
(N=150) to undergo multimodal biomarker assessment ([11C]UCB-J PET imaging, CSF and
blood-based biomarkers) at baseline and 2-year follow-up. Completion of this study has the
potential to provide invaluable insights and druggable targets for forestalling brain/cognitive
deterioration with advancing age or AD pathological burden.
项目总结/摘要
阿尔茨海默病(AD)是一种进行性和使人衰弱的老年神经系统疾病,
临床上以记忆丧失为特征,神经病理学上以A β斑块积聚为特征,
大脑中的神经系统缠结突触功能障碍最近成为另一种早期
AD的关键特征;有证据表明,在临床前,
与A β病理学相比,与认知缺陷的相关性更密切。虽然年龄
是发展为AD的最大风险因素,即使是遗传学上的个体,
具有AD风险或患有AD神经病理学的患者能够随着年龄的增长保持认知正常,
将研究重点从风险转移,并强调需要调查
赋予复原力,希望减少残疾和疾病的发生率。KLOTHO被称为
抗衰老和长寿基因,并在细胞代谢,中枢神经系统,
成熟和突触可塑性。对这一提议至关重要的是,KLOTHO似乎也
增强突触的完整性,防止神经变性。因此,这种综合的,临床上
相关项目将严格调查KLOTHO 1)是否赋予抗衰老的韧性-
和AD相关的突触功能障碍,和2)修改这种功能障碍之间的关系,
和认知能力的下降。拟议的研究将
嵌入在两个良好表征和纵向跟踪的强大框架内,
约2,000名有风险的中年晚期成年人(威斯康星州阿尔茨海默病登记处
预防[WRAP]和威斯康星州阿尔茨海默病研究中心[WADRC])。所有
参与者已经对KLOTHO进行了基因分型,并且已经对认知表型进行了长达
在WRAP/WADRC下工作了20年。R01将为这些参与者的一部分提供资源
(N = 150)接受多模式生物标志物评估([11 C] UCB-J PET成像、CSF和
基于血液的生物标志物)。完成这项研究,
潜在的提供宝贵的见解和药物的目标,以防止大脑/认知
随着年龄的增长或AD病理负担而恶化。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('OZIOMA C OKONKWO', 18)}}的其他基金
Longitudinal Investigation of Cardiorespiratory Fitness and AD Biomarkers in an At-Risk Cohort
高危人群心肺健康和 AD 生物标志物的纵向调查
- 批准号:
10064984 - 财政年份:2019
- 资助金额:
$ 77.75万 - 项目类别:
Longitudinal Investigation of Cardiorespiratory Fitness and AD Biomarkers in an At-Risk Cohort
高危人群心肺健康和 AD 生物标志物的纵向调查
- 批准号:
10318633 - 财政年份:2019
- 资助金额:
$ 77.75万 - 项目类别:
Longitudinal Investigation of Cardiorespiratory Fitness and AD Biomarkers in an At-Risk Cohort
高危人群心肺健康和 AD 生物标志物的纵向调查
- 批准号:
10082736 - 财政年份:2019
- 资助金额:
$ 77.75万 - 项目类别:
Longitudinal Investigation of Cardiorespiratory Fitness and AD Biomarkers in an At-Risk Cohort
高危人群心肺健康和 AD 生物标志物的纵向调查
- 批准号:
10535455 - 财政年份:2019
- 资助金额:
$ 77.75万 - 项目类别:
Genetic and Lifestyle Determinants of Cognitive Resilience in Midlife
中年认知弹性的遗传和生活方式决定因素
- 批准号:
9014375 - 财政年份:2016
- 资助金额:
$ 77.75万 - 项目类别:
Early detection of asymptomatic middle-age adults at risk for AD
早期发现有 AD 风险的无症状中年人
- 批准号:
8723051 - 财政年份:2013
- 资助金额:
$ 77.75万 - 项目类别:
Early detection of asymptomatic middle-age adults at risk for AD
早期发现有 AD 风险的无症状中年人
- 批准号:
8867116 - 财政年份:2013
- 资助金额:
$ 77.75万 - 项目类别:
Early detection of asymptomatic middle-age adults at risk for AD
早期发现有 AD 风险的无症状中年人
- 批准号:
9328299 - 财政年份:2013
- 资助金额:
$ 77.75万 - 项目类别:
Early detection of asymptomatic middle-age adults at risk for AD
早期发现有 AD 风险的无症状中年人
- 批准号:
8593003 - 财政年份:2013
- 资助金额:
$ 77.75万 - 项目类别:
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