Aging Symptom Trajectories in Mother Carriers of the FMR1 Premutation
FMR1 前突变母携带者的衰老症状轨迹
基本信息
- 批准号:10712277
- 负责人:
- 金额:$ 39.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-15 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAgeAge-associated memory impairmentAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAlzheimer’s disease biomarkerAmyloid beta-Protein PrecursorBiologicalChildClinical ManagementCognitiveConsensusDNA Sequence AlterationDataDementiaDevelopmentDiagnosisDiseaseFMR1FMR1 PremutationFXTASFailureFamilyFemaleFragile X SyndromeFunctional disorderFutureGenesGeneticGenetic VariationGenotypeHealthHigh PrevalenceImpaired cognitionKnowledgeLinkMediatingMethodsMolecular AbnormalityMolecular GeneticsMothersNeurodegenerative DisordersNeuropsychological TestsOutcomePaperParentsParticipantPathogenesisPathologic ProcessesPathway interactionsPerformancePhenotypePlayPopulationPostdoctoral FellowProtein BiosynthesisRegulationResearchResourcesRiskRoleSamplingSex ChromosomesSymptomsTandem Repeat SequencesTimeWomanWorkage relatedagedcareerclinical developmentclinical effectclinically significantcognitive performancedementia riskgenetic risk factorgenome wide association studyimproved outcomemalemenmild cognitive impairmentneuropathologynovelpreclinical studyrepositoryyoung mother
项目摘要
ABSTRACT
Overview. The FXpm is a prevalent genetic abnormality caused by an expanded CGG sequence on the FMR1
gene1. The associated phenotype includes age-related cognitive decline2-11, elevated rates of dementia12, and
risk for neurodegenerative disease13,14. Although the FXpm is about twice as prevalent in women than men
(1:151 females vs 1:468 males1,15), current understanding of age-related clinical effects of the FXpm comes
almost entirely from the study of men. Because FXpm women can pass the gene to their children which may
cause fragile X syndrome, most extant research has focused on young mothers and their children, with few
studies including FXpm women over the age of 60. Failure to characterize the age-related phenotype of FXpm
in women is a major barrier to clinical management, as we lack the data needed to understand the age-related
clinical effects of this genotype in women and develop treatments.
Emerging evidence suggests that FXpm women may be at heightened risk for Alzheimer’s Disease (AD) and
Related Dementias (ADRD). AD-type neuropathology has been observed in FXpm women at postmortem16-18
and FMR1 protein plays a known role in the pathogenesis of neurodegenerative disease, including in the
regulation of amyloid precursor protein (APP)19-24. Evidence suggests that FXpm men have ~6-fold increased
risk for dementia12. Yet, there has been no prior systematic study of ADRD in FXpm women. Our pilot data
suggest that FXpm women are 13x more likely to score below cut-offs for mild cognitive impairment (MCI) on
cognitive screeners than matched controls, underscoring the need to investigate ADRD risk in this group.
Moreover, preliminary studies suggest that AD mechanisms may interact with FMR1 to increase vulnerability for
disease in FXpm carriers. For example, FXpm carriers who have the APOE ε4 allele are at a 12-fold increased
risk for developing Fragile X Associated Tremor Ataxia Syndrome, a late onset neurodegenerative disease
caused by the FXpm25. However, no studies have examined APOE specifically in FXpm women or in relation to
other FXpm phenotypic outcomes, such as impaired cognitive performance or ADRD.
Supplement Aims. This proposal will extend our parent R01 focused on aging symptom trajectories in FXpm
women (R01AG073374) to add new questions regarding ADRD risk. Specifically, we aim to characterize MCI
cognitive phenotypes in FXpm women compared to matched women with MCI and health controls (Aim 1);
describe the rates clinician consensus MCI diagnoses in FXpm women (Aim 2); and examine potential genetic
risk factors (APOE ε4 and FMR1-related molecular genetic variation) in relation to impaired cognitive
performance (Aim 3). We will accomplish these aims by adding a comprehensive neuropsychological test
battery that has been well-established in ADRD research to the parent R01 (the NACC-UDS326). Leveraging
available resources, methods, and data from existing repositories (ADNI, Co-I Joseph’s R01AG55132) we will
compare the performance of FXpm women to matched women with MCI and healthy controls drawn from the
archival repositories. We will also add new APOE genotyping and clinician consensus MCI diagnoses to our
FXpm sample to inform genetic factors and the presentation of clinically significant cognitive impairment in FXpm
women. This approach is highly feasible and will yield data on a well-powered participant sample of 75 FXpm
carrier mothers, 140 matched MCI women, and 215 healthy control women, aged 45-80 years, to address our
aims.
Impact and Relevance to ADRD. This Supplement will represent the first attempt to characterize MCI
cognitive phenotypes and AD genetic risk factors in FXpm women, addressing a critical knowledge gap. A
direct link between FMR1 and AD is supported by a large body of research showing that FMR1 mediates APP
synthesis, which is central to AD pathogenesis24,27. However, because FMR1 is reflected by a
polymorphic
tandem repeat located on a sex chromosome, it has not been included in existing large-scale ADRD
genome-
wide association studies28,29, leaving major knowledge gaps. A significant impact of this Supplement will be
illuminating the role of FMR1 in ADRD risk. This pursuit is highly novel and will propel the field forward in
understanding genetic mechanisms and associated biological pathways implicated in ADRD. Another
significant impact will be describing, for the first time, ADRD risk in FXpm women as they age. These efforts
have significant implications for the development of clinical management strategies to improve outcomes for
both FXpm mothers and their children with fragile X syndrome. This Supplement has relevance to a large
swath of the population given the high prevalence of the FXpm genotype (1:151 females, 1:468 males)1,15.
Stimulating Future ADRD Research. This work will provide foundational new information on the overlap and
divergence of cognitive phenotypes across FXpm and MCI, laying the groundwork for future mechanistic
studies, such as those incorporating AD biomarkers or preclinical studies aimed at elucidating the mechanisms
through which the FMR1 may interact with ADRD pathological processes. This work will inform the
development of a larger R01 proposal and result in several papers and presentations on ADRD risk associated
with FMR1 gene dysfunction. Moreover, the PI’s lab also includes a number of graduate and postdoctoral
trainees who are pursuing research careers and will be introduced to ADRD through this work.
文摘
项目成果
期刊论文数量(0)
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Jessica Klusek其他文献
Jessica Klusek的其他文献
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{{ truncateString('Jessica Klusek', 18)}}的其他基金
Aging Symptom Trajectories in Mother Carriers of the FMR1 Premutation
FMR1 前突变母携带者的衰老症状轨迹
- 批准号:
10813530 - 财政年份:2022
- 资助金额:
$ 39.55万 - 项目类别:
Aging Symptom Trajectories in Mother Carriers of the FMR1 Premutation
FMR1 前突变母携带者的衰老症状轨迹
- 批准号:
10445687 - 财政年份:2022
- 资助金额:
$ 39.55万 - 项目类别:
Aging Symptom Trajectories in Mother Carriers of the FMR1 Premutation
FMR1 前突变母携带者的衰老症状轨迹
- 批准号:
10664902 - 财政年份:2022
- 资助金额:
$ 39.55万 - 项目类别:
Aging Language Trajectories in Premutation Carrier Mothers
早突变携带者母亲的衰老语言轨迹
- 批准号:
9892021 - 财政年份:2019
- 资助金额:
$ 39.55万 - 项目类别:
Defining the Language Phenotype of the FMR1 Premutation
定义 FMR1 前突变的语言表型
- 批准号:
9891045 - 财政年份:2019
- 资助金额:
$ 39.55万 - 项目类别:
Profiles and Predictors of Pragmatic Language Impairments in the FMR1 Premutation
FMR1 前突变中语用语言障碍的概况和预测因素
- 批准号:
8716154 - 财政年份:2014
- 资助金额:
$ 39.55万 - 项目类别:
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