Aging Symptom Trajectories in Mother Carriers of the FMR1 Premutation

摘要 概况. FXpm是由FMR 1上的CGG序列扩增引起的普遍遗传异常。 基因1。相关的表型包括与年龄相关的认知能力下降2 -11，痴呆率升高12， 神经退行性疾病的风险13，14.尽管FXpm在女性中的流行率是男性的两倍， （1：151女性vs 1：468男性1，15），目前对FXpm年龄相关临床效应的了解 几乎完全来自于对男性的研究。因为FXpm女性可以将基因遗传给她们的孩子， 由于脆性X综合征的原因，大多数现存的研究都集中在年轻母亲和她们的孩子身上， 研究对象包括60岁以上的FXpm女性。未能表征FXpm的年龄相关表型 是临床管理的一个主要障碍，因为我们缺乏了解与年龄相关的 这种基因型在女性中的临床效果，并开发治疗方法。 新出现的证据表明，FXpm女性可能患阿尔茨海默病（AD）的风险更高， 相关性痴呆（ADRD）。在FXpm女性中，在死后观察到AD型神经病理学16 -18 FMR 1蛋白在神经退行性疾病的发病机制中起着已知的作用，包括在 淀粉样前体蛋白（APP）的调节19-24。有证据表明，FXpm的男性有~6倍的增长， 痴呆症的风险12.然而，之前没有对FXpm女性进行ADRD的系统研究。我们的试点数据 这表明FXpm女性在轻度认知障碍（MCI）方面得分低于临界值的可能性高出13倍。 认知筛查者比匹配的对照组，强调需要调查这一组的ADRD风险。 此外，初步研究表明，AD机制可能与FMR 1相互作用，以增加易感性， FXpm携带者的疾病。例如，具有APOE ε4等位基因的FXpm携带者在12倍的增加， 脆性X相关震颤共济失调综合征是一种迟发性神经退行性疾病， 由FXPM 25引起的。然而，没有研究专门研究FXpm女性的APOE或与 其他FXpm表型结果，如认知能力受损或ADRD。 补充目标。该提案将扩展我们的父R 01，重点关注FXpm中的老化症状轨迹 女性（R 01 AG 073374），以添加有关ADRD风险的新问题。具体来说，我们的目标是表征MCI FXpm女性的认知表型与匹配的MCI女性和健康对照相比（目标1）; 描述FXpm女性中临床医生共识MCI诊断的比率（目标2）;并检查潜在的遗传 与认知功能受损相关的风险因素（APOE ε4和FMR 1相关的分子遗传变异） 性能（目标3）。我们将通过增加一项全面的神经心理学测试来实现这些目标。 在ADRD研究中已得到充分证实的电池与母体R 01（NACC-UDS 326）相比。利用 现有的资源，方法和数据从现有的知识库（ADNI，Co-I约瑟夫的R 01 AG 55132），我们将 将FXpm女性的表现与MCI和健康对照组的匹配女性进行比较， 档案库。我们还将增加新的APOE基因分型和临床医生共识MCI诊断， FXpm样本，以告知遗传因素和FXpm中临床显著认知障碍的表现 妇女这种方法是非常可行的，并将产生一个良好的动力参与者样本的数据75 FXpm 携带者母亲，140名匹配的MCI妇女和215名健康对照妇女，年龄45-80岁，以解决我们的问题。 目标。 对ADRD的影响和相关性。本附录将首次尝试描述MCI的特征 FXpm女性的认知表型和AD遗传风险因素，解决了关键的知识差距。一 FMR 1和AD之间的直接联系得到了大量研究的支持，这些研究表明FMR 1介导APP 合成，这是AD发病机制的核心24，27。然而，由于FMR 1由 多态 位于性染色体上的串联重复序列，它尚未被包括在现有的大规模ADRD中 基因组- wide association studies 28，29，leaving major knowledge gaps.本补编的一个重大影响是 阐明FMR 1在ADRD风险中的作用。这种追求是非常新颖的，将推动该领域的发展， 了解ADRD的遗传机制和相关的生物学途径。另一 显著影响将首次描述FXpm女性随着年龄增长的ADRD风险。这些努力 对临床管理策略的制定具有重要意义， FXpm的母亲和她们的孩子都患有脆性X综合征。这一补充与一个大的 在FXpm基因型高流行率的人群中（1：151女性，1：468男性）， 促进未来ADRD研究。这项工作将提供关于重叠的基本新信息， FXpm和MCI之间认知表型的差异，为未来的机制奠定基础 研究，如纳入AD生物标志物或旨在阐明机制的临床前研究 FMR 1可能通过其与ADRD病理过程相互作用。这项工作将告知 制定了更大的R 01提案，并产生了几篇关于ADRD相关风险的论文和演示文稿 FMR 1基因功能障碍此外，PI的实验室还包括一些研究生和博士后 学员谁是追求研究事业，并将通过这项工作介绍给ADRD。

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.