Aging Symptom Trajectories in Mother Carriers of the FMR1 Premutation

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.