Establishing an Alzheimer’s disease biomarker clock in Down syndrome using positron emission tomography and plasma analytes - PROJECT SUMMARY/ABSTRACT Individuals with Down syndrome (DS) represent the largest population of genetically determined Alzheimer’s disease (AD) in the world. This genetic form of AD is driven by triplication of chromosome 21, which encodes the gene responsible for amyloid precursor protein production, leading to earlier beta-amyloid plaque (Aβ) deposition. Advances in health care specific to this population have resulted in individuals with DS living longer, healthier lives. With this significant increase in life expectancy, AD is now the leading cause of death for individuals with DS over the age of 35, accounting for 70% of deaths in this demographic. Despite a >90% incident rate of AD dementia by age 60 for individuals with DS, this population has been overlooked for disease- modifying therapeutic trials. The research effort in AD therapeutics has rapidly progressed, with promising findings from recent “anti-amyloid” therapy clinical trials at delaying the onset of cognitive decline. For DS inclusion in these trials, many challenges exist pertaining to recruitment and design such as understanding the differences in biomarker progression between DS and neurotypical (NT) adults, their intellectual disability and their age at biomarker and symptom onset. Furthermore, there exists a 30-year span in the age at which AD biomarkers and dementia emerge in this population, which greatly hinders age-based trial recruitment. Minimally invasive and cost-effective methods for trial recruitment, such as blood-plasma measures, also have yet to be characterized in DS. To develop a better understanding of AD biomarker onset and progression, we have utilized positron emission tomography (PET) imaging in the DS population to evaluate longitudinal changes in amyloid, tau and neurodegeneration prior to dementia onset. This project will address this public health need by characterizing AD biomarker progression in the DS population at various stages of the disease, allowing for better insight into the initiation of AD treatment based on biomarker level and disease stage. To pinpoint suitable treatment windows at varying stages of DSAD, this project will model AD biomarker progression through the novel Biomarker Clock Framework, which creates a timeline of disease progression based on the onset of abnormal biomarker presence. This work will be carried out through three specific aims: 1) characterization of amyloid PET, plasma Aβ42/Aβ40 and p-tau217, 2) characterization of longitudinal tau PET within the revised AD staging framework, and 3) evaluation of cognitive decline on the AD timeline. Identifying the earliest changes in AD biomarkers will facilitate anti-amyloid clinical trial designs and the recruitment of individuals with DS into early intervention and secondary prevention trials. With the biomarker onset times developed in this proposal and with the direct comparisons to measures in NT cohorts, biomarker progression timelines will be developed to define clear therapeutic windows for AD treatment in DS, allowing for treatments specifically catered to these individuals.
