PROJECT SUMMARY/ABSTRACT Individuals with Down syndrome (DS) are at higher risk for developing Alzheimer’s disease (AD) compared to the general population. As such, they are considered an ideal target population for anti-AD therapy trials; however, there is no reliable measure for predicting dementia onset in this population. Intraindividual cognitive variability (IICV), a measure of variability in neuropsychological test performance within a person at a single timepoint, is a novel, low-cost, non-invasive biomarker of neurodegeneration and early dementia for the general population. However, IICV has not been investigated in adults with DS. Therefore, the current proposal will fill this knowledge gap by characterizing the associations between IICV, AD biomarkers, and dementia in adults with DS. Aims 1 and 2 of this proposal use data from the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) study, which is currently composed of cognitive and biomarker data collected at two different timepoints (baseline and 18 months), to calculate IICV measures for memory, executive function and processing speed, visuospatial construction, and multidomain cognition in 300 adults with DS. Using the longitudinal ABC- DS data, we will first examine whether IICV is associated with AD plasma biomarkers (β-amyloid 42/40, p- tau217, and NfL) and/or AD-related pathology (Aβ-PET and tau-PET) (K99, Aim 1). We will also examine whether IICV is associated with the clinical presentation of dementia and cognitive decline (K99, Aim 2). We expect our analyses to show that IICV is positively associated with AD-related biomarkers and pathology, and that IICV at baseline is associated with a follow-up diagnosis of dementia as well as cognitive decline from baseline to follow-up. These data will be critical for optimizing the design of a new cohort study of adults with DS that will test the outcome measures from Aims 1 and 2 in a new, more diverse, cross-cultural cohort of adults with DS from Washington State and São Paulo, Brazil, and include comparisons with a control group of individuals with autosomal dominant AD, due to its similarity with DS in early striatal amyloid- β deposition (R00, Aim 3). To complete these aims, we have developed a comprehensive, mentored training plan for me to (1) gain expertise in the relationship between neuropsychology, plasma biomarkers and neuroimaging; (2) broaden my knowledge of the similarities and differences between autosomal dominant AD and AD in DS; (3) explore cross-cultural similarities and differences in AD risk; and (4) develop advanced statistical skills. The data and training obtained in the K99 phase will lead to the successful implementation of a high-quality, international research program focused on IICV and AD biomarkers in DS. Findings have great potential to be used with the DS population worldwide, increasing the chances of early interventions and inclusion in anti-AD trials. The intense training in the K99 and the support of mentors with extensive expertise in all areas of the proposal, will provide the foundation for an independent scientific career on cross-cultural AD risk prediction in DS and other high-risk populations.

PROJECT NARRATIVE Through the proposed research, we will determine if intraindividual cognitive variability can be used to identify early, pre-symptomatic signs of Alzheimer’s disease in adults with Down syndrome. The results of these studies may provide support for the translational application of intraindividual cognitive variability as well as the inclusion of DS individuals in anti-Alzheimer’s disease trials. Furthermore, the proposed work may have important implications for public health because the less invasive and easily disseminatable ways to detect the early signs of neurodegeneration in the DS population used here could also be applied to low-resource communities, enabling earlier interventions to reduce the impact of dementia on individuals, their families, and society.