The risk of Alzheimer's disease and related dementias among individuals with Autism Spectrum Disorder (AsDRD) - PROJECT SUMMARY The rising prevalence of Alzheimer's disease and related dementias (ADRD) necessitates the early identification of subgroups at high risk of developing these diseases. Recent evidence suggests that individuals with neurodevelopmental disorders, particularly autism spectrum disorder (ASD), may face an increased risk of early ADRD. However, systematic knowledge on the aging process in individuals with ASD remains limited. Our preliminary data shows a higher risk of early ADRD in individuals aged 30-70 with ASD. In Sweden we observed 6-fold higher risk for early ADRD in individuals with ASD compared to non-ASD individuals. We observed 8-fold and 3-fold higher risk for ADRD in samples from Israel and US, respectively. Furthermore, individuals with ASD exhibited a 2-fold higher risk for cardiometabolic disorders and a 10-fold higher risk for depression, both of which are significant risk factors for ADRD. Our preliminary data also shows higher risk for ADRD in relatives of individuals with ASD (1.4-fold and 1.2-fold higher in parents and aunts/uncles, respectively), suggesting potential genetic links. Given the impending aging of a large ASD population and the associated societal costs, a rigorous study is urgently needed to establish the association of ASD with early ADRD, to identify the most important contributing factors, and explore underlying mechanisms. To address these questions, our team draws on multiple unique resources with which we have extensive experience: We will use the Swedish national health registries that include diagnostic, medical, and demographic information for >5 million individuals 30-70 years old. Replication will be done in samples from the US (>100 million) and Israel (>1.6 million) for validation and generalizability of results. To strengthen inference on the relationship of ASD with ADRD, we will test clustering of ADRD in relatives of ASD patients in Sweden. Then we will test potential genetic mechanisms underlying the association of ASD with ADRD using existing genomic and sequencing data (>400,000), including from Sweden and the US. In Aim 1a we will rigorously evaluate ADRD risk in ASD using Swedish national registers. We will assess potential modifiers including sex and comorbid conditions (intellectual disability, ADHD, epilepsy). Aim 1b will further use longitudinal statistical approaches to model the impact of changing medical conditions over time, including depression and cardiovascular disease, on the risk pathway linking ASD to ADRD. Aim 2 will test for replication in datasets from Israel and the US. Aim 3a will investigate familial clustering of ADRD in ASD and Aim 3b will determine whether there are genetic etiologies shared between ASD and ADRD. By triangulating multiple large data sources, the proposed study will rigorously address significant knowledge gaps on the association between ASD and ADRD. The knowledge obtained through this study will be vital in the development of evidence-based patient care programs and early diagnostic strategies aimed at minimizing or preventing early ADRD in individuals with ASD as they get older.
