Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred.

INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

Understanding the present and preparing for the future: Exploring the needs of diagnostic and elective genomic medicine patients.

Advances in genomic knowledge and technology have increased the use of comprehensive clinical sequencing tests. Genome sequencing has established utility for diagnosing patients with rare, undiagnosed diseases as well as interest in an elective context, without a clinical indication for testing. The Smith Family Clinic for Genomic Medicine, LLC in Huntsville, AL is a private practice genomic medicine clinic caring for both diagnostic (79%) and elective (21%) patients. Diagnostic and elective patients are seen on a clinical basis and receive standard care. Genome sequencing is provided on a self-pay basis, with assistance available for diagnostic patients who have financial need. Here, we describe demographics and motivations of the distinct patient populations and our experiences engaging patients in online education. Diagnostic patients were motivated by the possibility of receiving an explanation for symptoms (96%) while elective patients were motivated by the chance to learn about future disease risk (57%). Elective patients were less likely to engage with online education, with only 28% reading all assigned topics compared to 54% of diagnostic patients. Understanding the needs, interests, and barriers unique to diagnostic and elective patients is critical to inform individualized and scalable best practices in patient education and engagement.