Castilhos, Raphael Machado

Abstract Background Clinicians’ views on clinical readiness of Alzheimer's disease (AD) blood biomarkers (BBM) are not well understood. Method The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment Biofluid‐Based Biomarkers Professional Interest Area conducted a survey to elicit clinician opinions on AD BBM implementation, including contexts of use, assay selection, reporting and result interpretation. Result Clinician respondents ( n = 212) practiced in Europe (56%), North America (24%), Caribbean and Central or South America (11%) and other continents (9%). Most respondents were medical doctors (80%) practicing in secondary or tertiary care (88%) (Table 1). For 56% of respondents, CSF AD biomarkers or amyloid PET were accessible, but 48% agreed and 52% disagreed with implementation of AD BBM in any clinical context (Table 2). Respondents emphasized the need for data from diverse populations and educational resources to support test interpretation. Conclusion Surveyed clinicians generally agreed with published appropriate use recommendations but were divided on AD BBM readiness for clinical use.

Abstract INTRODUCTION Clinicians’ views on the clinical readiness of Alzheimer's disease (AD) blood biomarkers (BBMs) are not well understood. METHODS The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment Biofluid‐Based Biomarkers Professional Interest Area conducted a survey to elicit clinician opinions on AD BBM implementation, including contexts of use, assay selection, reporting, and result interpretation. RESULTS Clinician respondents ( n = 212) practiced in Europe (56%), North America (24%), the Caribbean and Central/South America (11%), and other continents (9%). Most respondents were medical doctors (80%) practicing in secondary or tertiary care (88%). For 56%, cerebrospinal fluid AD biomarkers or amyloid positron emission tomography were accessible, but 48% agreed and 52% disagreed with the implementation of AD BBMs in any clinical context. Respondents emphasized the need for data from diverse populations and educational resources to support test interpretation. DISCUSSION Surveyed clinicians generally agreed with published appropriate use recommendations but were divided on AD BBM readiness for clinical use. Highlights A survey of clinicians was conducted regarding clinical readiness of Alzheimer's disease (AD) blood biomarkers (BBMs). Views were split on AD BBM clinical readiness: 48% agreed, 52% disagreed. Most responders supported AD BBM use for treatment decisions. Most responders opposed AD BBM testing in asymptomatic individuals. Test performance data and educational materials to aid interpretation were of high importance.

AbstractBackgroundMore than 300 variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes have been reported to cause Dominantly Inherited Alzheimer Disease (DIAD). However, most of these reports come from non‐Hispanic whites and the full extent of DIAD remains understudied in Latin American (LatAm) countries. Here we describe five AD affected families from LatAm carrying novel DIAD variants.MethodsFive novel variants in the presenilin1 (PSEN1) gene were identified in Brazilian (p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se and p.Ala275Thr) and Mexican families (p.Ile414Thr). To assign the likelihood of pathogenicity among these variants of unknown significance, we report pedigree information, frequency in control populations, in silico predictions, and cell‐based models.ResultThe mean age at onset in newly identified families was 43.5 years (range 36‐54). The novel variants were absent from gnomAD genome and exome databases. Two PSEN1 variants (p.Val103_Ser104delinsGly and p.Lys395Ile) showed segregation with the disease status; segregation studies were not possible in the other three families. Additionally, PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr produced Aβ profiles consistent with known AD pathogenic mutations (i.e. increased extracellular Aβ42/40); thus, we consider them as likely pathogenic. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation; therefore, PSEN1 p.Ile414Thr likely represents an AD risk factor or benign polymorphism.ConclusionOur study provides further insights into the genetics of AD in LatAm by identifying novel DIAD pathogenic variants in Brazil and Mexico, two countries with distinct genetic admixtures. Expanding the families eligible to participate in observational and clinical trials of DIAD enhances the generalizability of diagnosis and treatment approaches.