Discovery and validation of dominantly inherited Alzheimer\u27s disease mutations in populations from Latin America

BACKGROUND: In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations. METHODS: Clinical data was collected from LatAm families at risk for DIAD. Symptomatic family members were identified and assessed by local clinicians and referred for genetic counseling and testing. To determine the likelihood of pathogenicity among variants of unknown significance from LatAm populations, we report pedigree information, frequency in control populations, in silico predictions, and cell-based models of amyloid-beta ratios. RESULTS: We identified five novel variants in the presenilin1 (PSEN1) gene from Brazilian and Mexican families. The mean age at onset in newly identified families was 43.5 years (range 36-54). PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr, and p.Ile414Thr variants have not been reported in PubMed, ClinVar, and have not been reported in dominantly inherited AD (DIAD) families. We found that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr produce Aβ profiles consistent with known AD pathogenic mutations. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation. CONCLUSIONS: Our study provides further insights into the genetics of AD in LatAm. Based on our findings, including clinical presentation, imaging, genetic, segregations studies, and cell-based analysis, we propose that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr are likely pathogenic variants resulting in DIAD, whereas PSEN1 p.Ile414Thr is likely a risk factor. This report is a step forward to improving the inclusion/engagement of LatAm families in research. Family discovery is of great relevance for the region, as new initiatives are underway to extend clinical trials and observational studies to families living with DIAD

Prevalence of parkinsonism and Parkinson disease in urban and rural populations from Latin America:A community based study

BACKGROUND: Age and gender specific prevalence rates for parkinsonism and Parkinson's disease (PD) are important to guide research, clinical practice, and public health planning; however, prevalence estimates in Latin America (LatAm) are limited. We aimed to estimate the prevalence of parkinsonism and PD and examine related risk factors in a cohort of elderly individuals from Latin America (LatAm). METHODS: Data from 11,613 adults (65+ years) who participated in a baseline assessment of the 10/66 study and lived in six LatAm countries were analyzed to estimate parkinsonism and PD prevalence. Crude and age-adjusted prevalence were determined by sex and country. Diagnosis of PD was established using the UK Parkinson's Disease Society Brain Bank's clinical criteria. FINDINGS: In this cohort, the prevalence of parkinsonism was 8.0% (95% CI 7.6%–8.5%), and the prevalence of PD was 2.0% (95% CI 1.7%–2.3%). PD prevalence increased with age from 1.0 to 3.5 (65–69vs. 80 years or older, p < 0.001). Age-adjusted prevalence rates were lower for women than for men. No significant differences were found across countries, except for lower prevalence in urban areas of Peru. PD was positively associated with depression (adjusted prevalence ratio [aPR] 2.06, 95% CI 1.40–3.01, I(2) = 56.0%), dementia (aPR 1.57, 95% CI 1.07- 2.32, I(2) = 0.0%) and educational level (aPR 1.14, 95% CI 1.01– 1.29, I(2) = 58.6%). INTERPRETATION: The reported prevalence of PD in LatAm is similar to reports from high-income countries (HIC). A significant proportion of cases with PD did not have a previous diagnosis, nor did they seek any medical or neurological attention. These findings underscore the need to improve public health programs for populations currently undergoing rapid demographic aging and epidemiological transition. FUNDING: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication

Discovery and validation of autosomal dominant Alzheimer’s disease mutations

Abstract Background Alzheimer’s disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes. Methods In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. Results We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379_382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity. Conclusions In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes

Discovery and validation of autosomal dominant Alzheimer’s disease mutations

Abstract Background Alzheimer’s disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes. Methods In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. Results We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379_382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity. Conclusions In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes

Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes

Introduction: A growing number of dominantly inherited Alzheimer's disease (DIAD) cases have become known in Latin American (LatAm) in recent years. However, questions regarding mutation distribution and frequency by country remain open. Methods: A literature review was completed aimed to provide estimates for DIAD pathogenic variants in the LatAm population. The search strategies were established using a combination of standardized terms for DIAD and LatAm. Results: Twenty-four DIAD pathogenic variants have been reported in LatAm countries. Our combined dataset included 3583 individuals at risk; countries with highest DIAD frequencies were Colombia (n = 1905), Puerto Rico (n = 672), and Mexico (n = 463), usually attributable to founder effects. We found relatively few reports with extensive documentation on biomarker profiles and disease progression. Discussion: Future DIAD studies will be required in LatAm, albeit with a more systematic approach to include fluid biomarker and imaging studies. Regional efforts are under way to extend the DIAD observational studies and clinical trials to Latin America.Fil: Llibre Guerra, Jorge J.. Washington University in St. Louis; Estados UnidosFil: Li, Yan. Washington University in St. Louis; Estados UnidosFil: Allegri, Ricardo Francisco. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chrem Mendez, Patricio Alexis. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Surace, Ezequiel Ignacio. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Llibre Rodriguez, Juan J.. Universidad de La Habana; CubaFil: Sosa, Ana Luisa. Instituto Nacional de Neurología y Neurocirugía; MéxicoFil: Aláez Verson, Carmen. Instituto Nacional de Medicina Genómica; MéxicoFil: Longoria, Erika Mariana. Instituto Nacional de Neurología y Neurocirugía; MéxicoFil: Tellez, Alberto. Instituto Nacional de Neurología y Neurocirugía; MéxicoFil: Carrillo Sánchez, Karol. Instituto Nacional de Medicina Genómica; MéxicoFil: Flores Lagunes, Luis Leonardo. Instituto Nacional de Medicina Genómica; MéxicoFil: Sánchez, Victor. Universidade de Sao Paulo; BrasilFil: Takada, Leonel Tadao. General Hospital of Fortaleza; BrasilFil: Nitrini, Ricardo. General Hospital of Fortaleza; BrasilFil: Ferreira Frota, Norberto Anizio. Grupo de Neurociencias de Antioquia; ColombiaFil: Benevides Lima, Joyce. Grupo de Neurociencias de Antioquia; ColombiaFil: Lopera, Francisco. Universidad de Puerto Rico; Puerto RicoFil: Ramírez, Laura. Universidad de Puerto Rico; Puerto RicoFil: Jiménez Velázquez, Ivonne. Universidad Nacional Pedro Henríquez Ureña; República DominicanaFil: Schenk, Christian. Universidad Nacional Pedro Henríquez Ureña; República DominicanaFil: Acosta, Daisy. Universidad de Chile.; Chile. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; ChileFil: Behrens, María Isabel. Washington University in St. Louis; Estados UnidosFil: Doering, Michelle. Washington University in St. Louis; Estados UnidosFil: Ziegemeier, Ellen. Washington University in St. Louis; Estados UnidosFil: Morris, John C.. Washington University in St. Louis; Estados UnidosFil: McDade, Eric. Washington University in St. Louis; Estados UnidosFil: Bateman, Randall J.. Washington University in St. Louis; Estados Unido