RESUMEN
INTRODUCTION: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. METHODS: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population. RESULTS: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio = 2.93 [2.37-3.63], P = 2.6 × 10-23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose. DISCUSSION: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations. HIGHLIGHTS: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.
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Enfermedad de Alzheimer , Azidas , Estudio de Asociación del Genoma Completo , Humanos , Chile , Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Normal aging involves changes in the ability to acquire, consolidate and recall new information. It has been recently proposed that the reconsolidation process is also affected in older adults. Reconsolidation is triggered after reminder presentation, allowing memories to be modified: they can be impaired, strengthened or changed in their content. In young adults it was previously shown that the presentation of repetitive reminders induces memory strengthening one day after reactivation and the presentation of at least one reminder increases memory persistence several days after reactivation. However, until now this process has remained elusive in older adults. We hypothesize that older adults need a stronger reminder to induce memory strengthening through the reconsolidation process than young adults. To test this, we perform a three-day experiment. On day 1, participants learned 15 sound-word associations, on day 2 they received no reminders (NR group), one reminder (R group) or two rounds of reactivations (Rx2 group). Finally, they were tested on day 7. We found that, contrary to our hypothesis, older adults show a memory improvement triggered by repeated labilization/reconsolidation processes to an equal extent than young adults. These results open new perspectives into the use of reconsolidation to improve daily acquired information and the development of therapeutic home used tools to produce memory enhancement in healthy older adults or those with cognitive decline.
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Envejecimiento/fisiología , Memoria , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.