The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease

Background\ud In order to identify novel loci associated with Alzheimer's disease (AD), we conducted a genome-wide association study (GWAS) in the Spanish population.\ud \ud Methods\ud We genotyped 1,128 individuals using the Affymetrix Nsp I 250K chip. A sample of 327 sporadic AD patients and 801 controls with unknown cognitive status from the Spanish general population were included in our initial study. To increase the power of the study, we combined our results with those of four other public GWAS datasets by applying identical quality control filters and the same imputation methods, which were then analyzed with a global meta-GWAS. A replication sample with 2,200 sporadic AD patients and 2,301 controls was genotyped to confirm our GWAS findings.\ud \ud Results\ud Meta-analysis of our data and independent replication datasets allowed us to confirm a novel genome-wide significant association of AD with the membrane-spanning 4-domains subfamily A (MS4A) gene cluster (rs1562990, P = 4.40E-11, odds ratio = 0.88, 95% confidence interval 0.85 to 0.91, n = 10,181 cases and 14,341 controls).\ud \ud Conclusions\ud Our results underscore the importance of international efforts combining GWAS datasets to isolate genetic loci for complex diseases

Adherencia a la dieta mediterránea en adultos inactivos, practicantes de ciclo indoor y ciclistas aficionados

Introducción: existe información limitada sobre la relación entre la adherencia a la dieta mediterránea (ADM) y la práctica deportiva. Objetivo: determinar la posible asociación de la práctica deportiva y el volumen de entrenamiento en bicicleta con la ADM y la influencia de la proximidad de una prueba ciclodeportiva sobre la ADM. Material y métodos: una primera evaluación de la ADM en 785 (84 mujeres) ciclistas aficionados (volumen = 7 horas/semana), 514 (224 mujeres) practicantes de ciclo indoor (volumen: 2-6 horas/semana) y 718 (411 mujeres) adultos inactivos fue desarrollada en mayo, coincidiendo con la participación de los ciclistas en una prueba ciclodeportiva. Una submuestra de 359 ciclistas y 148 inactivos fueron evaluados nuevamente en noviembre, en fecha alejada de la prueba ciclodeportiva. Se utilizó el cuestionario MEDAS-14 para valorar la ADM y un cuestionario autodiseñado para evaluar el volumen de entrenamiento. Resultados: un 40% de los sujetos evidenció alta ADM. En ambos sexos, los deportistas mostraron mayor ADM que los inactivos, con los mejores índices para los grupos de ciclistas (p < 0, 001). La relación entre la ADM y el volumen de entrenamiento fue débil (hombres: r = 0, 137, mujeres: r = 0, 173; p < 0, 001). La ADM de los ciclistas disminuyó de mayo a noviembre (p < 0, 001) sin cambios en los sujetos inactivos (p = 0, 535). Conclusiones: la práctica deportiva en bicicleta se asocia con una mayor ADM con limitada influencia del volumen de entrenamiento y con efectos positivos transitorios de la participación en una prueba ciclodeportiva. Introduction: There is limited information referred to the relationship between adherence to the Mediterranean Diet (AMD) and sports practice. Objective: To determinate the association of cycling practice and cycling training volume with the AMD and the influence of the participation in a high-demand cyclist event on the AMD. Material and methods: A first evaluation of AMD in 785 (84 women) amateur cyclists (volume: = 7 hours/week), 514 (224 women) indoor cycling practitioners (volume: 2-6 hours/week) and 718 (411 women) inactive adults was conducted in May coinciding with the participation of cyclists in a cycling event. A subsample of 359 cyclists and 148 inactive subjects agreed to be retested in November, far from the cycling event date. The MEDAS-14 questionnaire was used to assess the AMD and a self-designed questionnaire was used to assess the volume of training. Results: 40% of subjects showed high AMD. In both sexes, athletes showed higher AMD than inactive subjects, with the highest indexes for groups of cyclists (p < 0.001). The relationship between AMD and training volume was weak (men: r = 0.137, women: r = 0.173; p < 0.001). The AMD of cyclists decreased from May to November (p < 0.001) with no significant changes in inactive subjects (p = 0.535). Conclusions: Cycling is associated to higher values of AMD with a limited influence of training volume and transient positive effects of participation in a cycling endurance event

Enhanced Working Memory Binding by Direct Electrical Stimulation of the Parietal Cortex

Recent works evince the critical role of visual short-term memory (STM) binding deficits as a clinical and preclinical marker of Alzheimer’s disease (AD). These studies suggest a potential role of posterior brain regions in both the neurocognitive deficits of Alzheimer’s patients and STM binding in general. Thereupon, we surmised that stimulation of the posterior parietal cortex (PPC) might be a successful approach to tackle working memory deficits in this condition, especially at early stages. To date, no causal evidence exists of the role of the parietal cortex in STM binding. A unique approach to assess this issue is afforded by single-subject direct intracranial electrical stimulation of specific brain regions during a relevant cognitive task. Electrical stimulation has been used both for clinical purposes and to causally probe brain mechanisms. Previous evidence of electrical currents spreading through white matter along well defined functional circuits indicates that visual working memory mechanisms are subserved by a specific widely distributed network. Here, we stimulated the parietal cortex of a subject with intracranial electrodes as he performed the visual STM task. We compared the ensuing results to those from a non-stimulated condition and to the performance of a matched control group. In brief, direct stimulation of the parietal cortex induced a selective improvement in STM. These results, together with previous studies, provide very preliminary but promising ground to examine behavioral changes upon parietal stimulation in AD. We discuss our results regarding: (a) the usefulness of the task to target prodromal stages of AD; (b) the role of a posterior network in STM binding and in AD; and (c) the potential opportunity to improve STM binding through brain stimulation

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

The caudo-ventral pallium is a novel pallial domain expressing Gdf10 and generating Ebf3-positive neurons of the medial amygdala

In rodents, the medial nucleus of the amygdala receives direct inputs from the accessory olfactory bulbs and is mainly implicated in pheromone-mediated reproductive and defensive behaviors. The principal neurons of the medial amygdala are GABAergic neurons generated principally in the caudo-ventral medial ganglionic eminence and preoptic area. Beside GABAergic neurons, the medial amygdala also contains glutamatergic Otp-expressing neurons cells generated in the lateral hypothalamic neuroepithelium and a non-well characterized Pax6-positive population. In the present work, we describe a novel glutamatergic Ebf3-expressing neuronal subpopulation distributed within the periphery of the postero-ventral medial amygdala. These neurons are generated in a pallial domain characterized by high expression of Gdf10. This territory is topologically the most caudal tier of the ventral pallium and accordingly, we named it Caudo-Ventral Pallium (CVP). In the absence of Pax6, the CVP is disrupted and Ebf3-expressing neurons fail to be generated. Overall, this work proposes a novel model of the neuronal composition of the medial amygdala and unravels for the first time a new novel pallial subpopulation originating from the CVP and expressing the transcription factor Ebf3.This work was supported by Grants of the French National Research Agency (Agence Nationale de la Recherche; ANR) [ANR-13-BSV4-0011] and by the French Government through the ‘Investments for the Future’ LABEX SIGNALIFE [ANR-11-LABX-0028-01] to M.S., by the Spanish Government (BFU2007-60263 and BFU2010-17305) to A.F, and by the Medical Research Council (MR/K013750/1) to T.T. N.R.-R. is funded by a postdoctoral fellowship from the Ville de Nice, France (“Aide Individuelle aux Jeunes Chercheurs 2016”).Peer reviewe

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele