Multiomics integrative analysis identifies APOE allele-specific blood biomarkers associated to Alzheimer's disease etiopathogenesis.

Alzheimer's disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analysed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by APOE haplotype (APOE2, APOE3 and APOE4). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterised a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in APOE2 and APOE4 AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.

Key Bacteria in the Gut Microbiota Network for the Transition between Sedentary and Active Lifestyle.

Physical activity modifies the gut microbiota, exerting health benefits on the host; however, the specific bacteria associated with exercise are not yet known. In this work, we propose a novel method, based on hierarchical topology, to study the differences between the microbiota of active and sedentary lifestyles, and to identify relevant bacterial taxa. Our results show that the microbiota network found in active people has a significantly higher overall efficiency and higher transmissibility rate. We also identified key bacteria in active and sedentary networks that could be involved in the conversion of an active microbial network to a sedentary microbial network and vice versa.

A Critical Mutualism - Competition Interplay Underlies the Loss of Microbial Diversity in Sedentary Lifestyle.

Physical exercise improves the overall health status by preventing the development of several diseases. In recent years, it has been observed that physical exercise impacts gut microbiota by increasing the presence of beneficial bacteria and microbial diversity. In contrast, a sedentary lifestyle increases the incidence of chronic diseases that often have an associated loss of microbial diversity. The gut microbiota is a vast ecosystem in which microorganisms interact with each other in different ways; however, microbial ecosystem interactions are scarcely studied. The goal of this study was to determine whether individuals with a sedentary lifestyle have lower diversity in their gut microbiota and how microbial diversity is associated with changes in bacterial network interactions. For that purpose, diet, body composition, physical activity, and sedentarism behavior were characterized for individuals who did or did not comply with the World Health Organization recommendations for physical activity. The composition of the gut microbiome was determined by 16S rRNA gene sequencing. Reorganization of microbial structure with lifestyle was approached from network analysis, where network complexity and the topology of positive and negative interdependences between bacteria were compared and correlated with microbial diversity. Sedentary lifestyle was significantly associated with a diet low in fiber and rich in sugars and processed meat, as well as with high visceral and total corporal fat composition. The diversity (phylogenic diversity, Chao, observed species, and Shannon's index) and network complexity of the gut microbiota were significantly lower in sedentary compared to active individuals. Whereas mutualism or co-occurrence interactions were similar between groups, competitiveness was significantly higher in the active lifestyle group. The mutualism-competition ratio was moderate and positively associated with diversity in sedentary individuals, but not in active individuals. This finding indicates that there is a critical point in this ratio beyond which the stability of the microbial community is lost, inducing a loss of diversity.

Novel Mutation (Gly212Val) in the PS2 Gene Associated with Early-Onset Familial Alzheimer's Disease.

Mutations in the presenilin 2 gene (PS2) are an extremely rare cause of early-onset autosomal dominant Alzheimer's disease (AD), accounting for only 5% of these families. These cases represent a particular model of AD, and the scarcity of reports on their clinical phenotypes makes them of great interest. We report a family with early-onset autosomal dominant AD in four members, where the two living siblings were found to carry the novel PS2 mutation Gly212Val (exon 7, transmembrane domain IV) with highly predicted pathogenicity. Age at onset ranged from 60 to 65 years and three of the cases died between ages 74 and 76 years. Clinical phenotype was quite homogeneous among affected members of the family, and overall features, including cognitive decline, tau/p-tau and amyloid-ß cerebrospinal fluid markers, neuroimaging, and neuropathology were consistent with typical AD. Lewy bodies were present but restricted to the amygdala.