A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis

Predicting episodic memory performance using different biomarkers: results from Argentina-Alzheimer’s Disease Neuroimaging Initiative

María Julieta Russo,1 Gabriela Cohen,1 Patricio Chrem Mendez,1 Jorge Campos,1 Federico E Nahas,1 Ezequiel I Surace,1 Silvia Vazquez,1 Deborah Gustafson,2,3 Salvador Guinjoan,1 Ricardo F Allegri,1 Gustavo Sevlever1 On behalf of the Argentina-Alzheimer’s Disease Neuroim­aging Initiative group 1Center of Aging and Memory of Neurological Research Institute (FLENI), Buenos Aires, Argentina; 2Department of Neurology, State University of New York-Downstate Medical Center, Brooklyn, NY, USA; 3Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenPurpose: Argentina-Alzheimer’s Disease Neuroimaging Initiative (Arg-ADNI) is the first ADNI study to be performed in Latin America at a medical center with the appropriate infrastructure. Our objective was to describe baseline characteristics and to examine whether biomarkers related to Alzheimer’s disease (AD) physiopathology were associated with worse memory performance.Patients and methods: Fifteen controls and 28 mild cognitive impairment and 13 AD dementia subjects were included. For Arg-ADNI, all biomarker parameters and neuropsychological tests of ADNI-II were adopted. Results of positron emission tomography (PET) with fluorodeoxyglucose and 11C-Pittsburgh compound-B (PIB-PET) were available from all participants. Cerebrospinal fluid biomarker results were available from 39 subjects.Results: A total of 56 participants were included and underwent baseline evaluation. The three groups were similar with respect to years of education and sex, and they differed in age (F=5.10, P=0.01). Mean scores for the baseline measurements of the neuropsychological evaluation differed significantly among the three groups at P<0.001, showing a continuum in their neuropsychological performance. No significant correlations were found between the principal measures (long-delay recall, C-Pittsburgh compound-B scan, left hippocampal volume, and APOEε4) and either age, sex, or education (P>0.1). Baseline amyloid deposition and left hippocampal volume separated the three diagnostic groups and correlated with the memory performance (P<0.001).Conclusion: Cross-sectional analysis of baseline data revealed links between cognition, structural changes, and biomarkers. Follow-up of a larger and more representative cohort, particularly analyzing cerebrospinal fluid and brain biomarkers, will allow better characterization of AD in our country.Keywords: aging, Alzheimer’s disease, amyloid imaging, biomarkers, mild cognitive impairmen

Cognitive reserve and Aβ1-42 in mild cognitive impairment (Argentina-Alzheimer’s Disease Neuroimaging Initiative)

Paula Harris,1,2 Marcos Fernandez Suarez,1 Ezequiel I Surace,1,2 Patricio Chrem Méndez,1 María Eugenia Martín,1 María Florencia Clarens,1 Fernanda Tapajóz,1,2 Maria Julieta Russo,1 Jorge Campos,1 Salvador M Guinjoan,1,2 Gustavo Sevlever,1 Ricardo F Allegri1,2 1Instituto de Investigaciones Neurológicas, 2Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina Background: The purpose of this study was to investigate the relationship between cognitive reserve and concentration of Aβ1-42 in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment, those with Alzheimer’s disease, and in control subjects. Methods: Thirty-three participants from the Argentina-Alzheimer’s Disease Neuroimaging Initiative database completed a cognitive battery, the Cognitive Reserve Questionnaire (CRQ), and an Argentinian accentuation reading test (TAP-BA) as a measure of premorbid intelligence, and underwent lumbar puncture for CSF biomarker quantification. Results: The CRQ significantly correlated with TAP-BA, education, and Aβ1-42. When considering Aβ1-42 levels, significant differences were found in CRQ scores; higher levels of CSF Aβ1-42 were associated with higher CRQ scores. Conclusion: Reduced Aβ1-42 in CSF is considered as evidence of amyloid deposition in the brain. Previous results suggest that individuals with higher education, higher occupational attainment, and participation in leisure activities (cognitive reserve) have a reduced risk of developing Alzheimer’s disease. Our results support the notion that enhanced neural activity has a protective role in mild cognitive impairment, as evidenced by higher CSF Aβ1-42 levels in individuals with more cognitive reserve. Keywords: amyloid, biomarkers, cerebrospinal fluid, Alzheimer’s disease&nbsp