Electroencephalogram findings in patients with posterior cortical atrophy

Aim of the study: The aim of this study is to evaluate standard scalp EEG findings in patients with posterior cortical atrophy (PCA), an atypical variant of Alzheimer's disease (AD). Clinical rationale: PCA is a topographically selective variant of AD. Patients with typical AD have an increased likelihood of seizures, which may negatively impact overall functional performance and cognition. It is currently unknown what the typical EEG findings are for patients with PCA. Materials and methods: A retrospective chart review was performed on patients identified either with autopsy confirmed (n = 13) or clinically (n = 126) as PCA. Results: 139 patients were included though only 23 (16.5%) had undergone EEG recording. The EEG was normal in 6 (26%), while an abnormal EEG was present in 17 (74%). Interictal epileptic discharges (IEDs) were found in 2 of the 23 patients (9%). Conclusions: This study of limited sample size suggests that there may be an increased predilection to find IEDs within PCA when compared to typical AD. Larger cohorts are required to determine frequency of abnormal EEGs in PCA, roles of AEDs in therapy, and in the selection of preferred AED. Clinical implications: Patients with PCA would potentially benefit from an EEG for assessment of IEDs which may provide the clinician with a therapeutic opportunity

Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer's Disease Pathology

GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer's disease (LOAD) with reported odds ratios (ORs) ranging from 0.75-0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61-1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p<0.02) due to a potentially inflated effect size (OR = 0.61-0.66) only observed in the smallest series (702 LOAD, 209 controls). Despite the lack of association in our series, the previously reported protective association for GAB2 remained after meta-analyses of our data with all available previously published series (11,952-22,253 samples; OR = 0.82-0.88; all p<0.04). Using a freely available database of lymphoblastoid cell lines we found that protective GAB2 variants were associated with increased GAB2 expression (p = 9.5×10-9.3×10). We next measured GAB2 mRNA levels in 249 brains and found that decreased neurofibrillary tangle (r = -0.34, p = 0.0006) and senile plaque counts (r = -0.32, p = 0.001) were both good predictors of increased GAB2 mRNA levels albeit that sex (r = -0.28, p = 0.005) may have been a contributing factor. In summary, we hypothesise that GAB2 variants that are protective against LOAD in some populations may act functionally to increase GAB2 mRNA levels (in lymphoblastoid cells) and that increased GAB2 mRNA levels are associated with significantly decreased LOAD pathology. These findings support the hypothesis that Gab2 may protect neurons against LOAD but due to significant population heterogeneity, it is still unclear whether this protection is detectable at the genetic level. © 2013 Zou et al

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

Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions.

The availability of high-quality RNA-sequencing and genotyping data of post-mortem brain collections from consortia such as CommonMind Consortium (CMC) and the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) Consortium enable the generation of a large-scale brain cis-eQTL meta-analysis. Here we generate cerebral cortical eQTL from 1433 samples available from four cohorts (identifying &gt;4.1 million significant eQTL for &gt;18,000 genes), as well as cerebellar eQTL from 261 samples (identifying 874,836 significant eQTL for &gt;10,000 genes). We find substantially improved power in the meta-analysis over individual cohort analyses, particularly in comparison to the Genotype-Tissue Expression (GTEx) Project eQTL. Additionally, we observed differences in eQTL patterns between cerebral and cerebellar brain regions. We provide these brain eQTL as a resource for use by the research community. As a proof of principle for their utility, we apply a colocalization analysis to identify genes underlying the GWAS association peaks for schizophrenia and identify a potentially novel gene colocalization with lncRNA RP11-677M14.2 (posterior probability of colocalization 0.975)