Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.

Abstract. The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the ε4 allele of the APOE gene.

Probabilistic category learning involves complex interactions between the hippocampus and striatum that may depend on whether acquisition occurs via feedback or observation. Little is known about how healthy aging affects these processes. We tested whether age-related behavioral differences in probabilistic category learning from feedback or observation depend on a genetic factor known to influence individual differences in hippocampal function, the KIBRA gene (single nucleotide polymorphism rs17070145). Results showed comparable age-related performance impairments in observational as well as feedback-based learning. Moreover, genetic analyses indicated an age-related interactive effect of KIBRA on learning: among older adults, the beneficial T-allele was positively associated with learning from feedback, but negatively with learning from observation. In younger adults, no effects of KIBRA were found. Our results add behavioral genetic evidence to emerging data showing age-related differences in how neural resources relate to memory functions, namely that hippocampal and striatal contributions to probabilistic category learning may vary with age. Our findings highlight the effects genetic factors can have on differential age-related decline of different memory functions.

Objective: To facilitate interpretation of genetic association findings in amyotrophic lateral sclerosis (ALS) by creating a freely publicly available database aimed to serve as a comprehensive, unbiased, and regularly updated resource of genetic association studies in the field. Background ALS is a genetically complex and heterogeneous disorder. To date, mutations in several genes have been identified to cause familial forms of ALS. On the other hand, ALS without obvious familial aggregation is likely governed by a variety of genetic and non-genetic risk factors. In the past two decades, hundreds of reports, including several genome-wide association studies (GWAS), have been published claiming or refuting genetic association between certain genetic variants and susceptibility for ALS. Design/Methods: Using methodology developed earlier by our group (e.g. Bertram [2007] Nat Genet 39(1):17-23), database curation is currently ongoing and entails identifying and annotating published genetic association studies following systematic searches of scientific literature databases. Extracted data includes characteristics of the investigated populations as well as variant-specific results and genotyping details. In addition, we are in the process of including the results of several published GWAS derived from both observed and imputed genotype data. Up-to-date meta-analyses are presented for polymorphisms with data available in at least four independent case-control samples. Additional features of ALSGene will include the possibility to create custom meta-analyses (e.g. using existing or novel data), and an "ALSGene-Wiki" section (linking information on the potential molecular genetic and functional role of associated polymorphisms). Results: All data and results in ALSGene are freely available at www.alsgene.org. At the meeting, we will provide a detailed summary of the current "Top Results" including their potential relevance to ALS pathogenesis. Conclusions: Our systematic approach not only provides the most comprehensive account of non-Mendelian ALS genetics, but will also help prioritize future fine-mapping and functional genetic experiments