Alzheimer's disease (AD) is an age-related disease, which affects approximately 40% of the population at an age above 90 years. The heritability is estimated to be greater than 60% and there are rare autosomal dominant forms indicating a significant genetic influence on the disease process. Despite the successes in the early 1990s when four genes were identified, which directly cause the disease (APP, PSEN1 and PSEN2) or greatly increase the risk of disease development (APOE), it has proved exceedingly difficult to identify additional genes involved in the pathogenesis. However, several linkage and association studies have repeatedly supported the presence of susceptibility genes on chromosomes (chrms) 9, 10 and 12. The study populations have, however, mostly been of great genetic heterogeneity, and this may have contributed to the meagre successes in identifying the disease associated genetic variants. In this study, we have performed a genome wide linkage study on 71 AD families from the relatively genetically homogeneous Swedish population where it is also possible to study the genetic ancestry in public databases. We have performed nonparametric linkage analyses in the total family material as well as stratified the families with respect to the presence or absence of APOE varepsilon4. Our results suggest that the families included in this study are tightly linked to the APOE region, but do not show evidence of linkage to the previously reported linkages on chrms 9, 10 and 12. Instead, we observed the next highest LOD score on chromosome 5q35 in the total material. Further, the data suggest that the major fraction of families linked to this region is APOE varepsilon4 positive.

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Segregation and RNA analyses showed that the g.102delC mutation, previously reported, causes FTD in the Karolinska family. Our findings add further support to the significance of GRN in FTD etiology and the presence of modifying genes, which emphasize the need for further studies into the mechanisms of clinical heterogeneity. However, the results already call for attention to the complexity of predictive genetic testing of GRN mutations.

Background: SORL1, a neuronal sorting receptor that protects amyloid precursor protein (APP) from processing into amyloid beta, has recently been identified as a major genetic contributor to increased risk for late-onset Alzheimer disease (AD) in several populations. In this study, we aimed at replicating this finding in a large, well-characterized group of 550 Belgian late-onset AD patients (N ϭ 550, mean onset 79.0 Ϯ 5.2, 70.2% females, 80.2% probable AD, 14% definite AD) and 637 healthy control individuals (N ϭ 637, mean age at inclusion 61.9 Ϯ 15.3, 57.1% females). Methods: We used a gene-wide genotyping approach across the SORL1 locus. A total of 29 SNPs covering the entire SORL1 gene were genotyped. Using Chi-square statistics, genotypic frequencies were compared between late-onset AD patients and control individuals. Values were adjusted for onset age, gender and APOE genotype by means of logistic regression models. Haplotype analyses were performed using a sliding window analysis with a 3-SNP sized window. When significant, haplotype frequencies were further estimated and compared using score statistics. Results: We observed significant associations, both for individual SNPs (SNPs 6, 8, 9, 10 and 27; p-values ranging from 0.001 to 0.040) and 3-SNP haplotypes (SNPs 5-6-7 and SNPs 25-26-27; p-values ranging from 0.008 to 0.035) in the 5' and 3' regions of SORL1. Moreover, the associations at SNP 8, 9 and 10 represented a direct replication of the initial association data. The two signals in distinct regions of the gene were shown to be mutually independent, supporting allelic heterogeneity at the SORL1 locus in the Belgian population. Conclusions: Our study has independently replicated the previously described association between common polymorphisms in the 5' end of SORL1 and late-onset AD, providing further evidence of genetic variations in SORL1 affecting susceptibility of late-onset AD. In addition, we also found evidence of multiple associated regions in SORL1.

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