This work supports previous reports of an association between apoE-4 and the development of AD and demonstrates that apoE-4 exerts its maximal effect before age 70. These findings have important implications for the potential use of apoE genotyping for diagnosis and prediction of disease. They also underscore the need to identify additional genetic factors involved in AD with onset beyond age 70 years.

Alpha-2-macroglobulin (alpha-2M; encoded by the gene A2M) is a serum pan-protease inhibitor that has been implicated in Alzheimer disease (AD) based on its ability to mediate the clearance and degradation of A beta, the major component of beta-amyloid deposits. Analysis of a deletion in the A2M gene at the 5' splice site of 'exon II' of the bait region (exon 18) revealed that inheritance of the deletion (A2M-2) confers increased risk for AD (Mantel-Haenzel odds ratio=3.56, P=0.001). The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD (P=0.00009). These values were comparable to those obtained for the APOE-epsilon4 allele in the same sample, but in contrast to APOE-epsilon4, A2M-2 did not affect age of onset. The observed association of A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which we were unable to confirm in this sample. A2M, LRP1 (encoding the alpha-2M receptor) and the genes for two other LRP ligands, APOE and APP (encoding the amyloid beta-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neuropathogenic pathway leading to AD.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.

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This analysis identified 172 replicated new associations with SZ after careful correction for cell type heterogeneity and other potential confounders. The overlap with previous genome-wide association study data can provide potential insights into the functional relevance of genetic signals for SZ.