Genes and Alzheimer's disease: new data and systematic meta-analyses

Dementia News 69, January 2007

In the January 14th issue of Nature Genetics researchers have published the identification of a gene associated with late onset Alzheimer's disease: SORL1 (Rogaeva et al.). Forty-one scientists from seven different countries, including Italy, coauthor the paper. The research originated from a defined rationale derived from the amyloidogenic hypothesis of Alzheimer's disease. The generation of beta –amyloid, the neurotoxic derivative of the Amyloid Precursor Protein (APP), may likely occurr during the recycling of APP from the cell surface via the endocytotic pathway. Accordingly, the authors investigated the genetic associations between Alzheimer's disease and genetic variants of proteins regulating protein sorting, among which SORL1. SOLRL1 stands for sortilin-related receptor, and acts as a sorting receptor for APP. Absence of SORL1 switches APP from the recycling pathway and directs it into the beta secretase pathway to generate beta amyloid. Genetic variants may regulate tissue specific expression of SORL1, under expression of it may lead, as indicated, to increased beta amyloid generation. The observation that specific variants of SORL1, accompanied by a reduction of SORL1 expression, are associated with AD is in accord with previous post mortem observations showing that the expression of SORL1 is reduced in neurons of sporadic AD. Moreover the data suggest that SORL1 gene variants increase the risk of developing AD and point to new putative targets for researches aimed to investigate causes and heterogeneity of sporadic Alzheimer's disease as well as to design drugs to cure it. The results are pretty important, however it should be recalled that Alzheimer's disease is caused by a complex genetic puzzle and by its interaction with environment. Every new discovery is important but it is a tile of the puzzle, not the entire picture.

The importance of the genetic studies is underscored by another paper published online on the very last days of December, 2006 by the Tanzi group (Bertram et al.). The authors have built a publicly available database that includes all genetic association studies in the field of AD. The authors performed a systematic meta analysis of the data pinkpointing several potential AD susceptibility genes (see the paper for the list). The authors themselves emphasize that the results have to be interpreted with caution, as in any association study. However the results of the meta-analysis do indeed indicate promising AD candidate genes that deserve further follow up studies and that, in addition of providing information that will help to better profile the genetic risk for AD, may suggest new targets for therapeutic intervention.

prof. Stefano Govoni
Department of Experimental and Applied Pharmacology, University of Pavia, Italy

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