Genetics of Late-Onset Alzheimer's Disease: Update from the Alzgene Database and Analysis of Shared Pathways

Abstract

The genetics of late-onset Alzheimer's disease (LOAD) has taken impressive steps forwards in the last few years. To date, more than six-hundred genes have been linked to the disorder. However, only a minority of them are supported by a sufficient level of evidence. This review focused on such genes and analyzed shared biological pathways. Genetic markers were selected from a web-based collection (Alzgene). For each SNP in the database, it was possible to perform a meta-analysis. The quality of studies was assessed using criteria such as size of research samples, heterogeneity across studies, and protection from publication bias. This produced a list of 15 top-rated genes: APOE, CLU, PICALM, EXOC3L2, BIN1, CR1, SORL1, TNK1, IL8, LDLR, CST3, CHRNB2, SORCS1, TNF, and CCR2. A systematic analysis of gene ontology terms associated with each marker showed that most genes were implicated in cholesterol metabolism, intracellular transport of beta-amyloid precursor, and autophagy of damaged organelles. Moreover, the impact of these genes on complement cascade and cytokine production highlights the role of inflammatory response in AD pathogenesis. Gene-gene and gene-environment interactions are prominent issues in AD genetics, but they are not specifically featured in the Alzgene database.

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…One of their more telling findings was that clusterin is raised 10 years earlier in the course of the disease than is fibrillar A␤ deposition. Moreover, a metastudy has determined that CLU, the clusterin gene, is the second highest of a list of the 15 top-rated genes linked to AD on the Alzgene web-based collection (Olgiati et al, 2011). Taken together, these arguments are consistent with the key nature of inflammation in AD onset.…”

Lack of association of CR1, PICALM and CLU gene polymorphisms with Alzheimer disease in a Polish population

“…We studied 3 different SNPs of genes which encode proteins potentially involved in pathophysiology of AD [7]. Clusterin, also called apolipoprotein J, is a protein involved in membrane recycling and apoptosis.…”

The Role of PICALM in Alzheimer’s Disease

“…To our knowledge, there seems to be however little evidence-based studies suggestive of this association [117,118] and given the complicated picture of the genetic influence (of PICALM and ABCA7 [119]) on cholesterol transport, more in-depth studies warrant to validate and bolster the association among PICALM, AD risk, and lipid metabolism.…”