Table 1.
Schematic Overview of Major Alzheimer's Disease Gene
| Familial Genes | Locus | Functions |
|---|---|---|
| APP | 21q21.3 | APP gene encodes a membrane protein cleaved by secretase. Mutations in App locus causes autosomal dominant early onset AD and cerebroarterial amyloidosis. |
| PS1 | 14q24.2 | PS1 is involved in APP processing and mutations can interfere the production of Aβ42 and to form plaques. Numerous alternatively spliced transcript variants encoding different isoforms have been identified for this gene. |
| PS2 | 1q42.13 | Regulate APP processing as a part of the α-secretase complex. Familial mutations can change the production of Aβ42. |
| Risk Genes | ||
| APOE | 19q13.32 | ApoE regulates the normal catabolism of triglyceride-rich lipoprotein constituents. APOE binds Aβ and it is involved in Aβ clearance. Subjects carrying the E4 allele have an increased amyloid burden. |
| TAU | 17q21.31 | The transcript undergoes complex alternative splicing and tau exists as six splice isoforms. The mutations can alter microtubule binding efficacy. |
| DYRK1A | 21q22.13 | DYRK1A is localized in the critical region of chromosome 21 and is involved in tau and APP phosphorylation. Firstly the activity is upregulated by Aβ and APP phosphorylation result in increased amyloidogenic processing with BACE interaction. |
| GSK3β | 3q13.33 | The overexpression of this gene may be relevant for AD. GSK-3 phosphorylates tau and presenilin-1, which are involved in the development of AD. The phosphorylation of tau leads to tangle formation and APP cleavage products can activate GSK3β resulting increased tau phosphorylation. |
| New GWAS Genes | ||
| CLU | 8p21.1 | Clusterin is a chaperone molecule involved in clearence, aggregation and fibrillization of Aβ. It is associated with the progression of AD. |
| PICALM | 11q14.2 | Phosphatidylinositol binding clathrin assembly protein is associated with an increased risk of developing AD. PICALM plays a role in synaptic trasmission and may be involved in Aβ clearence. The protein is present in endosomes connected with AD. |
| CR1 | 1q32.2 | This gene is a member of the receptors of complement activation (RCA) family, precisely the complement C3b protein, a key inflammatory protein activated in AD. |
| BIN1 | 2q14.3 | This gene encodes several isoforms of a nucleocytoplasmic adaptor protein involved in endocytosis. BIN1 could have an effect on Aβ production and/or the clearance of Aβ. |
| ABCA7 | 19p13.3 | This gene is a member of the superfamily of ATP-binding cassette (ABC) transporters and is highly expressed in brain, particularly in the microglia. ABCA7 inhibit β-amyloid secretion in cultured cells overexpressing APP. |
| MS4A | 11q12.2 | The genes in the MS4A cluster are locolized on chromosome 11 and encode proteins with at least 4 potential transmembrane domains but do not have specific function yet. |
| CD2AP | 6p12.3 | C2AP encodes a scaffolding molecule that regulates the actin cytoskeleton and is involved in the regulation of receptor-mediated endocytosis. |
| EPHA1 | 7q35 | EPHA1 is a member of the ephrin receptor subfamily of the protein-tyrosine kinase family. It is implicated in synaptic development and plasticity but also axon guidance. Other functions have been proposed. |
| CD33 | 19q13.41 | CD33 molecule belongs to the family of sialic acid-binding, immunoglobulinlike lectins. CD33 regulate the functions in the adaptive and innate immune systems both involved into the inflammatory reactions observed in the brains of AD patients. |
Genes in genomic location are in according to Ensembl cytogenetic band