Table 1 Schematic Overview of Major Alzheimer's Disease Gene

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.