Disease Name: AD1

Inheritance Pattern:  Autosomal Dominant
Proportion:  10% of Early Onset Familial AD
Gene Locus Name: Amyloid precursor protein (APP)
Chromosomal Locus:  21q21.3-22
Normal Allelic Variants:  The APP gene has 19 exons and encodes a large precursor protein of 695-770 amino acids which is proteolytically cleaved to form A-beta peptide. The A-beta peptide portion is encoded by parts of exons 16 and 17.
Disease-causing Allelic Variants:  The most common APP mutation is a substitution of isoleucine for valine at codon 717 . Substitutions of phenyalanine and glycine may also occurr at this codon. Each of these mutations results in early onset familial AD. A double mutation at codons 670 and 671 in exon 16 also results in early onset AD (so-called Swedish mutation. Combined cerebral hemorrhage and presenile dementia has been caused by a mutation in codon 692 with substitution of glycine for alanine. A substitution of glutamine for glutamic acid at codon 693 results in cerebral hemorrhagic amyloidosis of the Dutch type (OMIM 104760), a disease in which dementia and brain amyloid plaques are uncommon.
Normal Gene Product:  The APP protein contains 695 to 770 amino acids and undergoes alternative splicing. There is a 57 amino acid portion with homology to Kunitz type protease inhibitors. The major transcripts in peripheral tissues are the APP 751 and APP 770 variants. The A-beta peptide contains 38 to 42 amino acids and resides in the transmembrane domain of the protein. APP may be cleaved by an alpha secretase within the A-beta peptide sequence, thus eliminating the possibility of A-beta accumulation. However, APP may also be cleaved by beta and gamma secretases that result in the accumulation of A-beta peptide.
Abnormal Gene Product:  unknown
 
 

Inheritance:  Autosomal Dominant
Proportion:  40-70% of Early Onset Familial AD
Gene/Locus Name:  Presenilin 1 (PS1)
Chromosomal Locus:  14 q24.3
Normal Allelic Variants:  The presenilin 1 (PS1) gene on chromosome 14 is also known as S182 (Sherrington et al, 1995). The coding region is composed of 10 exons numbered 3 through 12. Exon 8 and part of exon 3 are alternatively spliced, so shorter isoforms of the protein are predicted to exist. Alternative splicing may also introduce a new exon between exons 10 and 11. The PS1 and PS2 genes are highly homologous.
Abnormal Allelic Variants:  More than 25 mutations that result in early onset FAD have been described in more than 30 families (AD Collaborative Group, 1995; Campion et al, 1995). All mutations except for one are missense mutations. The single exception is a mutation destroying a splice site in which exon 9 is lost but the reading frame is unaltered and the protein is predicted to be 29 amino acids shorter. At least nine mutations occur in a cytosolic domain between transmembrane domains 6 and 7 and the rest of the mutations are within the other hydrophobic domains or immediately at the hydrophilic/hydrophobic junctions, especially of transmembrane domain 2. The relative frequency of mutations in the cytosolic domain that is encoded by the alternatvely spliced exon 8 suggests that this region of the protein is functionally important.
Normal Gene Product:  The PS1 gene is predicted to encode a 467 amino acid protein with 7-10 (probably 8) hydrophobic transmembrane domains. The PS1 protein is highly homologous to thePS2 protein; the regions of greatest divergence are between the two large hydrophilic loops, one at the amino terminal end and the other in the cytosolic domain between the 6th and 7th transmembrane domains (Doan et al, 1996; Li and Greenwald, 1996). This cytosolic domain contains a proteolytic cleavage site (Podlisny et al, 1997). The protein is a functional homolog of SEL-12, a c. elegans protein that facilitates signalling mediated by the Notch/LIN-12 receptor family.
Abnormal Gene Product:  unknown
 
 

Inheritance:  Autosomal Dominant
Proportion:  Infrequent cause of Early Onset Familial AD
Gene/Locus Name: Presenilin 2 (PS2)
Chromosomal Locus: 1q 31-42
Normal Allelic Variants:  The PS2 gene on chromosome 1q is highly homologous to the PS1 gene on chromosome 14.  There are 12 exons including 10 coding exons in a genomic region spanning 23,737 bp.  The first two exons encode the 5' untranslated region (Levy-Lahad, 1996).
Disease-Causing Allelic Variants:  Thus far, two mutations in the PS2 gene resulting in generally early onset FAD, but with a relatively broad range of onset age, have been described. A single mutation (N141I) has been found in several Volga German FAD pedigrees, confirming the founder effect in this population . Another mutation (Met 239VAl) has been reported in an Italian FAD kindred .
Normal Gene Product:  The PS2 gene is predicted to encode a 448 amino acid protein that is highly homologous to the PS1 protein. The PS2 protein is also thought to contain 8 transmembrane domains. The regions of greatest divergence between the two proteins are at the amino terminal end and in the cytosolic domain between the 6th and 7th transmembrane domains.
Abnormal Gene Product:  unknown
 
 

Inheritance:  Autosomal Dominant
Proportion:  10-25% of Late Onset Familial AD
Gene/Locus Name: Apolipoprotein E
Chromosomal Locus: 19q 13.2 (other unknown loci may also influence AD2)
Normal Allelic Variants:  The Apo E gene has 4 exons (3.6kb) and is contained on chromosome 19q in a lipoprotein gene cluster spanning approximately 40 kb and containing Apo E, Apo C2, Apo C1 and an Apo HC1 pseudogene. There is a normally occurring polymorphism that consists of single base changes at codons 112 and 158 that encode CYS-112 and CYS-158 for the e2 allele, CYS-112 and ARG-158 for the e3 allele and ARG-112 and ARG-158 for the e4 allele with respective allele frequencies of approximately .08, .78 and .14 in Caucasian populations (see Table 2).
Disease-causing Allelic Variants:  The normal polymorphisms described above result in six different geno types, the most common being e3/3 and e3/4. The e4/4 genotype occurs in about 1 to 2% of the general population and has the strongest association with AD.
Normal Gene Product:  Apo E is a 299 amino acid protein involved in lipid transport by mediating the cellular uptake of lipid complexes through interactions with LDL and hepatic receptors .
Abnormal Gene Product:  Unknown