Familial Alzheimer disease

Familial Alzheimer's disease (FAD) is an uncommon form of Alzheimer's disease that comes on earlier in life (usually between 30 and 60 years of age) and is inherited in an autosomal dominant fashion. While it only accounts for 5% or less of total Alzheimer's disease, it has presented a useful model in studying various aspects of the disorder.

Clinical features
Alzheimer disease (AD) is the most common form of dementia. It usually occurs in old age, and starts gradually with early signs being forgetfulness, particularly in remembering recent events and the names of people and things. There may be some other cognitive difficulties early on, but nothing overly alarming.

As the disease progresses, the patient may start to exhibit greater problems. They may forget how to do simple things such as brushing their hair, and later in the disease may become anxious or aggressive, ultimately needing full-time care.

Familial Alzheimer disease is an uncommon form of Alzheimer's that comes on earlier in life (usually between 30 and 60 years) and is inherited in an autosomal dominant fashion. There are a number of types of familial (or early-onset) AD, which are identified by their genetics and other characteristics such as the age of onset. As a whole, this form of the disease only accounts for roughly 10% to 15% of all cases of AD.

Histologically, familial AD is practically indistinguishable from other forms of the disease. Deposits of amyloid can be seen in sections brain tissue (visible as an apple-green yellow birefringence under polarised light). This amyloid protein forms plaques and neurofibrillary tangles that progress through the memory centres of the brain. Very rarely the plaque may be unique, or uncharacteristic of AD; this can happen when there is a mutation in one of the genes that creates a functional, but malformed, protein instead of the ineffective gene products that usually result from mutations.

Genetic causes and mutations
There are multiple genetic causes of Alzheimer disease. Two of these are the presenilin polymorphisms on chromosomes 1 and 14, Others include several amyloid precursor protein polymorphisms and one of the four common alleles of apolipoprotein E. Several other gene polymorphisms have also been identified to increase susceptibility to Alzheimer's.

PSEN1 - Presenilin 1
The presenilin 1 gene (PSEN1) was linked to the long arm of chromosome 14 (14q24.3) using a pedigree of 34 people suffering from early-onset Alzheimer disease by Campion (1995). The actual gene was identified by Sherrington (1995) to be PSEN1, and multiple mutations were identified. Mutations in this gene cause familial Alzheimer's type 3. This protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP (see below).

The gene contains 14 exons, and the coding portion is estimated at 60 kb, as reported by Rogaev (1997) and Del-Favero (1999). The protein the gene codes for (PS1) is an integral membrane protein. As stated by Ikeuchi (2002) it cleaves the protein Notch1 so is thought by Koizumi (2001) to have a role in somitogenesis in the embryo. It also has an action on an amyloid precursor protein, which gives its probable role in the pathogenesis of FAD. Homologs of PS1 have been found in plants, invertebrates and other vertebrates.

There are many allelic variants in PSEN1 that cause AD including Met146Leu which has been found in unrelated families in Italy by Sherrington (1995), and in Argentina by Morelli (1998). There are other mutations at this same amino acid position including Met146Val, found by the Alzheimer's Disease Collaborative Group (1995), and Met146Ile identified as two different point mutations, one in a Danish family by Jorgensen (1996), and another in a Swedish family by Gustafson (1998).

Some of the mutations in the gene, of which there are over 90, include: His163Arg, Ala246Glu, Leu286Val and Cys410Tyr. Most display complete penetrance, but a common mutation is Glu318Gly and this predisposes individuals to familial Alzheimer disease, with a study by Taddei (2002) finding an incidence of 8.7% in patients with familial AD.

PSEN2 - Presenilin 2
The presenilin 2 gene (PSEN2) is very similar in structure and function to PSEN1. It is located on chromosome 1 (1q31-q42), and variants of this gene cause type 4 FAD. A study by Kovacs (1996) showed that PS1 and PS2 proteins are expressed in similar amounts, and in the same organelles as each other, in mammalian neuronal cells. Levy-Lahad (1996) determined that PSEN2 contained 12 exons, 10 of which were coding exons, and that the primary transcript encodes a 448 amino acid polypeptide with 67% homology to PS1. This protein has been identified as part of the enzymatic complex that cleaves amyloid beta peptide from APP (see below).

The mutations have not been studied as much as PSEN1, but distinct allelic variants have been identified. These include Asn141Ile, which has been identified by many studies in Volga German families with familial Alzheimer disease. One of these studies by Nochlin (1998) found severe amyloid angiopathy in the affected individuals in a family. This phenotype may be explained by a study by Tomita (1997) suggesting that the Asn141Ile mutation alters amyloid precursor protein (APP) metabolism causing an increased rate of protein deposition into plaques.

Other allelic variants are Met239Val which was identified in an Italian pedigree by Rogaev (1995) who also suggested early on that the gene may be similar to PSEN1, and a Asp439Ala mutation in exon 12 of the gene which is suggest by Lleo (2001) to change the endoproteolytic processing of the PS2.

APP &#8211; Amyloid beta (A4) precursor protein
Mutations to the amyloid beta A4 precursor protein (APP) located on the long arm of chromosome 21 (21q21.3) can also cause familial Alzheimer disease (type 1) as well as other problems. The different mutations have different ages of onset.

Research done by Yoshikai (1990) found that the multiple isoforms of this protein were caused by alternative splicing of the 19-exon gene.

APP is cleaved by gamma-secretase integral membrane proteins such as PS1 and PS2 discussed above.

Allelic variants of APP that cause Alzheimer disease include three mutations from a valine at position 717 to isoleucine, phenylalanine or glycine.

In addition, a form of FAD has been discovered that has no mutation in the APP protein but a mutation in the APP promoter region.

APOE - Apolipoprotein E
The APOE gene codes for an apolipoprotein, so is involved with the transport of lipids around the body. Its role in the cause of Alzheimer disease is not an autosomal dominant effect as with the previous three genes; some variants may cause a slight predisposition to AD (Corder, 1993), and Amouyel (1994) reported an increased the risk of other neurological disorders such as Creutzfeldt-Jakob disease.

The variant discussed by Corder (1993) was apolipoprotein E type 4 (ApoE&#949;4) - the greater the number of copies of this allele a person possessed, the greater their chance of developing Alzheimer disease. This gene lies on chromosome 19 (its locus is 19q13.2), and the subgroup of FAD it causes is type 2.

Other mutations summary
There is considerable genetic heterogeneity in familial Alzheimer disease, and obvious genetic causes of Alzheimer's account for a small proportion of the disease. With each gene, there are usually many different mutant alleles that are capable of causing the problem.

Clinically there is rarely any correlation of the disease phenotype with the genotype, though there may be biochemical and histological tests where a difference can be picked up.

The types of FAD include type 1, caused by APP mutation; type 2, the susceptibility to which is increased with APOE*E4; and type 3 and type 4 caused by PSEN1 and PSEN2 mutations respectively. The PSEN and the APP mutations show autosomal dominant inheritance. As well as these there are other types including a mitochondrial DNA association identified by Lin (1992), and an association of a variant of alpha 2-macroglobulin with FAD reported by Liao (1998) (although later studies have not been able to reproduce this). Zubenko (2001) showed Alzheimer disease type 7 is associated with a gene (D10S1423) whose locus is 10p3. Olson (2002) found a locus for late-onset Alzheimer disease (type 8) on the short arm of chromosome 20. Many of these genes affect APP (which is not surprising given the pathology of Alzheimer disease), and there are other lipoprotein associations apart from Apolipoprotein E.