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. more...

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.

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