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Familial Alzheimer's disease

Neuro-Degenerative Diseases

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by Giuliano Binetti

General outline

Alzheimer’s disease where there is a family link, called familial Alzheimer’s disease (FAD), is more common amongst younger people (under the age of 65).

Mutations in three genes were shown to be causative of familial Alzheimer’s disease (FAD):

  • About 12 families worldwide have a genetic fault on chromosome 21 in a gene called amyloid precursor protein (APP), which affects production of the protein amyloid. Amyloid build up in the brain has been linked to Alzheimer’s.
  • A slightly larger number of families carry a fault on chromosome 14 (“presenilin-1”) causing early onset familial Alzheimer’s. Mutations in presenilin-1 (PS1) gene accounted for the majority of FAD cases and more than 70 mutations have been described.
  • A very small group of families (7 members of kin with FAD were described) carry a fault on chromosome 14 (“presenilin-2”). The presenilin-2 (PS2) gene is generally considered responsible for a variable penetrant clinical phenotype.

The three genes involve account for the 30-50% of all autosomal dominant early-onset cases, or around 10% of familial early onset cases.

The genetic link in some late onset cases of Alzheimer’s disease (in people aged 65 and over) is more complex than the link for younger people. The presence of a positive family history in the late onset cases is considered as a risk factor, but a clear autosomal dominant pattern of inheritance is rare.

Synonyms

Monogenic Alzheimer’s disease

Symptoms and course

Mutations on the APP gene Age of onset: 40-65 years. Aggressive form of dementia. Duration of the disease: 9-16 years.

Mutations on the PS1 gene Age of onset: 35-55 years. These mutations are largely associated with early onset FAD, but at least two mutations have been observed with late onset FAD.

The clinical phenotype is characterised by early onset memory impairment, rapid global cognitive decline along with the presence of myoclonus and generalised seizures.

In a few (PS1) pedigrees, atypical clinical presentations, including spastic paraparesis and, more recently, fronto-temporal dementia (FTD) were reported. Duration of the disease: 5.8-6.8 years.

Mutations on the PS2 gene Age of onset: 45-88 years. They show some overlaps with late-onset AD. The clinical features similar to those presented in the sporadic Alzheimer’s disease patients. Duration of the disease: 4.4-10.8 years.

Causes and risk factors

These mutations in patients with early-onset AD appear to result in the increased production of Amyloid b42 peptide (Ab42), which is probably the primary neurotoxic species involving in the pathogenesis of the disease.

The mutations can shift the cleavage site to favor the g-secretase site, and to favor increased production of the toxic Ab42 peptide over the shorter, less toxic Ab40 peptide.

Frequency

  1. About 12 families worldwide have a genetic fault on chromosome 21 in a gene called amyloid precursor protein (APP).
  2. A slightly larger number of families carry a fault on chromosome 14 (“presenilin-1”) causing early onset familial Alzheimer’s. Mutations in presenilin-1 (PS1) gene accounted for the majority of FAD cases and more than 70 mutations have been described.
  3. A very small group of families (7 members of kin with FAD were described) carry a fault on chromosome 14 (“presenilin-2”).

Diagnostic procedures

Genetic test: A genetic test is the analysis of human DNA, RNA, chromosomes, proteins, or certain metabolites in order to detect alterations related to a heritable disorder.

Care and treatment

As yet, there is no preventative or curative treatment for Alzheimer's disease. A number of drugs exist, which can help alleviate certain symptoms such as agitation, anxiety, depression, hallucinations, confusion and insomnia. Unfortunately, these drugs tend to be effective for a limited number of patients, only for a short period of time and may cause undesirable side effects. It is therefore generally considered advisable to avoid medication unless really necessary. It has been found that patients suffering from Alzheimer's disease have reduced levels of acetylcholine - a neurotransmitter (chemical substance responsible for transmitting messages from one cell to another) which plays a role in memory processes. Certain drugs have been introduced in some countries, which can inhibit the enzyme responsible for destroying acetylcholine. In some patients these drugs improve memory and concentration. There is additional evidence that they have the potential to slow down the progression of symptoms temporarily. But, there is no evidence that they halt or reverse the process of cell damage. Such drugs treat the symptoms, but do not cure the disease. As European countries have widely differing legislation, we recommend that you consult a specialist in all cases.

Studies demonstrating that accumulation and aggregation of the amyloid b protein within the brain is likely to cause Alzheimer’s disease (AD) have provided the rationale for therapeutic strategies aimed at influencing Ab production, aggregation and clearance. g-secretase catalyzes the final cleavage that releases the Abfrom its precursor; therefore, it is a potential therapeutic target for the treatment of AD. Recent data show that the polytopic membrane proteins presenilin 1 and presenilin 2 are either catalytic components or essential co-factors of a membrane-bound proteolytic complex that possesses g-secretase activity.


Available services

Alzheimer Europe 145 Route de Thionville L- 2611 Luxembourg Tel: +352 / 29.79.70 Fax: +352 / 29.79.72 info@alzheimer-europe.org www.alzheimer-europe.org

Alzheimer's Disease International 45-46 Lower Marsh London SE1 7RG United Kingdom Tel: +44 / 20 7620 3011 Fax: +44 / 20 7401 7351 info@alz.co.uk www.alz.co.uk


References

  • Goate AM. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991;349:704-706.
  • Sherrington R, Rogaev EI, Liang Y, et al. Cloning a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995;375:754-760.
  • Rogaev EI, Sherrington R, Rogaeva EA, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 1995;376:775-778.
  • Crutz M, van Duijin CM, Backhovens H, et al. Estimation of the genetic contribution of presenilin-1 and –2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet 1998;7:43-51.
  • Finckh U, Alberici A, Antoniazzi M, et al. Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. Neurology 2000;54:2006-2008.

 

 
 

Last Updated: vendredi 07 septembre 2012

 

 
  • Acknowledgements

    This information was gathered in the framework of the European Commission financed project "Rare forms of dementia". Neither the European Commission nor any person acting on its behalf is responsible for any use that might be made of the following information.
  • European Union
 
 

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