Since the discovery of the APP (Amyloid Precursor Protein) gene, the first causative gene for Alzheimer's disease, at St Mary's Hospital in 1991 our understanding of the disease process has increased enormously. Familial Alzheimer's disease appears to affect people at a younger age than Sporadic Alzheimer's disease, the age at onset in some of our families is as young as 35 and there are some cases in the literature where the disease began in the mid-twenties. 

Three causative genes for Alzheimer's disease have been identified to date: the APP gene on chromosome 21, the Presenilin-1 (PSEN1) gene on chromosome 14 and the Presenilin-2 (PSEN2) gene on chromosome 1. These genes account for approximately 1-5% of all cases of Alzheimer's disease. The mutation (genetic fault) runs in families and is handed on from parent to child. The risk of a parent with the gene passing the mutation on to a child is 50% (autosomal dominant inheritance). If the child inherits the mutation then he/she will develop the disease, and is in turn at risk of passing the gene to their children. If they do not inherit the gene they will not develop familial Alzheimer's disease and cannot pass it on to their children- i.e. the disease does not skip generations.

Since the APP gene was first identified in 1991 [Reference 1] in a British Family from the Alzheimer disease collection of families at St Mary's and the National Hospitals, a further 8 mutations in the APP gene have been identified. These mutations are thought to cause Alzheimer's disease by causing the accelerated build up of amyloid.

PSEN1 was identified in 1995 [Reference 2] and appears to be the commonest causative gene accounting for approximately 60% of familial Alzheimer's disease [Reference 3]. To date in excess of 60 mutations in this gene have been identified including an intronic mutation. 

PSEN2 was discovered shortly after PSEN1 by searching for a similar looking gene to PSEN1 on the previously suspected chromosome 1 [Reference 4]. This gene was found in a close knit group in America who are known as Wolga Germans (these are ethnic Germans who emigrated first to Russia and then to America). 3 mutations have been identified to date 2 mutations in 7 Wolga German families and 1 mutation in an Italian family. 

If you think that you may belong to a family with genetic Alzheimer's disease we would be pleased to answer any questions you may have, please telephone CANDID on 020 7829 8772.

References:

Goate et al. (1991) Nature 349, 704-706

Sherrington et al. (1995) Nature 375, 754-760, Rogaev et al. (1995) Nature 376, 775-778

Cruts et al (1998) Hum. Mol. Genet. 7, 43-51

Levy-Lahad et al. (1995) Science 269, 973-977