Alzheimer disease is the leading cause of dementia in the elderly in the developed nations affecting over four million patients in the United States alone. It is a catastrophic neurodegenerative disorder manifesting as loss of memory and declining cognitive and physical functions. Its long and arduous clinical course makes it a major public health problem.
Studies aimed at defining the genetic component(s) of Alzheimer disease have been severely hampered by diagnostic uncertainties. Definite diagnosis requires pathological confirmation after death and there has been a tendency for all elderly patients with dementia for which there is no other known cause to be diagnosed as suffering from the disease. Although there are now standard criteria for the clinical diagnosis of the disease, recent findings suggest that these still include about ten percent of patients where the diagnosis is not confirmed at autopsy.
It is generally agreed that first degree relatives of patients have an increased risk of developing Alzheimer disease but estimates of this risk vary from five to one hundred percent. Twin studies show increased but not total concordance in monozygotic compared with dizygotic twins. Until recently, therefore, while it was widely accepted that the aetiology of the disease involved one or more genetic components, there was no general agreement about their nature or their importance compared with possible environmental factors. Now two research groups have published data which, if independently confirmed, seem to point the way to a much clearer understanding of the genetics of the disease.
The first, based on family studies of 251 patients with Alzheimer disease, suggests that susceptibility to the disease is determined in part by a major autosomal dominant gene (Farrer et al, 1991). The second provides evidence for linkage of the disease with chromosome 19 Pericak-Vance et al, 1991). This result was somewhat unexpected since previously several workers had reported a linkage with chromosome 21 which seemed not unlikely given that Down syndrome patients who live beyond the age of 30 or 40 develop a neuropathology essentially the same as Alzheimer disease.
When patients with the disease are divided into two groups, early-onset (ie before the age of 65) and late-onset (ie after 65), the apparent contradiction between the two linkages largely disappears. Those families showing linkage to chromosome 21 are mostly those with early-onset while late-onset families seem to show linkage to both chromosome 19 and chromosome 21. It seems likely, therefore, that the major gene detected by Farrer et al is on chromosome 21. The nature of the gene on chromosome 19 together with other possible genes and certainly one or more environmental factors remains to be established but it now seems reasonable to hope that the genetic components in the aetiology of the disorders now known as Alzheimer disease will be determined in the near future.
References:
Farrer et al, Amer. J. Hum. Genet. v. 48, p1026, 1991.
Percak-Vance et al, Amer. J. Hum. Genet. v. 48, p1034, 1991.
John Timson