FEATURE ARTICLE
Alzheimer's Disease
The molecular origins of the disease are coming to light, suggesting several novel therapies
Vernon Ingram
Alzheimer's Genetics
The youngest cases of Alzheimer's disease are found among people with Down syndrome, which is not usually an inherited condition. Down syndrome patients have an extra copy of chromosome 21, for a total of three; this genetic cause for Down syndrome is described as trisomy 21. Because the gene that codes for APP protein is on chromosome 21, Down syndrome individuals have more of the amyloid protein, and neurotoxic accumulation of the Aβ1-42 fragment becomes noticeable much earlier. Every person with Down syndrome has already started to develop the characteristic plaques and tangles of Alzheimer's disease by age 40.
Some genes passed from parent to child do cause Alzheimer's disease. Fewer than 10 percent of cases can be linked to an autosomal dominant gene, where one mutant allele, or altered gene locus, is sufficient to cause the disease. This small percentage represents several different genes, found in different families but sharing a common inheritance pattern, each one causing Alzheimer's disease in that particular kindred. These individuals have relatively early onset in the 50s and 60s, and their condition deteriorates rapidly.
A much larger number of people have an inherited susceptibility to the disease, but they experience onset in their late 60s, 70s and 80s with slower progression. That leaves a sizeable proportion of idiopathic cases—ones without an identified cause, genetic or otherwise. However, every year more genetic risk factors are discovered, and it is possible that every case will eventually be traced to some genetic susceptibility. The idea offers mixed hope, as sorting out the genetics will not necessarily tell us how to intervene in the disease. For the present, only one risk factor is completely reliable: advancing age.
Why is aging such an important risk factor? To date there are only a few speculations about the mechanism of an old-age trigger for Alzheimer's disease. One of these models suggests that an age-associated decrease in the all–important, energy–containing molecule adenosine triphosphate, or ATP, is responsible. Neuronal ATP is reduced in the aging brain, and neurons need lots of it—more than most other cells, even at rest. Without ATP, the cells may be unable to reestablish their equilibrium and defend against the neurotoxic effects of the Alzheimer's peptide.
» Post Comment