Alzheimer's Accelerated by Faulty Gene

A particular variant of an immune system gene can hasten the onset of Alzheimer's, according to a study published today in Neurology. Patients with this allele tended to lose their memory and develop other symptoms 3 to 7 years earlier than people without the allele. Those who also carried the apoE4 gene--already associated with accelerated development of Alzheimer's--were likely to show signs of the disease at even younger ages.

The link between the apoE4 gene, which makes a protein involved in fat transport in the body, and Alzheimer's disease was established 5 years ago. But researchers had already begun to suspect an additional player: HLA histocompatibility genes, whose protein products are needed to trigger immune cell activity. Several teams found indications that abnormal immune responses might be involved in Alzheimer's. For example, they noted abnormally high amounts of these HLA proteins in the brains of people with the disease. Other teams had found that anti-inflammatory drugs may delay the onset of symptoms.

The large number of HLA genes complicated the search for the trouble-making genes. But by examining the frequency of the HLA variants in young Alzheimer's patients, Haydeh Payami, a geneticist at Oregon Health Sciences University in Portland, and her colleagues implicated one called HLA-A2. To firm up the link, Payami and her colleagues first looked for the occurrence of HLA-A2 in 111 Alzheimer's patients from eight medical centers.

They found that the HLA-A2 variant is present in about 83% of the people who first showed signs of memory loss before age 50--an incidence about twice that in the general population. A follow-up study of 96 other patients with Alzheimer's disease confirmed that this HLA variant is associated with earlier onset of Alzheimer's, although Payami cautions that another gene very close to HLA-A2, and not HLA-A2 itself, could be at fault.

But if the HLA-A2 gene turns out to be the culprit, then the immune system is probably involved somehow in Alzheimer's symptoms, says Payami, perhaps by damaging nerve cells. These inflammatory reactions are "becoming an area of great interest" to Alzheimer's researchers, says Zaven Khachaturian, a neurobiologist who works with the Chicago-based Alzheimer's Association. "It gives us a lot of hope that it may be possible to delay the age of onset, possibly with drugs or some other approach."