Most Alzheimer’s disease isn’t hereditary; the key risk factor is age, not family history. But if inherited genes can cause the illness, even in rare cases, then zeroing in on those genes should offer general insights into the disease process. The idea that a defective APP gene might cause Alzheimer’s dates back to 1987, when researchers made a pair of tantalizing findings. One team discovered the APP gene on the 21st chromosome. A second team analyzed tissue samples from four Alzheimer’s-prone families and, without pinpointing an actual mutation, traced their trouble to the APP region of chromosome 21. Researchers grew skeptical of the second finding when other high-risk families exhibited perfectly normal copies of the 21st chromosome. But further studies suggested that the disease can involve different genes in different families, so the St. Mary’s researchers kept pursuing the APP connection.
Their persistence paid off. In the current study, they analyzed tissue samples from a family prone to early Alzheimer’s and found that the stricken individuals shared a specific “point mutation” within the APP gene. The mutation didn’t show up in unafflicted members of the same family, nor in 200 healthy individuals from the general population. Yet it did show up in two Alzheimer’s victims from a second high-risk family. Dr. John Hardy, the leader of the St. Mary’s group, says the new finding gives us “more reason than ever” to think that amyloid is the key to the mystery. If this mutation causes the illness by producing unusual amounts of beta amyloid, he says, other mutations might yield the same effect by interfering with enzymes that normally digest it.
Still, the case isn’t closed. The APP mutation could turn out to be nothing more than a marker, says Dr. Peter St. George Hyslop, a prominent Alzheimer’s researcher currently based in Toronto; the true culprit might be a nearby gene that has nothing to do with amyloid production. The beauty of the new finding is that it provides tools for resolving such questions. In future experiments, researchers hope to transplant the aberrant APP gene into lab mice to see what effect it has. If the gene causes something resembling Alzheimer’s disease, the case against amyloid will at last be closed - and researchers working on treatments will know what they’re trying to fix.
