By William J. Cromie

Gazette Staff

The mystery of what caused as many as 128 cases of early-onset Alzheimer's disease among an exceptionally large family group in Colombia has been solved. An international team of researchers, including neurologists from the Medical School, found that the Colombians all have the same genetic mutation.

It was a neat piece of scientific detective work, described in a recent issue of the Journal of the American Medical Association, but it leads to a horrendous dilemma.

Every one of 2,892 known relatives of these people, who have the same mutation, will also get Alzheimer's. Those too young to develop the disease, including babies in the womb, can be tested for the mutation before any mind-destroying symptoms occur. But if the result is positive, these people will discover that they have a terrible infirmity for which no cure exists.

"Individuals can determine if, but not when, they will get Alzheimer's," notes Kenneth Kosik, professor of neurology. "Would you want to know? If you have the gene but no symptoms, do you have a disease? Will knowing about the future affect your eligibility for a job, insurance coverage, and disability benefits?"

As yet, there are no good answers to these questions.

Nor is there a solution to another mystery raised by the discovery. Some who carry the sickening mutation get the disease in their early 30s, others not until their mid-50s. If it's all due to the same mutation, why do some develop Alzheimer's 20 years after others?

"If we could learn what factor, or factors, delay early-onset Alzheimer's, we might be able to delay the onset of the conventional form of the disease," Kosik speculates. "That form usually occurs after age 65, so a delay of 20 years could be like a cure."

Kosik and his colleagues found no major differences in the autopsied brains of the relatively young Colombians and elder victims of Alzheimer's. He is hopeful that further study of the family will reveal information about how all people get the disease, and provide clues about how an incurable malady might be made curable.

Certain Death

While doing research in Colombia five years ago, Kosik met Francisco Lopera of Antioquia University School of Medicine, who told him about a large number of cases of early-onset Alzheimer's. These people live in villages around Medellín and all of them seemed to be related by names and genes.

A search by Kosik, Lopera, and their Antioquia colleagues turned up 3,000 people in five related family groups. Of these, 128 had or were suspected of having early-onset Alzheimer's. Typical symptoms include memory loss followed by negative changes in behavior and personality, such as aggressiveness or loss of interest in everything. They progressively lose their ability to converse. In later stages of the disease, they have trouble walking and experience seizures and muscle spasms.

One victim, a 47-year-old bankrupt coffee farmer, had started losing his memory before Lopera's team first saw him. His family reported that he often forgot their names and had difficulty initiating or following a conversation. He began to wander and sometimes did not seem to recognize his own house. Later, he had difficulty walking and was struck by frequent seizures. He died at age 50.

Another patient, a middle-aged housewife, grew agitated and aggressive after an onset of memory loss. She wandered aimlessly, neglected her personal hygiene, and could not speak normally. Later, she developed incontinence and muscle jerks of her trunk. She died at age 47.

Of the 128 cases of proven, probable, and possible Alzheimer's, 66 were men and 62 women. Average age of onset of the disease was about 47, although the youngest patient was only 34. Victims lived an average of only eight years after their symptoms began.

Kosik and Lopera's group, joined by a team from Washington University in St. Louis, traced the problem to a gene called presenillin 1, first identified in 1995. Of the 3,000 people in this extended family, many carry the mutation that will cut their lives short.

The mutation can be passed on from either parent, or from both parents. Once it is inherited, the chance of getting the disease and dying at an early age is 100 percent.

The Colombians are caught in the same burdensome situation as those with Huntington's disease, another type of dementia characterized by involuntary, jerky motions and mental impairment. Physicians can determine with high accuracy if someone carries the abnormal gene that inevitably leads to Huntington's, but they cannot provide a cure.

Brain Damage

Six of the Colombians, including the two described earlier, have undergone autopsy. Their brains show more damage of the cerebellum, or balance center, than suffered by victims of conventional Alzheimer's. But nothing has been found to reveal why some get the disease 20 years sooner than others.

"There must be some genetic or environmental factor that controls the onset of the disease," Kosik says.

At this stage, there is no obvious clue in the environment. The great majority of the people live in the same rural area in the high plains of western Colombia. They are poor and not well-educated. Most of the men labor on coffee farms and the women work as housewives.

Alternately, another gene could switch presenillin 1 on at an age that varies from person to person. "We are looking at the families to see if we can identify such a modifier," Kosik notes. "We want to know, if someone gets a mutated gene from both their mother and their father, will that cause an earlier onset, or a more severe form of the disease, than a single mutated gene?"

Once the abnormal gene is turned on, researchers have only a sketchy idea of what happens. In other experiments done by Medical School researchers, Dennis Selkoe, professor of neurology, and his collaborators found that a mutated human presenillin 1 gene doubles production of a protein known as amyloid beta in the brains of mice.

Unaffected brains make the same protein, showing that it is something that the body needs. Too much of it, however, forms plaques that surround connections between brain cells, preventing normal communications between its separate areas. Autopsies of those who die of Alzheimer's show masses of such plaques and stringy tangles that savage the ability of a brain to direct the operation of memory, language, behavior, and gait.

It seems like a little amyloid beta is normal, a lot is mind-numbing, and, if overproduction begins at a young age, the result is early-onset Alzheimer's. The early variety strikes an estimated 5 percent of Alzheimer's patients, or some 20,000 people in the United States.

"Mutations of the presenillin 1 gene are far and away the major cause of inherited early-onset Alzheimer's disease," Kosik says.

Since not much difference exists between behavior and the condition of the brain in both early and conventional Alzheimer's, new information about the former may help solve mysteries of the latter. For example, Selkoe and his colleagues are looking for drugs that turn down the production of amyloid beta. Kosik and his collaborators want to find and change the mechanism that starts the relentless Alzheimer's clock ticking too early.

"By studying the Colombian families," Kosik says, "we may be able to help both those who can learn if they will get Alzheimer's and those who are stricken in their 60s, 70s, and 80s."