November 8, 2010
For Edge on Alzheimer’s, Hunting Its Early Signs
By PAM BELLUCK

Much of the research on Alzheimer’s next year will be about going back in time, trying to determine when and how the brain begins to deteriorate.

Scientists now know Alzheimer’s attacks the brain long before people exhibit memory loss or cognitive decline. But the specifics are crucial because so far, drug after drug has failed to effectively treat Alzheimer’s in people who already show symptoms. Many scientists now think the problem may be that the drugs were given too late, when, as Dr. John C. Morris, an Alzheimer’s expert at Washington University in St. Louis, puts it, “there’s a heck of a lot of brain cell damage and we’re trying to treat a very damaged brain.”

If drugs could be given sooner, tailored to specific biological changes, or biomarkers, in the brain, treatment, or even prevention, might be more successful.

“We’re trying to go earlier and earlier in the course of the disease,” said Neil Buckholtz, chief of the Dementias of Aging branch at the National Institute on Aging. “The idea is to locate how people move through these stages and what indications there are of each stage.”

Several research projects are expecting to make strides next year.

One involves the world’s largest family to experience Alzheimer’s disease, an extended clan of about 5,000 people in Colombia, many of whom have inherited a genetic mutation that guarantees they will develop dementia, usually in their 40s. Except for its clear genetic cause and that it strikes people so young, the Colombian condition is virtually identical in its disease process to more common Alzheimer’s, which has unknown causes and afflicts millions of elderly people.

A team of American and Colombian scientists plans to test treatments on Colombians in their late 30s and early 40s who are destined to get Alzheimer’s but have not yet developed symptoms to see if dementia can be prevented or significantly delayed. The treatment, to be chosen by an independent panel, will be a drug or vaccine that attacks beta-amyloid, the protein associated with plaques, deposits between nerve cells. A project leader, Dr. Eric Reiman, director of the Banner Alzheimer’s Institute in Phoenix, said testing on as many as 2,000 people, including about 750 with the mutation, is likely to begin late next year or early in 2012.

Meanwhile, the project, begun this year, has had some tantalizing findings. To try to find the youngest age at which brain changes appear, brain scans, spinal taps and memory tests were conducted with 44 family members, ages 18 to 26.

While Dr. Reiman said he could not discuss specific data yet, the tests showed enough evidence of Alzheimer’s-related biomarkers on people with the mutation that fMRI brain scans will be done on even younger family members, ages 8 to 17. If the scans reveal children with the mutation have Alzheimer’s-like anomalies, like atrophy in the hippocampus, which is involved in forming new memories, that would suggest the brain begins transforming decades before symptoms appear.

To examine when beta-amyloid begins accumulating, the project will also conduct amyloid imaging on an additional 50 family members, age 18 and older.

Dr. Reiman’s team also plans to test drug treatments on an unrelated group: 60- to 80-year-old Americans with a different rare trait: two copies of the ApoE4 gene, which does not cause but increases risk of common Alzheimer’s.

A different project, the Dominantly Inherited Alzheimer Network, or DIAN, led by Dr. Morris, is studying members of families in the United States, Australia and Britain who have mutations that cause dementia at age 46, on average. DIAN has recruited 100 people, 18 and older, whose parents had Alzheimer’s-causing mutations but who do not yet show symptoms; it plans to recruit 300 more. So far, researchers have found evidence that “biomarker changes do seem to occur at least 10 years, maybe 20 years before the age of onset” of symptoms, Dr. Morris said.

DIAN also plans to test drugs on participants, hopefully within three years, and is talking with companies, which are interested, but need assurance that testing drugs on apparently healthy people, those without symptoms, is worth the investment and potential risk, Dr. Morris said.

The Colombia and DIAN projects are “really the first time companies have come to grips with this,” said Dr. Morris, who believes Alzheimer’s is so complex that a combination of drugs will be needed to attack different biomarkers.

Another project looking for early signs is the Alzheimer’s Disease Neuroimaging Initiative, or ADNI, a collaboration of government and industry, involving scientists at 55 research sites in the United States and Canada. It has been following about 800 people for about six years and has yielded significant findings about changes in the hippocampus, and about screening for Alzheimer’s proteins with PET scans and spinal fluid tests.

ADNI will recruit 550 more participants, including many with budding memory loss called early mild cognitive impairment.

They will be, Dr. Buckholtz said, “not quite as sharp as they were previously, but not to the point where they are really forgetting.”