A preclinical phase of Alzheimer’s disease appears to begin years or decades before the onset of dementia—and researchers hope to prevent dementia by providing treatment during this phase.

SAN DIEGO—Researchers’ emerging ability to detect Alzheimer’s disease years before the onset of clinical symptoms may pave the way for an effective treatment, said Reisa Sperling, MD, at the 136th Annual Meeting of the American Neurological Association. Dr. Sperling, Associate Professor of Neurology at Harvard Medical School, Boston, headed a workgroup responsible for formulating recently adopted guidelines on the disease’s preclinical stage.

“Since we put forth the criteria for preclinical Alzheimer’s disease, the question I have heard most often is, ‘Why would you possibly want to diagnose Alzheimer’s disease even earlier if there’s absolutely nothing you can do about it?’” she said. “But I believe early diagnosis is how we’re going to be able to do something about it.”

A Long Pathophysiologic Process
The pathophysiologic process of Alzheimer’s disease is now believed to begin years and probably more than a decade prior to dementia, Dr. Sperling noted. “Amyloid accumulation in the cortex, particularly in the default network, is associated with functional and structural changes before we can see clear clinical symptoms,” she said.

Recent research suggests that such accumulation is highly prevalent in older, asymptomatic individuals. By using the amyloid tracer Pittsburgh Compound-B, investigators have found that about one-third of this population has amyloid accumulation at nearly the same levels and in the same distribution as patients with clinical Alzheimer’s disease dementia. These findings confirm those of autopsy studies, which indicate that about a quarter to a third of older individuals who were asymptomatic at the time of death had neuropathologic changes associated with the disease.

Other findings suggest that it may be too late to treat patients for Alzheimer’s disease once they progress from preclinical disease to mild cognitive impairment (MCI), Dr. Sperling added. Memory-related fMRI studies indicate that patients with MCI experience increasing failure of the hippocampus over two years and that loss of hippocampal activation is associated with clinical decline. Patients with early MCI tend to experience paradoxical hyperactivity in the hippocampus, possibly indicating excitotoxicity and impending neuronal failure. “Even if you could suck all the amyloid out of the brain, you’d be unlikely to grow these neurons back,” Dr. Sperling said. “We have to go back and treat even earlier if we’re really going to save the hippocampus.”

During the course of Alzheimer’s disease, changes in the hippocampus appear tightly coupled with changes in the default network, she said. Activity in the parietal cortex—and, in particular, the posterior cingulate and the precuneus—is just as predictive as activity in the hippocampus with regard to whether a person will retain a memory for 30 minutes. A high amyloid burden is associated with failure of default network activity both during memory encoding and at rest. In addition, the hippocampus and the posterior cingulate are no longer functionally connected to each other in asymptomatic older individuals with amyloid accumulation.

Prediction and Treatment Possibilities
Researchers are now focusing their prediction and treatment efforts on the disease’s preclinical stage, said Dr. Sperling.

With regard to prediction, “You might ask, ‘How can you walk around with a head full of amyloid for 10 years and not show evidence of cognitive impairment?’” she said. “I think part of the answer is that we haven’t been looking hard enough.”

Using more challenging memory tests may uncover subtle cognitive decline in apparently asymptomatic persons, according to Dr. Sperling. Among such individuals, those with a high amyloid load perform significantly worse on challenging tests than do those with a low amyloid load. In addition, higher IQs and education levels appear to represent a “cognitive reserve” that protects against the effects of amyloid accumulation. A relationship between amyloid accumulation and poor memory is much more common in persons who lack such reserve, Dr. Sperling said.

The proposed Anti-Amyloid Treatment in Asymptomatic AD (A4) trial, which is being considered by the Alzheimer’s Disease Cooperative Study, would attempt to treat older individuals with preclinical Alzheimer’s disease. The trial would provide older, asymptomatic persons with a biologically active compound intended to decrease amyloid accumulation, Dr. Sperling explained.

“We’ll test the hypothesis that changing upstream amyloid accumulation will have an impact on downstream neurodegeneration and the likelihood of progression toward MCI and Alzheimer’s disease dementia,” she said. “This might be considered somewhat controversial, because not all of these individuals who have early changes will indeed progress toward those stages. But not everybody with hypercholesterolemia progresses to stroke, either—and most of us still think it’s a good idea to treat it.”

—Jack Baney

Can Early Detection of Alzheimer's Disease Lead to an Effective Treatment?