Lengthy Prodromal Phase of MCI and Alzheimer's Disease

Megan Brooks

March 16, 2011

March 16, 2011 — The diagnosis of Alzheimer's disease (AD) and its precursor, mild cognitive impairment (MCI), is preceded by 5 to 7 years of progressively accelerating decline in memory and thinking skills, according to a study in the March issue of Archives of Neurology.

"The length of this prediagnosis period of decline was surprising, particularly for mild cognitive impairment," first study author Robert S. Wilson, PhD, of the Rush Alzheimer's Disease Center in Chicago, Illinois, told Medscape Medical News. "For example, the amnestic type of mild cognitive impairment was preceded by an average of nearly 7 years of increased cognitive decline."

'Extremely Important' Finding

Gustavo C. Román, MD, medical director of the Nantz National Alzheimer Center at the Methodist Neurological Institute in Houston, Texas, said, "The main lesson is that by the time we put the label of Alzheimer's disease on a patient, you have lost 5 to 7 years of interventions and that's extremely important."

It's generally assumed that treatments for AD and MCI will be more effective if started as early as possible, before significant cognitive problems set in. "We need to let people know that if they suspect memory problems, they should not hesitate to come in," said Dr. Román, who was not involved in the study.

"Although we still don't have an actual cure or mechanism to stop the progression, I think there are enough vascular risk factors that can be controlled and need to be looked for in patients who complain of memory problems." He added that with early imaging studies, "we should be able to see some changes that correlate with the memory loss."

Years of Early Warning

By definition, dementia due to AD is preceded by a minimum of 6 months of cognitive decline, Dr. Wilson and colleagues note in their article. They characterized the course of cognitive decline during the prodromal phases of AD and MCI in more than 2000 elderly individuals enrolled in 2 ongoing longitudinal studies — the Religious Orders Study, which began in 1994, and the Rush Memory and Aging Project, which began in 1997. All participants were followed up annually with cognitive function tests for up to 16 years.

During follow-up, 462 individuals developed AD. Among these, the rate of global cognitive decline "increased sharply" about 5 to 6 years before diagnosis, the investigators report. "After AD was diagnosed, there was a further increase of about one-third in annual rate of global cognitive decline," they note.

The acceleration in cognitive decline occurred slightly earlier for semantic memory (76 months before diagnosis) and working memory (75 months before diagnosis) than for other cognitive functions.

The study also showed that MCI is preceded by roughly 4.5 years of gradual global cognitive decline, "with a further doubling in the rate of decline after MCI was diagnosed."

Cognitive decline in MCI began earlier in the amnestic than in the nonamnestic subtype (80 vs 62 months before diagnosis) and proceeded more rapidly. This finding is "consistent with neuropathologic and neuroimaging data suggesting that medial temporal lobe structures that support episodic memory are among the first brain regions affected by the disease," the investigators say.

"These results," Dr. Wilson added, "indicate that Alzheimer's disease has a much longer symptomatic course, and we think that this may be preceded by a period of similar length during which pathologic changes are accumulating in the brain but not yet producing symptoms.

"We also think that there is a lot of variability in how well people cope with these very early stages of the disease and that important clues on how best to delay the disease may come from studying those who have been more successful in coping with it," he added.

Consistent with prior research, the study also found little cognitive decline in subjects who did not develop MCI or AD during follow-up, suggesting, the investigators say, that cognitive decline "may not be an inevitable consequence of old age."

The study was supported by the National Institute on Aging and the Illinois Department of Public Health. The study authors and Dr. Román have disclosed no relevant financial relationships.

Arch Neurol. 2011;68:351-356.

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