The study is published in the February 2002 Annals of Neurology.

The study may help point the way to even more effective use of the drugs -- or to new therapies altogether.

The researchers focused on brain structures known to be affected by Alzheimer's disease and failed to find predicted deficits in the signaling molecule (or "neurotransmitter") acetylcholine (ACh) in subjects in the earliest stages of the disorder.

"This report is newsworthy because it challenges the rationale for current Alzheimer therapy, which has been the premise that acetylcholine deficits exist early in the illness and contribute to clinical symptoms such as memory impairment," said John C. Morris, M.D., of the Washington University School of Medicine, who wrote an editorial accompanying the article.

The research team in the current study, led by Steven T. DeKosky, M.D., of the University of Pittsburgh, measured brain levels of an ACh-synthesizing enzyme that has been shown to correlate well with actual levels of the neurotransmitter.

Their subjects were elderly priests and nuns who had died while enrolled in the ongoing Religious Orders Study run by Rush Medical School in Chicago. They ranged in age from 66 to 98 years at the time of death.

Within six months before they died, the subjects had undergone a thorough psychological examination and had been assigned one of three diagnoses: normal, mild cognitive decline (MCI), or mild or moderate Alzheimer's disease. A diagnosis of MCI requires some loss of memory and is considered by many researchers to represent the earliest stages of Alzheimer's.

When they compared the brains of 58 normal subjects with those of 18 with MCI and 14 with mild Alzheimer's disease, the researchers in this study were surprised to find elevated, rather then reduced, levels of the ACh enzyme marker in several critical brain areas of the MCI subjects relative to the normal subjects.

This observation runs counter to the theory that the ACh system is depleted in early Alzheimer's.

"This indicates that as the pathology of Alzheimer's disease is developing in the human brain, parts of the acetylcholine system are probably up-regulated as a compensatory response, perhaps to try to maintain normal function," said DeKosky.

In particular, the marker was elevated in the hippocampus and frontal cortex, critical for memory and cognitive functions and which are some of the most vulnerable brain areas in Alzheimer's disease.

A second finding of the study puts the idea of ACh depletion in early stages of the disease into further doubt: subjects with a diagnosis of mild-to-moderate Alzheimer's disease had levels of the enzyme comparable to the normal subjects, even in the hippocampus and frontal cortex.

Still, the cholinesterase inhibitors currently used to try to boost ACh levels in patients who are in the early stages of the disease do seem to improve patients' ability to think.

Taken together with the study's results, this fact suggests to both DeKosky and Morris that researchers should focus on identifying which underlying destructive processes might be triggering the acetylcholine system to increase its activity in patients in the early stages of the disease.

In addition, DeKosky noted, "Since the acetylcholine system is clearly perturbed later in the disorder, controlled studies of the cholinesterase inhibitors should be undertaken in more advanced Alzheimer's disease."

05-Feb-2002