Drugs called cholinesterase inhibitors have shown modest benefits for patients with mild to moderate Alzheimer's. In the February Annals of Neurology, researchers led by Steven DeKosky, of the University of Pittsburgh, challenge the prevailing theory of how these drugs work.
Focusing on the hippocampus and frontal cortex-brain areas critical for memory and cognitive functions that are particularly vulnerable in Alzheimer's disease-the researchers failed to find predicted deficits in the cholinergic system in subjects with early AD. They measured brain levels of choline acetyl transferase (ChAT), an acetylcholine-synthesizing enzyme known to correlate with actual levels of this neurotransmitter.
"This report challenges the rationale for current Alzheimer therapy, which has been the premise that deficits exist early in the illness and contribute to clinical symptoms such as memory impairment," said John C. Morris of Washington University School of Medicine, who also wrote an accompanying editorial.
The subjects were priests and nuns who had died between the ages of 66 to 98 while enrolled in the ongoing Religious Orders Study run by Rush Medical School in Chicago. Within six months before they died, the subjects had undergone a psychological examination and been assigned one of three diagnoses: normal, mild cognitive impairment (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 incipient AD.
Surprisingly, a comparison of the brains of 26 normal subjects with brains of 18 MCI subject and 14 Alzheimer's subjects showed elevated rather than reduced ChAT levels in hippocampus of the MCI subjects relative to the normal subjects. Subjects with a diagnosis of mild-to-moderate Alzheimer's had levels comparable to the normal subjects. This runs counter to the theory that the cholinergic system is depleted in early Alzheimer's. "This indicates that as the pathology of Alzheimer's disease is developing, parts of the acetylcholine system are probably upregulated as a compensatory response, perhaps to try to maintain normal function," said DeKosky.
Still, the cholinesterase inhibitors currently used to boost ACh levels in patients in the early stages of the disease do seem to improve patients' ability to think. Taken together with the study's results, this 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." For detailed information, see comments below.—Hakon Heimer
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