The cholinergic theory of Alzheimer's disease holds that the loss of choline acetyltransferase and acetylcholinesterase causes at least some of the cognitive decline that occurs in patients with this dementing illness. Davis and associates conducted a study to determine whether the cholinergic deficits occur before or after the cognitive deficits.

Eighty-one study subjects were selected from a group of 278 consecutive patients on whom autopsies had been performed. After a record review, the patients were assigned a Clinical Dementia Rating (CDR) score, based on cognitive and functional status over the past six months of their lives. Based on neuropathologic assessment at autopsy, the following patients were excluded from the study: those with Pick disease, diffuse Lewy body disease, Parkinson's disease, stroke, multi-infarction dementia or severe cerebrovascular disease. A variety of sections were examined for signs of neuropathologic lesions (specifically, neurofibrillary tangles and neuritic plaques); these were correlated with cholinergic enzyme markers in the same regions. Patients were given CDR scores of 0.0, 0.5, 1.0, 2.0 and 4.0 to 5.0 (13 of 18 patients in the 0.0 group did not have Alzheimer's disease; 15 of 15 patients in the 4.0 to 5.0 group had definite Alzheimer's disease).

Patients with CDR scores of 4.0 to 5.0 had significantly less choline acetyltransferase and acetylcholinesterase activity than those with lower CDR scores. However, when the group with definite Alzheimer's disease (CDR scores of 4.0 to 5.0) was excluded, choline acetyltransferase activity did not correlate with CDR scores. For example, those with CDR scores of 1.0 (one half of whom had definite Alzheimer's disease) did not have lower cholinergic activity than those with CDR scores of 0.0. The 2.0 group did not have cholinergic marker activity that was lower, either. The neuritic plaque density level did correlate with the level of cholinergic activity in various regions.

The authors conclude that a cholinergic deficit does not seem to be an early marker for Alzheimer's disease. This suggests that it is less likely that cholinergic activity could be used to screen for Alzheimer's disease before a patient is symptomatic. Currently approved cholinesterase inhibitors (i.e., tacrine and donepezil) are given to patients with mild to moderate Alzheimer's disease. The authors posit that this study supports the use of such medications in patients with severe disease; that is, patients who actually have a significant cholinergic deficit.

editor's note: More and more anecdotal reports of patients with late-stage Alzheimer's disease receiving donepezil have been appearing in the literature. In these few patients, it seems that there may be a modest functional improvement but an insignificant cognitive change. This study may provide some early support for the theory that these agents should be used to treat end-stage dementia, but realistic expectations must take precedence in family discussions; as similar studies become known to the lay public, such discussions will become more common.—g.b.h.