ABSTRACT
Nearly 10 years after the dramatic success of L-dopa therapy for Parkinson’s disease, it seemed that a similar treatment approach for Alzheimer’s disease (AD) may be on the horizon when substantial presynaptic cholinergic abnormalities were found in the post-mortem brains of affected individuals (see Chapter 29). The results so far have been relatively modest which may not be surprising if we reconsider that these were rather overoptimistic and unrealistic expectations. First, even quite marked cholinergic loss is not necessarily associated with cognitive impairment. For instance, studies of Parkinson’s disease show that choline acetyltransferase (ChAT) loss is more severe in patients with dementia than in those without, despite the fact that plaque densities are similar (Perry et al., 1985). While this supports the cholinergic hypothesis, the fact that ChAT levels are also reduced in non-demented patients appears to challenge this. Olivopontocerebellar atrophy (OPCA) also presents an interesting conundrum. For example, in one pedigree the patients show a 40-50 per cent reduction in ChAT levels in temporal and frontal cortex, 20-40 per cent decrements in hippocampus and degeneration of the nucleus basalis of Meynert (nbM), but no evidence of dementia (Kish et al., 1990). One possible interpretation of these data would be to suggest that the importance of forebrain acetylcholine (ACh) in cognition and memory may have been overestimated. By extrapolation then, the cognitive deficits occurring as a direct result of loss of ACh may be quite subtle, so it is perhaps not surprising that cognitive benefits resulting from increasing ACh levels are small. What is becoming clear is that the cholinergic deficit seen in any chronic brain disease may be the result of a variety of insults, rather than the cause of a specific condition like AD.
