Should we be treating alzheimer's disease now?

A number of approaches to the treatment of Alzheimer’s disease have been under investigation in recent years. Most have been based on trying to correct, albeit temporarily the neurotransmitter changes known to occur in this disease. These changes are now thought to occur ‘downstream’ from the more basic neurobiological changes such as the accumulation o fp A4 amyloid and the abnormal phosphorylation of tau considered by some to be the pivotal events leading to the formation of the characteristic neuritic plaques and neurofibrillary tangles. It is nevertheless recognised that reversal or arrest of these basic disturbances is likely to take some time to be achieved and that in the meantime symptomatic improvement arising from neurotransmitter-based strategies may nevertheless be worthwhile (Levy, 1993). Faced by the need to evaluate such treatment, both the United States Food and Drug Administration (FDA, 1989) and its European equivalent, the Committee for Proprietary Medicinal Products (CPMP, 1992) have drafted guidelines for the design and conduct of clinical trials of ‘antidementia’ drugs. These have in common the need for parallel group placebo-controlled double blind studies lasting not less than three months, evaluated by changes of a predetermined level on widely accepted cognitive tests, on a global measure and (in the case of CPMP) on an improvement in activities of daily living or in the quality of life. Having met the required criteria, the cholinesterase inhibitor tacrine has recently been approved by the FDA and the French regulatory authorities. Active consideration is also currently being given both to this drug and to the related aminoacridine velnacrine by other regulatory bodies in Europe. This makes it imperative that the profession consider how to respond to demands from patients and carers which will inevitably follow. Both tacrine and velnacrine are thought to exert their therapeutic influence through their activity as cholinesterase inhibitors. In therapeutic trials, both have been found to produce symptomatic irnprovement in the treated group as compared to the placebo control group (Eagger et al., 1991; Farlow et al., 1992; Knapp et a1 1994). However, this relatively small therapeutic benefit in the group taken as a whole is a reflection of a very heterogenous response, with some patients showing marked improvement and others remaining unchanged (Eagger et al., 1991). The order of magnitude of the effect is roughly equivalent to the decline which would have occurred over six months in an untreated group. This therapeutic benefit must be set against the potential unwanted effects of the drugs, the most frequent of which are nausea, vomiting and elevation in liver enzymes in some patients. The task is facilitated by the fact that improvement will usually manifest itself in the first month (Eagger et al., 1992) and signs of liver toxicity have hitherto always emerged within the first three months and have invariably been reversible (Eagger et al., 1991; Watkins et al., 1994). It is recommended that patients taking aminoacridines should receive twoweekly (once weekly in the US) liver function tests for the first three months and be tested at longer intervals thereafter. The case for early diagnosis previously based on the largely theoretical advantages that may accrue from the opportunity for early planning and the avoidance of crises now acquires important empirical support since the type of systematic improvement achieved by neurotransmitter-based therapy is likely to be most worthwhile in cases where the disease has not progressed too far. The need for such early and specific diagnosis together with the cost of the drug ($3 a day in the United States) and the need for regular monitoring of liver function is likely to prove beyond the resources of the average general practice and place an additional burden on the already overstretched psychogeriatric, geriatric and neurological services. This will need to be balanced against both the cost of the disease itself and of its effects on carers. Estimates suggest that 635,735 in the UK suffer