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The cholinergic hypothesis of Alzheimer's disease

K. Siegfried
Central Clinical Research/Neuroscience, Hoechsl AG, ~)'anhji~rt ( M ), Germany

Key wor&." Cholinergic system; Alzheimer's disease; Velnacrine

Summary

The purpose of this paper is to discuss the usefulness of the central cholinergic deficit hypothesis of Alzheimer's disease
(AD) as the basis for a treatment approach in the light of clinical data obtained with velnacrine, a cholinesterase inhibitor. The
paper will also try to point out the limitations of the cholinergic treatment strategy and characterize its specificity.

Introduction

In the late "70s/early '80s, biochemical studies conducted on autopsy brain tissue of patients with AD by several separate
research groups had consistently brought about marked deficits in the cholinergic system (see Siegfried, 1992): in comparison
to age-matched controls, patients with AD were reported to have significantly (i.e., up to 90%) reduced levels of the enzyme
choline acetyltransferase (CAT) in major cortical areas. In addition, high affinity choline uptake and choline synthesis were
found to be decreased as well as cholinesterase. Although reductions were also observed in other neurotransmitter systems the
cholinergic deficit represents 'the most consistent and most extensive neurochemical abnormality yet detected', according to a
review of brain chemistry studies made by Perry in 1987 (p, 890). In addition to the above-mentioned autopsy findings, the
following observations lent support to the central cholinergic deficit hypothesis of AD: the cholinergic deficit was found in
brain areas known to be most strongly affected by AD, i.e., the hippocampus and temporal cortex as well as prefrontal and
parietal cortical regions. The degree of the cholinergic deficit proved to correlate with both the number of senile plaques in the
patients' brains and dementia scores they had obtained in certain scales before their death. Furthermore, pharmacological
studies of compounds which cause a blockade of central cholinergic receptors (e.g., atropine, scopolamine) were found to
show both in animals and in humans impairments of attention, short-term and recent memory which resembled cognitive
dysfunction observed in dementia patients. These cognitive deficits could be improved and reversed by the administration of
the cholinesterase inhibitor physostigmine or by arecoline, a cholinergic agonist. The multiple sources of evidence enumerated
above converged to the assumption that a cholinergic treatment strategy is beneficial for patients with AD.

Results obtained with cholinergic treatments

Initial attempts to enhance cholinergic function by increasing the availability of a precursor of acetylcholine, choline
(lecithin), proved to be largely unsuccessful. Conflicting results were obtained with cholinergic agonists, presumably because
the function of the different postsynaptic cholinergic receptor subtypes (M l, M2, nicotinic receptors) in AD was not well
understood. Most consistent were the results of several pilot studies with the cholinesterase inhibitor physostigmine which
both in healthy subjects and in patients with AD showed mild effects on cognitive functions (see Bartus et al., 1987: Siegfried,
1992). Due to its very short elimination half-life and problems in bioavailability, the effects of physostigmine were, however,
very mild and short-lasting and therefore of no clinical relevance. This is why new compounds have been developed which
have the same biochemical mode of action but more promising pharmacokinetic properties. These are expected to have more
robust and sustained effects than physostigmine. Velnacrine, a tetrahydroaminoacridine, is an example of such a
cholinesterase inhibitor. By now the compound has been tested in approximately 150 healthy volunteers and in more than
1600 patients with "probable AD" (according to NINCDS-ADRDA criteria) and a mild to moderately severe degree of the
disease (Folstein Mini-Mental Scale total score 10 27) (Siegfried and Murphy, 1991, 1993). Double-blind placebo-controlled
pharmacodynamic studies with velnacrine demonstrated that even single doses can significantly improve cognitive
deterioration induced by scopolamine in healthy volunteers, enhance recent memory functions in patients with AD and
increase regional cerebral blood flow (SPECT) in prefrontal and parietal areas (Siegfried, 1993b). Double-blind placebo-
controlled treatment studies of different durations have consistently shown that the compound has significant effects on core
symptoms of AD (as measured by the cognitive subscale total score of the Alzheimer's Disease Assessment Scale (ADAS) and
the Clinical Global Impression of Change (CGI-Change); see Siegfried and Murphy, 1991, 1993). Finally, a recent interim
analysis of a 6-month double-blind placebo-controlled parallel group study conducted in the USA (Prot. 301) produced
evidence that treatment with velnacrine has sustained effects. Approximately 40% of all patients treated proved to be
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responders (according to a predefined response criterion of ~>4 points on the A DAS Cognitive Total; US Study 201) without
having any significant tolerability/safety problems; another 15 20% responded but had also side effects. On average,
velnacrine's effects on the dementia syndrome were only of a moderate degree; however, a subgroup of approx. 1(~15% of all
patients showed a dramatic improvement. Attempts to find a set of clinical, demographic or pharmacokinetic predictors of
response have hitherto been without much success. Velnacrine's main side effects are peripheral cholinergic effects (e.g.,
nausea~ stomach pain) and (reversible) elevations of transaminases.

Discussion

The results obtained with aminoacridines like velnacrine demonstrate that the central cholinergic deficit hypothesis has led
to a first generation of effective AD agents. However, clinical results also leave some unanswered questions and indicate some
limitations: a cholinergic therapy can obviously improve core symptoms of the dementia of the Alzheimer type and at best also
slow down but not stop the disease process. The observation that only 4(~60% of the patients responded and only a smaller
subgroup showed marked effects suggests that patients with AD represent a pharmacologically heterogeneous population.
Clinical, biochemical or other markers that are able to subtype patients and could serve as predictors of response still need to
be found. Increases in responder rates and average effect size may be obtained when using agents that influence multiple
neurotransmitter systems, for example the noradrenergic and serotoninergic system in addition to the cholinergic system.
It is concluded that cholinergic therapy represents a symptomatic treatment of core features of the dementia syndrome. A
symptomatic treatment is, by definition, not disease-specific; however, cholinergic compounds seem to have effects which are
directed at a major pathophysiologic characteristic of AD. Also other types of progressive dementias (e.g., Parkinson's
disease; progressive supranuclear palsy), Korsakofl's syndrome (alcoholic amnestic disorder) and even cognitive aging seem to
be related to some, though most probably smaller degrees of cholinergic pathology (Bartus et al., 1987; Perry, 1987). It is also
not unlikely that subgroups of multi-infarct dementias show some degree of cholinergic deficit, depending on where the lesions
(infarcts) are located. It is therefore speculated that the cholinergic deficit hypothesis describes a dysfunction of a certain brain
system that occurs at some stage of the pathogenesis of perhaps several age-related diseases and represents a common
pathway. This stage seems to be characterized by a damage of the central cholinergic system (e.g., degeneration of cholinergic
axons and cell bodies) which is particularly marked in AD and leads to certain cognitive syndromes (e.g., disorders of
attention and the central executive of working memory; recent memory; semantic memory). Depending on whether the
cholinergic deficit is more confined to certain subsystems or more widespread, this may result in the occurrence of an amnestic
or confusional syndrome or in a dementia syndrome.

References

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