To answer my own question, yes it would appear a reduction in brain atrophy would give us a drug, it would be considered a "neuroprotective effect". Donezepil has never claimed congnitive benefits but relieves other symptoms (or does it?).
Further Information on Donepezil:
Does Donepezil Treatment Slow the Progression of Hippocampal Atrophy in Patients With Alzheimer’s Disease?
OBJECTIVE: The only approved pharmacological approach for the symptomatic treatment of Alzheimer’s disease in Japan is the use of a cholinesterase inhibitor, donepezil hydrochloride. Recent in vivo and in vitro studies raise the possibility that cholinesterase inhibitors can slow the progression of Alzheimer’s disease. The purpose of the present study was to determine whether donepezil has a neuroprotective effect in Alzheimer’s disease by using the rate of hippocampal atrophy as a surrogate marker of disease progression. METHOD: In a prospective cohort study, 54 patients with Alzheimer’s disease who received donepezil treatment and 93 control patients with Alzheimer’s disease who never received anti-Alzheimer drugs underwent magnetic resonance imaging (MRI) twice at a 1-year interval. The annual rate of hippocampal atrophy of each subject was determined by using an MRI-based volumetric technique. Background characteristics, age, sex, disease duration, education, MRI interval, apolipoprotein E (APOE) genotype, and baseline Alzheimer’s Disease Assessment Scale score were comparable between the treated and control groups. RESULTS: The mean annual rate of hippocampal volume loss among the treated patients (mean=3.82%, SD=2.84%) was significantly smaller than that among the control patients (mean=5.04%, SD=2.54%). Upon analysis of covariance, where those confounding variables (age, sex, disease duration, education, MRI interval, APOE genotype, and baseline Alzheimer’s Disease Assessment Scale score) were entered into the model as covariates, the effect of donepezil treatment on hippocampal atrophy remained significant. CONCLUSIONS: Donepezil treatment slows the progression of hippocampal atrophy, suggesting a neuroprotective effect of donepezil in Alzheimer’s disease.
And another interesting piece that mentions placebo groups which over perform and reasons why in the subsequent answer:
The cholinergic hypothesis of Alzheimer’s disease: a review of progress T BABIC
Department of Neurology, Medical School University of Zagreb, Croatia.
I read with interest the review of Franciset al regarding the progress of the cholinergic hypothesis of Alzheimer’s disease.1 They mentioned that donepezil produced improvement or no deterioration in more than 80% of patients, and that such responses should be viewed positively considering the progressive, degenerative nature of the disease. Various donepezil manufacturer’s medical representatives presenting data from a clinical study2 also commonly use this statement. However, this only partially reveals the truth. In fact, the same study produced improvement or no deterioration in 59% patients on placebo. I think that the beneficial effect of donepezil in particular clinical trials should always be critically reviewed in comparison with placebo. In addition, as both 24 week placebo controlled donepezil trials performed so far excluded patients with behavioural disturbances, my impression is that the positive effect of donepezil on the symptoms of behavioural disturbances still remains controversial. In fact there are reports that donepezil might induce behavioural disturbances in patients with Alzheimer’s disease.3 4 Therefore I would be extremely cautious about prescribing donepezil to patients with Alzheimer’ s disease accompanied by behavioural disturbances.
Finally, donepezil was never investigated in a 30 week randomised double blind study as was mentioned in the review. The authors are probably referring to the randomised 24 week double blind placebo controlled trial with an additional 6 week single blinded placebo phase.
PAUL T FRANCIS Neuroscience Research Centre, GKT School of Biomedical Science, King’s College London, London SE1 9RT, UK
We thank Professor Babic for the letter, which raises several interesting points. We agree that it may be more helpful to put the results attributed to treatment with donepezil in the context of the placebo response. In general, looking at this as a class effect in relation to several compounds, the picture emerging is that about twice as many people obtain a response to active treatment as to that with placebo. The high placebo response is a common factor in most studies in this field and is worthy of some explanation in its own right. Although it seems that these studies compare drug treatment with that of a placebo (one treatment against no treatment), the reality is that it is a comparison of patients receiving two treatments against other patients who are receiving one form of treatment. The additional treatment regime is, of course, the care and attention that they receive by being part of the clinical study, which often seems to have an impact, not just on the patient but also on their main carer or carers.
As far as behavioural disturbances are concerned, however, our review was making the point that evidence is emerging from clinical trials to suggest that cholinomimetic drugs as a whole may have a beneficial effect on some non-cognitive behavioural symptoms. This has now been reported for at least two cholinesterase inhibitors, and two muscarinic agonists.1-1-1-5 In particular, a clear link is emerging between psychotic symptoms and cholinergic dysfunction. Thus, Bodick et al 1-2 have shown that the M1/M4 agonist xanomeline causes a dose dependent reduction in hallucinations, agitation, and delusions in a 6 month randomised double blind placebo controlled, parallel group trial. In addition, Cummings and Kaufer1-6 have shown that the cholinesterase inhibitor tacrine is more effective in reducing psychotic features than cognitive disturbances; tacrine also reduces or abolishes hallucinations in Parkinson’s disease.1-7 Another cholinesterase inhibitor, metrifonate, was also shown to reduce the number of hallucinations in a 26 week randomised, double blind, placebo controlled safety and efficacy study in patients with Alzheimer’s disease. Further support for a link between acetylcholine and psychosis derives from postmortem data showing that the activity of choline acetyltransferase in the temporal cortex of patients with Lewy body dementia was lower in those patients with hallucinations than in patients without this feature.1-8 Finally, in animals the partial M2/M4 agonist (5R,6R)6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane produced a preclinical profile suggestive of antipsychotic efficacy1-9 and that the psychomimetic NMDA receptor antagonist ketamine (when administered at subanaesthetic doses) reduced brain concentrations of acetylcholine.1-10 Thus, on the basis of both clinical and preclinical data, a clear rationale is emerging for prescribing cholinomimetic agents for treating the non-cognitive behavioural symptoms associated with dementia, particularly psychosis.
Professor Babic is also correct in identifying two of the studies referred to as the 30 week randomised multicentre placebo controlled parallel group studies, which included a 24 week double blinded treatment phase.
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