This review shows that none of the listed clinical trials on MCI met their primary objectives. A short 6 month donepezil trial and a 3 year secondary prevention study confirmed previous observations from AD trials on the symptomatic effects of AChEI. Nevertheless, the scientific community has gained both valuable information on the natural course of MCI as defined by currently accepted clinical criteria as well as lessons for the future with regard to the design and methodology of MCI trials.
The question arises whether the study objectives were justified by scientific proof or were based on assumptions. The common assumption is that we know the effects of treatment in this still controversial early stage of the disease and that effects would be clearly demonstrated on cognitive and functional measures used in earlier AD trials.
Despite the consensus on a generally accepted clinical definition of amnestic MCI that isolates individuals at high risk of developing AD within a few years, the “conversion” rate varied considerably among the trials from 4.5% and 6.4%/year in the rofecoxib trial to 16%/year in the MIS (donepezil and vitamin E study). Obviously, different populations of patients, a number of whom in some centres were probably early AD cases, were chosen using very similar entry criteria. In their most recent article, Visser et al64
investigated retrospectively the diagnostic accuracy of MCI criteria used in different MCI trials for predementia Alzheimer's disease in a cohort of non‐demented patients from their clinic. The authors pointed out that there were marked differences in the definition of cognitive impairment. The MIS had a strict cut‐off score for memory impairment and a higher positive predictive value and “conversion” rate in contrast to the GAL‐INT‐11 and rofecoxib studies, which used a more lenient cut‐off score. In the MIS, a considerably higher percentage of patients (55%) were carriers of the APOE e4 allele as compared with those published in a meta‐analysis of 42 case‐control series where reported frequencies of the e4 allele were 32% in sporadic AD cases over 65 years of age and 41% in sporadic AD cases under 65 years of age.65
One possible explanation is that the variation in the APOE e4 prevalence across the studies results from variation in the definition of memory impairment, meaning that more severe impairment in the MIS is clearly associated with higher APOE e4 allele frequency.
Another important methodological concern is the choice of primary and secondary outcome measures. In the current trials these measures were chosen according to previous FDA guidelines for AD trials and should include assessments of global function and cognition with scales well validated in AD patients, such as CGIC and its more popular formats the Clinician's Interview‐Based Impression of Change (CIBIC) and the Clinician's Interview‐Based Impression of Change with caregiver input (CIBIC‐plus), and ADAS‐Cog. Although these scales have been adapted for MCI patients, there is still uncertainty about the expected rate of change during the trial period, as the rate differs from that in AD patients where it has been shown that the rate of cognitive deterioration is strongly related to baseline severity.66
Very few studies have investigated the performance of normal subjects on ADAS‐Cog and the effect of age, gender, and level of education.67
Such normative studies provide a reference for the clinician to distinguish variations in normal cognitive aging from those accelerated by subclinical neurodegenerative disorders as probably occur in most individuals with MCI. With respect to the MCI version of the ADL scale, there is concern that it does not measure high‐order instrumental tasks previously shown to have high predictive validity for future conversion to AD. Low “conversion” rates are also influenced by strict entry criteria in some studies which exclude significant co‐morbidity that probably determines faster progression and “conversion” rates. These limitations might considerably reduce the therapeutic potential of agents with effects on microcirculation, such as piracetam, which have documented efficacy in elderly patients with an aetiologically broad range of cognitive disorders.42
Exclusion of patients with depressive symptoms and silent cerebrovascular pathology on CT or MRI probably means the selection of a very exclusive group not representative of MCI in general or the overall clinical population. It has been observed that placebo treated AD patients in clinical trials declined by 0.55 MMSE points per year as compared with 2.5–3 points per year in natural cohorts.68,69
Differences in study populations raise the question of whether current generally accepted clinical criteria are also generally applicable across different clinical centres in a multicentre international trial. It could be of importance that multicentre cross‐cultural studies report the intersite variability of baseline measures as well as the outcomes. Furthermore, there is evidence that there is ~20% discordance between clinical diagnosis of probable AD and definite pathological diagnosis.70
Therefore, if a clinical diagnosis of AD can be questioned from a neuropathological perspective, an aetiological diagnosis of MCI based exclusively on clinical grounds should be a matter of even greater concern. Would it help increase sensitivity and specificity and ensure the outcome if inclusion criteria were further enriched by the addition of biological markers, such as genetic and CSF markers or atrophy measures on MRI? In most of the listed trials, instrumental investigations and biochemical and genetic markers were included as exploratory objectives, but none of the trials included them as enrichment criteria.
An useful approach has been suggested recently which combines a number of predictor variables for AD, such as age, MMSE score, degree of functional impairment, neuropsychological test impairment, medial temporal lobe atrophy, and APOE genotype in the Preclinical Alzheimer's Disease scale (PAS).71
Study samples enriched in this way could have a higher diagnostic sensitivity and specificity for prodromal AD,72
which would be very important for the clinician who needs greater certainty as to possible clinical outcome in order to initiate treatment in MCI subjects. Indeed, predementia or prodromal AD could be a better designation for the selection of non‐demented subjects for secondary prevention trials in AD.
While sub‐analysis of the predictors of progression to AD is still ongoing in most of the trials, in particular in APOE e4 allele carriers, it has been reported that the APOE e4 carriers in the MIS progressed faster and showed more sustained response on the donepezil treatment.56
Epidemiological, clinical, and basic science evidence supports a relationship between APOE genotype and risk for AD.73,74,75,76
Furthermore, it has been reported that APOE e4 carriers over the age of 50 demonstrated a modest decline in memory skills over a median period of 33 months prior to the symptomatic onset of MCI.76
In a subpopulation of 494 subjects participating in the InDDEx study and consenting to pharmacogenetic assessment, APOE e4 genotype was associated with greater memory and functional impairment and hippocampal atrophy.60
It could be that in such a heterogeneous condition as MCI, subjects with APOE e4 are more likely to have AD as the underlying pathology, which might also explain the better treatment response. While the post‐mortem study of MCI subjects by DeKosky et al77
showed that choline acetyltransferase activity was up‐regulated in the frontal cortex and hippocampus, this compensatory mechanism might be compromised in MCI patients who are also APOE e4 carriers and who, therefore, might respond better to AChEI therapy. However, observed treatment difference according to APOE e4 status in the MIS was not statistically impressive and taken together with the results from the entire study cohort, could suggest the alternative explanation that the beneficial effects of treatment wear off, as noted in the editorial accompanying the article.78
It should be noted that in AD trials with tacrine, galantamine, and donepezil, APOE e4 allele was not found to be a predictor of more favourable outcome.79,80,81
Evaluation of treatment effects in long‐term trials of donepezil+vitamine E, rivastigmine, and rofecoxib is also compromised by the effect of missing data due to high dropout rates, which varied between 40% and 45% in the case of MCI trials lasting more than 24 months. Although reported adverse events were equally balanced between the active treatment and placebo groups in most studies, in the MIS a higher withdrawal rate was observed in the donepezil group due to the more severely impaired cognitive status at baseline. Analysing a random sample of dropout patients is not an optimal solution to the problem of dropout bias, which compromises understanding of group differences in the clinical trials. A retrieved dropout analysis should be established as a standard method since it minimises dropout bias by assessing as many as possible of the patients who did not completed a trial for various reasons.82
A secondary objective in most of the secondary prevention trials is improvement on the specific tests in the neuropsychological battery covering major cognitive domains. What do small statistical improvements on test scores on an individual neuropsychological test mean for the patient's overall functioning? The clinical relevance of improvements on cognitive tests and global measures of change has been questioned from the perspective of caregivers of AD patients.83
The CBCS used in the piracetam trial as a primary outcome, in general enhances the effects of standardised change in any of eight tests that compose this battery; however, it is difficult to interpret either positive or negative results in terms of clinically meaningful effects. In addition, a few outliers could influence the magnitude of standardised change on CBCS. Correspondence with secondary outcomes encompassing global cognitive and functional measures could support findings in primary efficacy parameters. Still, there remains a concern that a 1 year trial in a population that shows ceiling effects on some of the tests at baseline and does not deteriorate quickly, could not detect any significant changes. Indeed, in the piracetam trial there was a ceiling effect on the Free and Cued Selective Reminding task at baseline and neither the placebo nor the treatment groups deteriorated during the course of the trial.
In summary, experience with the clinical trials in MCI performed so far has shown that even though they were using the same criteria for amnestic MCI, which were created to increase specificity and reduce the heterogeneity of MCI, various studies were recruiting different samples with respect to the “conversion” rates to dementia and other biological characteristics such as APOE genotype. The lack of effects on symptom progression questions not only the clinical efficacy of the evaluated agents in MCI but also the sensitivity of the outcome measures used in the trials and calls for more effective and reliable markers of disease progression. The fact that none of the drugs previously shown to have clinical efficacy in AD trials as well as benefit in everyday practice have met the primary objectives of the respective trials, indicates that the clinical trial design in MCI has to be further developed with special attention being paid to the selection of more homogeneous samples at entry, optimal treatment duration, and multidimensional and reliable outcomes. Both validation of natural cohorts of MCI subjects followed for longer in clinical settings and biological markers are needed. Because of these unresolved issues, it is still premature to conclude that lack of proof of efficacy in the MCI trials performed so far confirms a definite lack of efficacy of the therapeutic agents being evaluated.