The early signs of Alzheimer’s disease (AD) often include memory loss that disrupts daily life, confusion over time or place, difficulty completing once familiar tasks and changes in mood and personality. Once diagnosed, one of the main treatments for patients with mild to moderate AD are acetylcholinesterase inhibitors (ChEIs). Conducting clinical trials to discover new treatments to counteract the disease requires a control group for comparison; however allowing an AD patient to go without treatment altogether for the purposes of a long-term clinical trial is considered unethical. Such trials to test the potential of novel therapies are instead carried out over longer periods of time with a control group that is already receiving ChEIs. Carina Wattmo and colleagues from Lund University, Sweden carried out a longitudinal study into mild AD progression with patients receiving ChEI therapy, to identify the effect of socio-demographic and clinical factors on disease outcomes. Wattmo explains more about their results, published in an Alzheimer’s Research & Therapy study, and their development of prediction models based on data obtained from patients at the start of ChEI treatment.
What are acetylcholinesterase inhibitors and how are they used in the treatment of Alzheimer’s disease (AD)?
Acetylcholinesterase inhibitors (ChEIs) prevent the degradation of acetylcholine (ACh) by inhibiting the enzyme acetylcholinesterase, resulting in increased levels of ACh in the synaptic cleft available for receptor absorption. This enhances cholinergic transmission and improves the communication between neurons, which temporarily might counteract the associated cognitive deficits of Alzheimer’s disease (AD). Randomised clinical trials in AD have demonstrated that ChEIs are effective in slowing cognitive, global and functional decline compared with placebo-treated controls, and naturalistic, observational studies have reported positive long-term effects of ChEI on these measures.
Although the three ChEIs – donepezil, rivastigmine and galantamine – display various biochemical mechanisms and their effect on acetylcholinesterase activity might vary, the observed short-term response to therapy and long-term effect does not seem to differ among the drugs. However, not every individual with AD benefits from ChEI treatment. The heterogeneity in the outcomes emphasizes the importance of identifying patients who respond positively to ChEI, to enhance the effectiveness of the drug and its cost benefits in AD.
In this study, you followed patients with mild AD on acetylcholinesterase inhibitor treatment, to see if this treatment skewed results when these patients were included in a study for a new AD drug. What did you observe?
Our mild Swedish Alzheimer Treatment Study (SATS) cohort exhibited a slower cognitive decline in comparison with mild AD studies previously reported from the United States. However, participants were included in those studies from the US about 1-2 years after AD diagnosis. Thus, those patients had been treated with ChEIs and/or memantine (a NMDA receptor antagonist) before the baseline, whereas the baseline in the SATS was the start of ChEI therapy. The slower disease progression observed in the SATS cohort might reflect the benefits of continuous ChEI treatment started almost immediately after AD diagnosis and the positive treatment response in the first months after initiation (baseline). When comparing changes in scores between studies, it may be important to consider the point of time when ChEI therapy was initiated because the first months of positive response after initiation could imply a more favourable mean outcome over time.
The participants’ high level of education (about 14.7 mean years of education) in the previously reported studies of mild AD from the US might also be one reason for their faster cognitive decline compared with the SATS cohort (9.6 mean years of education). Patients with a lower level of education were assumed to have a reduced cognitive reserve and therefore would be more vulnerable to the effects of neurodegeneration. They would also be expected to perform worse on standardized cognitive tests that use a single threshold to identify dementia, such as the Mini-Mental State Examination and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). These consequences of a lower education level might lead to an earlier manifestation of the typical symptoms of AD and detection of the disease. Diagnosis and treatment might occur in a milder stage of AD, which may improve the effects of ChEI therapy.
Why do you think there was a greater deterioration in the ability to perform daily activities compared to cognitive and global overall outcomes?
Functional decline in AD is progressive and once lost, the ability to perform daily activities (ADL) is rarely recovered. The effect of ChEI treatment on function is most likely to be observed as a delay in the time to decline rather than as an improvement over baseline. Patients showing a rapid functional deterioration have previously been shown to exhibit significantly greater impairment of cognitive ability at the time of AD diagnosis.
Surprisingly, three years after AD diagnosis, 70-85 percent of the remaining individuals in the mild SATS cohort could not carry out instrumental activities of daily living (IADL) tasks independently. The number of concomitant medications and usage of specific medications at baseline were not significant predictors of progression in IADL in our multivariate models, suggesting that comorbidity did not influence the functional outcome. Consistently, a marked decline in IADL capacity was also reported in the previous US studies of mild AD.
The question of why the mild AD patients have a faster functional deterioration than cognitive or global decline is difficult to explain. Further research on functional ability in the milder stages of AD is required.
What implications do your results have for clinical practice?
The mild AD patients’ fast deterioration in IADL compared with cognitive and global performance stresses the importance of functional evaluations even during the early stages of AD in clinical routine. This information is also essential for the care planners and the community-based services. The present study shows that socio-demographic and clinical factors such as age, years of education and the dose of ChEI, might alter the participants’ outcomes. A higher level of education might be a risk factor in AD patients regarding a more advanced disease at diagnosis and a faster rate of progression. Higher doses of ChEIs were related to a more favourable long-term cognitive and functional outcome in this study, which shows the importance of optimizing the ChEI dose for the individual patient with AD.
How could these results affect studies of future therapies for AD?
Some randomized trials, such as the anti-beta-amyloid antibody solanezumab and the medical food souvenaid, have shown small but significant positive cognitive effects in mild AD exclusively. Knowledge of longitudinal progression (cognitive, global and functional) in mild AD patients receiving current standard treatment (i.e. ChEIs), is required for the evaluation of disease-modifying therapies. This is essential to compare the trajectories of those who have received a new therapy in addition to ChEI with those of patients treated only with ChEI, especially since therapies that may modify disease progression in AD require thorough long-term evaluation. The outcomes of this well-designed, observational, 3-year study can be used as a reference for future studies in mild AD.
In the current study, inconsistent long-term cognitive outcomes (depending on the scale used) were found between carriers and non-carriers of the genetic risk factor apolipoprotein E (APOE) ε4-allele, which is noteworthy since this variable has been used to stratify patients in some clinical trials of immunotherapy. Exploratory data analyses from the anti-Aβ antibody bapineuzumab phase II trial observed that non-carriers of the APOE ε4-allele responded better cognitively than ε4-carriers; however, the phase III trials failed to replicate these results.
You present prediction models of mild AD, how might these be useful in clinical practice and research?
Because placebo-controlled clinical trials of more than six months duration in untreated individuals with AD are considered unethical, new longer studies are instead being conducted on patients who are already being treated with ChEI and/or memantine. The Stern equation (Am J Psychiatry, 1994;151:390-6) derived from untreated mild-to-moderate AD patients has been used in several previous long-term studies of ChEIs to calculate the expected ADAS-cog decline over time as if these patients had been untreated.
Prediction models of expected rate of change have not been reported exclusively in mild AD patients. Empirical statistical models derived from ChEI-treated AD patients in a routine clinical setting, such as SATS may reflect more closely the effectiveness of ChEIs under the conditions of usual clinical care. The baseline-dependent prediction models of mild AD presented in the current study might be a useful tool to estimate the cognitive and functional outcomes that may be expected using ChEI monotherapy over time.
What further research is needed?
In the future, research efforts will focus on the development of AD starting in the early and pre-symptomatic stages. The timing of the start of therapy during the course of AD appears to be an essential factor that influences disease progression and the outcome of clinical trials. Long-term observational studies of ChEI-treated AD patients exclusively in the milder stages are warranted to demonstrate realistic treatment expectations. Moreover, longitudinal studies of patients in other separate stages of AD, comparisons between disease stages and studies including participants with different characteristics, such as APOE genotype are needed to evaluate future therapies.
It is also challenging but important to develop more advanced empirical models of AD progression that allow the prediction of variations in the disease course, and to determine the sources of these variations as completely as possible. Prediction models that better reflect an individual patient’s specific pattern of cognitive and functional decline are more useful for counselling clinicians and caregivers about the disease prognosis and for application in long-term studies that assess future treatments for AD.