Swedish Alzheimer Treatment Study

Background

Alzheimer’s disease (AD) is an insidiously progressive neurodegenerative disorder characterized by multiple cognitive deficiencies, including increasing impairment in memory, orientation, language and executive ability, as well as deterioration of functional capacity. After more than 20 years, cholinesterase inhibitors (ChEIs) are still the predominant symptomatic treatment for AD. Modest improvements in cognition and global performance compared with placebo on a group-level have been reported in mainly 6-month randomized clinical trials. The advantages of this therapy in activities of daily living (ADL) were also observed. Moreover, extension studies of placebo-controlled trials have shown that the effect of ChEI may last even longer, and some long-term observational studies in a routine clinical setting have also described the positive results of ChEIs.
However, not every AD patient benefits from ChEI treatment. The level of short-term therapeutic response and longitudinal disease progression may vary among individuals with different genetic, socio-demographic and clinical characteristics. By investigating the entire mild-to-moderate Swedish Alzheimer Treatment Study (SATS) cohort, our group found that both short-term cognitive response to ChEIs and prognosis after 3 years were better in males, older participants, non-carriers of the apolipoprotein E (APOE) epsilon4 allele, persons treated with non-steroidal anti-inflammatory drugs/acetylsalicylic acid, and those receiving a higher dose of ChEI, regardless of drug agent. The heterogeneity in cognitive outcome and response to therapy emphasize the importance of identifying patients who respond favourably to the treatment, to enhance the drug efficacy and its cost benefits in AD.
New longer-term clinical trials are usually an add-on to ChEIs, i.e. performed using participants who are already being treated with a ChEI, because placebo-controlled trials lasting longer than 6 months in individuals with untreated AD are not permitted for ethical reasons. Therapies that might modify AD progression require thorough assessment over several years; hence, the rates of change in well-designed observational ChEI studies can also be used for comparisons.
Despite several hundred studies with different mechanisms, there have been no new drugs approved since 2003 for AD. The treatment strategies include various drug candidates that mainly aim to interfere with biological changes occurring in the brain during AD, such as the formation of beta-amyloid (Abeta) plaques and abnormal accumulation of tau protein. The majority of phase 3 trials of passive immunization with anti-Abeta antibodies demonstrated reduced beta-amyloid in the brain, but no significant cognitive and functional effects. Clinical trials of immunization with anti-tau antibodies are now ongoing and the results remain to be seen. Subsequent exploratory data analyses from anti-Abeta antibody trials revealed that patients in a milder stage of AD and non-carriers of the APOE epsilon4 allele responded better cognitively. Knowledge of the longitudinal cognitive and functional outcomes in different subgroups of AD is of great importance for the evaluation of future therapies.

Purpose of the study

The current aims are:
1) To merge a large number of SATS patients with similar cognitive and/or functional trajectories into AD subgroups using advanced multivariate statistical methods and to explore how genetic, socio-demographic and clinical characteristics, as well as the response to ChEI treatment, differ among the groups.
2) To investigate the needs of care and community-based services, somatic and psychiatric comorbidities, time to nursing home placement, survival time in nursing homes and life expectancy in the various subgroups of AD.
3) To increase understanding of subgroups of individuals with similar disease progression to improve the possibilities of finding effective AD therapies, specifically targeted at certain groups.

Material and methods

The SATS was started in August 1997 to assess the long-term effectiveness of ChEI treatment (donepezil, rivastigmine or galantamine) over 3 years in AD patients in clinical practice. SATS was a prospective, open-label, non-randomized, multicentre study, whose purpose was to evaluate cognitive ability, global performance, instrumental and basic ADL, and service utilization (e.g. home help services and nursing home placement) every 6 months. In total, 1,258 patients with predominantly mild-to-moderate AD were enrolled from 14 participating memory clinics across Sweden up until April 2008. Of these, more than 1,000 individuals have died over the years and their date of death has been recorded. SATS is the largest observational AD study and has the longest follow-up of mortality (now 20 years) in the world.
The above-mentioned aims will be explored using e.g. k-means cluster analysis and discriminant analysis. Cluster analysis is an advanced statistical method for grouping variables or observations (in this study the AD patients’ outcomes over time measured by different assessment scales) into subgroups with a strong relationship. Discriminant analysis is another multivariate statistical approach that uses the included variables in an analysis to distinguish subgroups. By dividing the SATS cohort into subsets according to various characteristics and separately investigating these groups with e.g. mixed-effects models, a deeper understanding of the longitudinal course of AD and potential predictive characteristics, as well as short-term treatment response in different subgroups with AD might be expected.

Clinical importance

By identifying and increasing the knowledge about subgroups with similar cognitive and functional progression in AD, the potential for finding effective therapies directed at specific subsets of patients might be greatly improved. It can be difficult to demonstrate statistical significance in clinical trials of new drug candidates when the rates of change in different capacities over time vary appreciably between the individuals. Results from drug trials may differ between AD subgroups with e.g. various cognitive and functional trajectories, concomitant somatic and psychiatric disorders, as well as genetic, socio-demographic and clinical factors.
The SATS research is clinical- and patient-centred, which means that many results are immediately applicable and useful for currently affected persons with AD. For example, the use of higher ChEI doses, regardless of drug, showed enhanced effectiveness in cognition and instrumental ADL and increased the potential for a more positive long-term prognosis. We also reported that a higher ChEI dose was associated with a longer time to the need of home help services or nursing home placement. In addition, older or more cognitively impaired AD patients at the start of ChEI treatment had a better treatment response after 6 months, which emphasizes the importance of also offering these groups ChEIs. These observations are essential for therapeutic recommendations to specialists in dementia and general practitioners.
An optimal treatment strategy targeted at AD subgroups might lead to improved cognitive and functional performance, increased independence and quality of life, and reduce the societal costs of care for the growing number of people with AD. It is also important to detect subsets of patients with risk factors that are likely to deteriorate faster and will need more resources, such as home care and nursing homes. Predicted disease progression over a longer period, expected needs of care, time to nursing home admission and survival time in subgroups of AD are essential information for the families, clinicians and community-based services.