Currently available treatments for Alzheimer's disease (AD) are disappointing and their modest benefits do not reflect the increased understanding of the condition that has arisen from the last 50 years of research or the huge investments made by the pharmaceutical industry and academia in developing therapies. Cholinesterase inhibitors and memantine are evidence-based symptomatic treatments that offer benefits at the margins of clinical significance, but successive failures in trials of putative disease-modifying drugs have led researchers to investigate the potential efficacy of non-drug interventions. Exercise and cognitive-based interventions have received the most attention, but we are still a long way from understanding whether any can offer real benefit to patients with AD (Huntley et al., Reference Huntley, Gould, Liu, Smith and Howard2015).
This is why large-scale and high quality clinical trials, such as the ETNA3 study reported in this month's International Psychogeriatrics are so important. The ETNA3 team conducted a long-term interventional study involving both AD patients and their caregivers in order to compare the effects of cognitive training, reminiscence therapy, and cognitive rehabilitation with treatment as usual (TAU) on progression to severe AD or death. As the authors of the study point out, Cochrane reviews have not been supportive of cognitive training or reminiscence therapy, and individualized cognitive rehabilitation has not been tested by clinical trials, in the AD population (Bahar-Fuchs et al., Reference Bahar-Fuchs, Clare and Woods2013)
Six hundred and fifty three patients, recruited from 40 centers in France, were randomized to receive cognitive training, reminiscence therapy, cognitive rehabilitation, or TAU. The primary outcome was proportion of participants alive and without moderate to severe dementia at two years. The trial achieved 72% follow-up to the end point and none of the interventions showed superiority over TAU on the primary outcome. Further, for cognitive training and reminiscence therapy, there were no benefits on any of the secondary outcome measures (institutionalization, cognitive function, behavioral symptoms, activities of daily living, quality of life, caregiver burden, and resource utilization). However, the cognitive rehabilitation group showed significantly less functional decline and reduced rates of institutionalization (19.1% vs. 27.3% for TAU participants). There were trend level advantages for cognitive rehabilitation over TAU on behavioral symptoms, caregiver burden, and medical and social care costs.
What do these results mean? Clearly, the complete failure of cognitive training and reminiscence therapy to show superiority to TAU on any of the outcomes is disappointing, particularly as interventions based upon them are now commonly offered within services for people with AD. The ETNA3 study team went to some lengths to ensure that interventions were delivered by experienced dementia psychologists, interventions were manualized and adherence to the manualized protocol was monitored. Intervention sessions were weekly for the first 12 weeks and then once every 6 weeks for the next 21 months. Cognitive training tasks involved two levels of difficulty so that groups of participants with different levels of ability could engage with them and the tasks were linked to activities of day-to-day living such as domestic finances. Support group sessions were held for caregivers alongside the AD patients’ groups. Reminiscence therapy groups were organized in a very similar way, with parallel groups for caregivers. Cognitive rehabilitation therapy was delivered to individual participants, as opposed to the group delivery of cognitive training and reminiscence therapy. Activities selected for cognitive rehabilitation were carefully selected to fit with each participant's personal goals, delivery was adapted to individual cognitive ability, and training activities were reviewed at each session.
Given the more individualized and adaptive nature of the cognitive rehabilitation utilized in ETNA3, it is perhaps not surprising that this outperformed TAU and the alternative study interventions. Increasingly, it appears that cognitive-based interventions that involve presentation of an adaptive task format – difficulty level appropriate to ability and increases as performance on trained task improves – are more likely to lead to generalized cognitive benefits. This makes sense on an intuitive level since adaptive training allows participants to be constantly tested at their individual limit, providing continual stretching of cognitive effort that may be required for improving cognitive performance. The lack of adaptive trial designs in AD may partly explain the discrepancy between the largely positive effects of recent computerized cognitive training reported in studies with healthy elderly participants (Lampit et al., Reference Lampit, Hallock and Valenzuela2014; Corbett et al., Reference Corbett2015) and the lack of efficacy of cognitive training seen in AD studies such as ETNA3. Cognitive rehabilitation was the only intervention administered within “made to measure” individual sessions. It is, of course, possible that this introduced particular positive therapist effects and higher participant motivation to the intervention that were lacking in the group-based therapies.
Such difficulties with directly comparing the “apples and oranges” of different cognitive-based interventions bedevil trial design in this area and make interpretation of the significance of results difficult. The positive message from ETNA3 is that – whether or not this is due to the intrinsic properties of cognitive rehabilitation – a cognitive-based intervention can impact upon important clinical outcomes in AD. The ETNA3 investigators’ conclusion, that cognitive rehabilitation delayed institutionalization by six months, is a bold and important one and is comparable with the effects of cholinesterase inhibitor treatment (Howard et al.,
Reference Howard2015). Of course, the use of a TAU comparison, rather than an active control, and the open-label design of this and so many other trials of cognitive-based interventions, mean that a placebo effect cannot be discounted. Whatever the reasons for the positive effects associated with the cognitive rehabilitation intervention in ETNA3, there are lessons here for both clinical practice and the design of future trials of non-drug interventions for AD.
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Currently available treatments for Alzheimer's disease (AD) are disappointing and their modest benefits do not reflect the increased understanding of the condition that has arisen from the last 50 years of research or the huge investments made by the pharmaceutical industry and academia in developing therapies. Cholinesterase inhibitors and memantine are evidence-based symptomatic treatments that offer benefits at the margins of clinical significance, but successive failures in trials of putative disease-modifying drugs have led researchers to investigate the potential efficacy of non-drug interventions. Exercise and cognitive-based interventions have received the most attention, but we are still a long way from understanding whether any can offer real benefit to patients with AD (Huntley et al., Reference Huntley, Gould, Liu, Smith and Howard2015).
This is why large-scale and high quality clinical trials, such as the ETNA3 study reported in this month's International Psychogeriatrics are so important. The ETNA3 team conducted a long-term interventional study involving both AD patients and their caregivers in order to compare the effects of cognitive training, reminiscence therapy, and cognitive rehabilitation with treatment as usual (TAU) on progression to severe AD or death. As the authors of the study point out, Cochrane reviews have not been supportive of cognitive training or reminiscence therapy, and individualized cognitive rehabilitation has not been tested by clinical trials, in the AD population (Bahar-Fuchs et al., Reference Bahar-Fuchs, Clare and Woods2013)
Six hundred and fifty three patients, recruited from 40 centers in France, were randomized to receive cognitive training, reminiscence therapy, cognitive rehabilitation, or TAU. The primary outcome was proportion of participants alive and without moderate to severe dementia at two years. The trial achieved 72% follow-up to the end point and none of the interventions showed superiority over TAU on the primary outcome. Further, for cognitive training and reminiscence therapy, there were no benefits on any of the secondary outcome measures (institutionalization, cognitive function, behavioral symptoms, activities of daily living, quality of life, caregiver burden, and resource utilization). However, the cognitive rehabilitation group showed significantly less functional decline and reduced rates of institutionalization (19.1% vs. 27.3% for TAU participants). There were trend level advantages for cognitive rehabilitation over TAU on behavioral symptoms, caregiver burden, and medical and social care costs.
What do these results mean? Clearly, the complete failure of cognitive training and reminiscence therapy to show superiority to TAU on any of the outcomes is disappointing, particularly as interventions based upon them are now commonly offered within services for people with AD. The ETNA3 study team went to some lengths to ensure that interventions were delivered by experienced dementia psychologists, interventions were manualized and adherence to the manualized protocol was monitored. Intervention sessions were weekly for the first 12 weeks and then once every 6 weeks for the next 21 months. Cognitive training tasks involved two levels of difficulty so that groups of participants with different levels of ability could engage with them and the tasks were linked to activities of day-to-day living such as domestic finances. Support group sessions were held for caregivers alongside the AD patients’ groups. Reminiscence therapy groups were organized in a very similar way, with parallel groups for caregivers. Cognitive rehabilitation therapy was delivered to individual participants, as opposed to the group delivery of cognitive training and reminiscence therapy. Activities selected for cognitive rehabilitation were carefully selected to fit with each participant's personal goals, delivery was adapted to individual cognitive ability, and training activities were reviewed at each session.
Given the more individualized and adaptive nature of the cognitive rehabilitation utilized in ETNA3, it is perhaps not surprising that this outperformed TAU and the alternative study interventions. Increasingly, it appears that cognitive-based interventions that involve presentation of an adaptive task format – difficulty level appropriate to ability and increases as performance on trained task improves – are more likely to lead to generalized cognitive benefits. This makes sense on an intuitive level since adaptive training allows participants to be constantly tested at their individual limit, providing continual stretching of cognitive effort that may be required for improving cognitive performance. The lack of adaptive trial designs in AD may partly explain the discrepancy between the largely positive effects of recent computerized cognitive training reported in studies with healthy elderly participants (Lampit et al., Reference Lampit, Hallock and Valenzuela2014; Corbett et al., Reference Corbett2015) and the lack of efficacy of cognitive training seen in AD studies such as ETNA3. Cognitive rehabilitation was the only intervention administered within “made to measure” individual sessions. It is, of course, possible that this introduced particular positive therapist effects and higher participant motivation to the intervention that were lacking in the group-based therapies.
Such difficulties with directly comparing the “apples and oranges” of different cognitive-based interventions bedevil trial design in this area and make interpretation of the significance of results difficult. The positive message from ETNA3 is that – whether or not this is due to the intrinsic properties of cognitive rehabilitation – a cognitive-based intervention can impact upon important clinical outcomes in AD. The ETNA3 investigators’ conclusion, that cognitive rehabilitation delayed institutionalization by six months, is a bold and important one and is comparable with the effects of cholinesterase inhibitor treatment (Howard et al., Reference Howard2015). Of course, the use of a TAU comparison, rather than an active control, and the open-label design of this and so many other trials of cognitive-based interventions, mean that a placebo effect cannot be discounted. Whatever the reasons for the positive effects associated with the cognitive rehabilitation intervention in ETNA3, there are lessons here for both clinical practice and the design of future trials of non-drug interventions for AD.