- Email: [email protected]
Lessons from the Multidomain Alzheimer Preventive Trial – Authors' reply
Correspondence
effects, research could also focus on identifying the therapeutic elements of multidomain intervention and trying to maximise any effect in future studies.9 HNY reports grants from the National Institute of Heart, Lung and Blood and the Alzheimer’s Association. LSS reports grants from the National Institute on Aging and the State of California, and other from University of Southern California; grants from Eli Lilly, Lundbeck, Novartis, and Biogen; grants and personal fees from, Merck, Roche/ Genentech, and TauRx; and personal fees from AC Immune, Avraham, Boehringer Ingelheim, Cerespir, Cognition, Neurim, Stemedica, Takeda, vTv, Toyama/FujiFilm, Nestle, Heptares, Allergan, Axovant, and Impel NeuroPharma.
*Hussein N Yassine, Lon S Schneider [email protected] Keck School of Medicine of USC, Los Angeles, CA 90033, USA 1
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Andrieu S, Guyonnet S, Coley N, et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol 2017; 16: 377–89. Yassine HN, Rawat V, Mack WJ, et al. The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease. Alzheimers Res Ther 2016; 8: 25. Yassine HN, Braskie MN, Mack WJ, et al. Association of docosahexaenoic acid supplementation with Alzheimer disease stage in apolipoprotein E ε4 carriers: a review. JAMA Neurol 2017; 74: 339–47. van de Rest O, Geleijnse JM, Kok FJ, et al. Effect of fish oil on cognitive performance in older subjects a randomized, controlled trial. Neurology 2008; 71: 430–38. Quinn JF, Raman R, Thomas RG, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA 2010; 304: 1903–11. Umhau JC, Zhou W, Carson RE, et al. Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography. J Lipid Res 2009; 50: 1259–68. Hooijmans CR, Pasker-de Jong PC, de Vries RB, Ritskes-Hoitinga M. The effects of long-term omega-3 fatty acid supplementation on cognition and Alzheimer’s pathology in animal models of Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimer’s Dis 2012; 28: 191–209. Laitinen M, Ngandu T, Rovio S, et al. Fat intake at midlife and risk of dementia and Alzheimer’s disease: a population-based study. Dement Geiatry Cogn Disord 2006; 22: 99–107. Kivipelto M, Mangialasche F, Ngandu T. Can lifestyle changes prevent cognitive impairment? Lancet Neurol 2017; 16: 338–39.
Authors’ reply
We thank Hussein Yassine and Lon Schneider for their interest in the MAPT trial1 and their analysis of its contribution to research on the prevention of cognitive decline. Given the nature of the intervention, it would have been virtually impossible for the multidomain component of our intervention to be doubleblind. We acknowledge that this is a limitation of our study, as underlined in the discussion section of the Article.1 However, we made every effort to make sure that the trial was at least singleblind by using blinded evaluators and asking participants not to disclose their multidomain group assignment to these evaluators. Moreover, use of a control arm with similar interpersonal interactions (ie, twice a week for the first month, once a week for the second month, and once a month for the remainder of the 3 years), would have been a very active control for elderly and often isolated individuals. And although it was only a minor part of the intervention, the MAPT multidomain intervention also aimed to improve social contacts, both through the group nature of the multidomain sessions, and by encouraging the participants to engage in other social activities. Finally, the study was double-blind for all participants for the omega 3 polyunsaturated fatty acid alone or placebo alone component, which could have helped to minimise any potential biases arising from the singleblind evaluation of the multidomain intervention. We agree that it can be difficult to understand the clinical relevance of cognitive changes in asymptomatic individuals, particularly for composite measures based on Z scores, and we suggest that this is an area requiring specific research. As mentioned in our discussion, our initial estimate of a clinically important difference in the
MAPT composite score, which was obtained by using a 1 year change from clinical dementia rating (CDR) of 0 to CDR of 0·5 (ie, relatively fast decliners) as an anchor measure, was –0·3 points, although this might not necessarily be the minimum clinically important difference. It is also interesting to note that the difference in change from baseline to 3 years between CDR 0 and 0·5 participants in MAPT was roughly 0·19 points. Finally, the daily dose of omega 3 supplementation was fixed without exceeding the maximum daily intake limit of 2 g per day (as per the recommendations of the French food safety authority). It is possible that a higher dose or longer duration of omega 3 supplementation than those used in our trial could be needed for cognitive benefits. However, since prevention trials are done in healthy populations, the safety of the intervention is of upmost importance, and therefore we decided to use a dose well below the maximum. It would be very challenging to study the late-life cognitive effects of supplementation in younger adults for a very long period, and further evidence of the midlife effects of supplementation is needed before embarking on such a trial. SA has received grants from Europe, Ipsen, and France Alzheimer, served as a consultant for Ipsen, Pierre Fabre, Lilly, Nestlé, Sanofi, and Servier, and received non-financial support from Biogen, Nutrition Santé, Pfizer, and Icon, and other support from the AMPA Association. NC declares no competing interests.
Nicola Coley, *Sandrine Andrieu, for the MAPT Study Group [email protected] INSERM UMR 1027, University of Toulouse III, Department of Epidemiology and Public Health, CHU Toulouse, Toulouse, France 1
Andrieu S, Guyonnet S, Coley N, et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol 2017; 16: 377–89.
www.thelancet.com/neurology Vol 16 August 2017
effects, research could also focus on identifying the therapeutic elements of multidomain intervention and trying to maximise any effect in future studies.9 HNY reports grants from the National Institute of Heart, Lung and Blood and the Alzheimer’s Association. LSS reports grants from the National Institute on Aging and the State of California, and other from University of Southern California; grants from Eli Lilly, Lundbeck, Novartis, and Biogen; grants and personal fees from, Merck, Roche/ Genentech, and TauRx; and personal fees from AC Immune, Avraham, Boehringer Ingelheim, Cerespir, Cognition, Neurim, Stemedica, Takeda, vTv, Toyama/FujiFilm, Nestle, Heptares, Allergan, Axovant, and Impel NeuroPharma.
*Hussein N Yassine, Lon S Schneider [email protected] Keck School of Medicine of USC, Los Angeles, CA 90033, USA 1
2
3
4
5
6
7
8
9
586
Andrieu S, Guyonnet S, Coley N, et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol 2017; 16: 377–89. Yassine HN, Rawat V, Mack WJ, et al. The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease. Alzheimers Res Ther 2016; 8: 25. Yassine HN, Braskie MN, Mack WJ, et al. Association of docosahexaenoic acid supplementation with Alzheimer disease stage in apolipoprotein E ε4 carriers: a review. JAMA Neurol 2017; 74: 339–47. van de Rest O, Geleijnse JM, Kok FJ, et al. Effect of fish oil on cognitive performance in older subjects a randomized, controlled trial. Neurology 2008; 71: 430–38. Quinn JF, Raman R, Thomas RG, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA 2010; 304: 1903–11. Umhau JC, Zhou W, Carson RE, et al. Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography. J Lipid Res 2009; 50: 1259–68. Hooijmans CR, Pasker-de Jong PC, de Vries RB, Ritskes-Hoitinga M. The effects of long-term omega-3 fatty acid supplementation on cognition and Alzheimer’s pathology in animal models of Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimer’s Dis 2012; 28: 191–209. Laitinen M, Ngandu T, Rovio S, et al. Fat intake at midlife and risk of dementia and Alzheimer’s disease: a population-based study. Dement Geiatry Cogn Disord 2006; 22: 99–107. Kivipelto M, Mangialasche F, Ngandu T. Can lifestyle changes prevent cognitive impairment? Lancet Neurol 2017; 16: 338–39.
Authors’ reply
We thank Hussein Yassine and Lon Schneider for their interest in the MAPT trial1 and their analysis of its contribution to research on the prevention of cognitive decline. Given the nature of the intervention, it would have been virtually impossible for the multidomain component of our intervention to be doubleblind. We acknowledge that this is a limitation of our study, as underlined in the discussion section of the Article.1 However, we made every effort to make sure that the trial was at least singleblind by using blinded evaluators and asking participants not to disclose their multidomain group assignment to these evaluators. Moreover, use of a control arm with similar interpersonal interactions (ie, twice a week for the first month, once a week for the second month, and once a month for the remainder of the 3 years), would have been a very active control for elderly and often isolated individuals. And although it was only a minor part of the intervention, the MAPT multidomain intervention also aimed to improve social contacts, both through the group nature of the multidomain sessions, and by encouraging the participants to engage in other social activities. Finally, the study was double-blind for all participants for the omega 3 polyunsaturated fatty acid alone or placebo alone component, which could have helped to minimise any potential biases arising from the singleblind evaluation of the multidomain intervention. We agree that it can be difficult to understand the clinical relevance of cognitive changes in asymptomatic individuals, particularly for composite measures based on Z scores, and we suggest that this is an area requiring specific research. As mentioned in our discussion, our initial estimate of a clinically important difference in the
MAPT composite score, which was obtained by using a 1 year change from clinical dementia rating (CDR) of 0 to CDR of 0·5 (ie, relatively fast decliners) as an anchor measure, was –0·3 points, although this might not necessarily be the minimum clinically important difference. It is also interesting to note that the difference in change from baseline to 3 years between CDR 0 and 0·5 participants in MAPT was roughly 0·19 points. Finally, the daily dose of omega 3 supplementation was fixed without exceeding the maximum daily intake limit of 2 g per day (as per the recommendations of the French food safety authority). It is possible that a higher dose or longer duration of omega 3 supplementation than those used in our trial could be needed for cognitive benefits. However, since prevention trials are done in healthy populations, the safety of the intervention is of upmost importance, and therefore we decided to use a dose well below the maximum. It would be very challenging to study the late-life cognitive effects of supplementation in younger adults for a very long period, and further evidence of the midlife effects of supplementation is needed before embarking on such a trial. SA has received grants from Europe, Ipsen, and France Alzheimer, served as a consultant for Ipsen, Pierre Fabre, Lilly, Nestlé, Sanofi, and Servier, and received non-financial support from Biogen, Nutrition Santé, Pfizer, and Icon, and other support from the AMPA Association. NC declares no competing interests.
Nicola Coley, *Sandrine Andrieu, for the MAPT Study Group [email protected] INSERM UMR 1027, University of Toulouse III, Department of Epidemiology and Public Health, CHU Toulouse, Toulouse, France 1
Andrieu S, Guyonnet S, Coley N, et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol 2017; 16: 377–89.
www.thelancet.com/neurology Vol 16 August 2017