Methodological Issues in Primary Prevention Trials for Neurodegenerative Dementia

Article type: Review Article

Authors: Andrieu, Sandrine^{a; b; 1; *} | Coley, Nicola^{a; 1} | Aisen, Paul^c | Carrillo, Maria C.^d | DeKosky, Steven^e | Durga, Jane^{f; g} | Fillit, Howard^h | Frisoni, Giovanni B.ⁱ | Froelich, Lutz^j | Gauthier, Serge^k | Jones, Roy^l | Jönsson, Linus^m | Khachaturian, Zavenⁿ | Morris, John C.^o | Orgogozo, Jean-Marc^p | Ousset, Pierre-Jean^{a; q} | Robert, Philippe^r | Salmon, Eric^s | Sampaio, Cristina^t | Verhey, Frans^u | Wilcock, Gordon^v | Vellas, Bruno^{a; q}

Affiliations: [a] Inserm U558, Toulouse, France | [b] Department of Epidemiology and Public Health, Toulouse University Hospitals, Toulouse, France | [c] Georgetown University, Washington, DC, USA | [d] Alzheimer's Association, Chicago, IL, USA | [e] Alzheimer Disease Research Center, Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA | [f] Wageningen University, Wageningen, The Netherlands | [g] Top Institute Food and Nutrition, Wageningen, The Netherlands | [h] Alzheimer's Drug Discovery Foundation and Institute for the Study of Aging, New York, NY, USA | [i] Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Fatebenefratelli San Giovanni di Dio Scientific Institute, Brescia, Italy | [j] Central Institute for Mental Health, Mannheim, Germany | [k] Alzheimer's Disease Research Unit, McGill Centre for Studies of Aging, Montreal, Canada | [l] RICE (The Research Institute for the Care of Older Peopler), Bath, UK | [m] European Health Economics, Stockholm, Sweden | [n] Keep Memory Alive, Lou Ruvo Brain Institute, Las Vegas, NV, USA | [o] Department of Neurology and Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA | [p] Department of Neurology, Pellegrin Hospital, Bordeaux, France | [q] Alzheimer Disease Research and Clinical Center, Gerontopole, Toulouse University Hospitals, Toulouse, France | [r] Memory Center, Nice University Hospital, Nice, France | [s] Memory Center, Department of Neurology, University Hospital of Liège, Liège, Belgium | [t] Laboratory of Clinical pharmacology and Therapeutics, Faculty of Medicine, Lisbon, Portugal | [u] Alzheimer Centre Limburg, University Hospital of Maastricht, Maastricht, Netherlands | [v] Nuffield Department of Medicine, University of Oxford, Oxford, UK

Correspondence: [*] Corresponding author: Professor Sandrine Andrieu, MD, PhD, Department of Public Health, Toulouse University Hospitals, 37 allées Jules Guesde, 31073 Toulouse, France. Tel.: +33 561145932 or +33 609587814; Fax: +33 562264240; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: The prevention of neurodegenerative dementias, such as Alzheimer's disease, is a public health priority. Due to the large numbers of affected patients, even interventions bringing about a relatively small delay in disease onset could have large public health effects. Randomized controlled trials (RCTs) are required to demonstrate the effectiveness of preventive interventions, but such trials raise specific methodological questions because they are new in the field of neurodegenerative diseases, and require large numbers of elderly subjects and lengthy follow-up periods. We performed a literature search to identify primary prevention RCTs for neurodegenerative dementia. The methodology of the trials was summarized and discussed during two expert meetings. Overall, 39 trials were identified that assessed dementia incidence or cognitive decline as a primary or secondary study outcome. Age was the most common selection criteria for target populations. Follow-up periods ranged from one month to nine years and were longest in studies measuring dementia incidence as an outcome. Results of RCTs have so far been generally negative and conflicting with those of observational studies, perhaps due to methodological issues. Future trials must therefore carefully consider the target population, outcomes and duration of follow-up to be used, and should assess the problem of attrition.

Keywords: Alzheimer's disease, clinical trials, clinical trials methodology, cognitive aging, cognitive decline, dementia, prevention trials, study design

DOI: 10.3233/JAD-2009-0971

Journal: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 235-270, 2009