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Disease-modifying therapies for Alzheimer disease

Challenges to early intervention

From the Departments of Neurology, Psychiatry, and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA (J.L.C.); Department of Neurology, Baylor College of Medicine, Houston, TX (R.D.); and Department of Neurology, University of Pennsylvania, Philadelphia, PA (C.C.).

Address correspondence and reprint requests to Dr. Jeffrey L. Cummings, UCLA Alzheimer Disease Center, 10911 Weyburn Ave., Ste. 200, Los Angeles, CA 90095-7226 jcummings{at}mednet.ucla.edu

Prevention of Alzheimer disease (AD) is a national and global imperative. Therapy is optimally initiated when individuals are asymptomatic or exhibit mild cognitive impairment (MCI). Development of therapeutically beneficial compounds requires the creation of clinical trial methodologies for primary and secondary prevention. Populations in primary prevention trials selected only on the basis of age will have low rates of emergent MCI or AD. Epidemiologically based risk factors or biomarkers can be used to enrich trials and increase the likelihood of disease occurrence during the trial. Enrichment strategies for clinical trials with MCI include use of biomarkers such as amyloid imaging, MRI with demonstration of medial temporal lobe atrophy, bilateral parietal hypometabolism on PET, and reduced amyloid beta peptide and increased tau protein in CSF. Neuropsychological measures appropriate for trials of MCI may not be identical to those measures most suited for AD trials. Attention to these and other features of trial design, clinical assessment, and use of biomarkers is critical to improving the detection of disease-modifying effects of emerging therapies in presymptomatic or minimally symptomatic populations. The neurologic health of the growing aging population demands disease-modifying therapies and the development of methods to identify and test promising candidate agents.

GLOSSARY: AD = Alzheimer disease; ADAPT = Alzheimer’s Disease Anti-inflammatory Prevention Trial; ADAS-cog = Alzheimer’s Disease Assessment Scale–Cognitive subscale; ADCS = Alzheimer’s Disease Cooperative Study; FDG = fluorodeoxyglucose; GSK = glycogen synthase kinase; MCI = mild cognitive impairment; NAA = N-acetylaspartate; PPAR = peroxisome proliferator-activated receptor.

Dr. Cummings is supported by a National Institute on Aging Alzheimer’s Disease Research Center grant (P50 AG16570), an Alzheimer’s Research Center of California grant, the Sidell Kagan Foundation, and the Deane F. Johnson Alzheimer Research Foundation. Dr. Doody acknowledges support from the Cynthia Woods Mitchell Endowed Research Fund for AD and the RSMIS Foundation.

Disclosure: Dr. Cummings has provided consultation to the following pharmaceutical companies: Acadia, Astellas, Athenagen, Avanir, Cephalon, Eisai, EnVivo, Forest, Janssen, Lundbeck, Merck, Merz, Myriad, Novartis, Ono, Pfizer, and Sanofi-Aventis. Dr. Clark serves on data monitoring committees for Elan Pharmaceuticals, Wyeth Research, Ono Pharmaceutical, and Myriad Pharmaceuticals. He has provided consultation services for Ortho Clinical Diagnostics. Dr. Doody has provided consultation to the following pharmaceutical companies in the past 12 months: Astra-Zeneca, Athenagen, Bristol-Myers Squibb, Eisai, Elan, Forest, GlaxoSmithKline, Lundbeck, Medivation, Myriad, Novartis, Ono Pharmaceutical, Pfizer, Sanofi-Aventis, Teva, Voyager, and Wyeth.

Received February 10, 2007. Accepted in final form April 17, 2007.

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