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From the Departments of Neurology (P.H.L., E.T., K.T., J.L.C.) and Psychiatry and Biobehavioral Sciences (J.L.C.), David Geffen School of Medicine at UCLA, Los Angeles; Department of Neuroscience (S.D.E.), University of California at San Diego; Neurobehavior Unit (E.T.), Greater Los Angeles VA Healthcare System, West Los Angeles, CA; and Department of Neurology (R.C.P.), Mayo Clinic College of Medicine, Rochester, MN.
Address correspondence and reprint requests to Dr. Po H. Lu, Mary S. Easton Center for Alzheimer's Disease Research, 10911 Weyburn Avenue, Suite 200, Los Angeles, CA 90095-7226 plu{at}mednet.ucla.edu.
Objective: To determine whether the presence of depression predicts higher rate of progression to Alzheimer disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and whether donepezil treatment beneficially affect this relationship.
Methods: The study sample was composed of 756 participants with aMCI from the 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study drug trial of donepezil and vitamin E. Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and participants were followed either to the end of study or to the primary endpoint of progression to probable or possible AD.
Results: Cox proportional hazards regression, adjusted for age at baseline, gender, apolipoprotein genotype, and NYU paragraph delayed recall score, showed that higher BDI scores were associated with progression to AD (p = 0.03). The sample was stratified into depressed (BDI score 
10; n = 208) and nondepressed (BDI <10; n = 548) groups. Kaplan-Meier analysis showed that among the depressed subjects, the proportion progressing to AD was lower for the donepezil group than the combined vitamin E and placebo groups at 1.7 years (p = 0.023), at 2.2 years (p = 0.025), and remained marginally lower at 2.7 years (p = 0.070). The survival curves among the three treatment groups did not differ within the nondepressed participants.
Conclusions: Results suggest that depression is predictive of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD) and treatment with donepezil delayed progression to AD among depressed subjects with aMCI. Donepezil appears to modulate the increased risk of AD conferred by the presence of depressive symptoms.
Abbreviations: AD = Alzheimer disease; ADCS = Alzheimer's Disease Cooperative Study; aMCI = amnestic mild cognitive impairment; BDI = Beck Depression Inventory; CDR = Clinical Dementia Rating; ChEI = cholinesterase inhibitors; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; HAM-D = Hamilton Depression Rating Scale; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association.
*Members of The Alzheimer's Disease Cooperative Study Group are listed in the appendix.
Supported by grants from the National Institute on Aging (K23-AG028727), Alzheimer's Association (NIRG-07-60424), the Alzheimer's Disease Cooperative Study (U01 AG010483), the Alzheimer's Disease Research Center (P50 AG-16570 from the National Institute on Aging), Alzheimer's Disease Research Center of California, Jim Easton, and the Sidell Kagan Foundation.
Medications: Donepezil (Aricept; Pfizer, New York, NY, and Eisai, Tokyo, Japan).
Disclosure: Author disclosures are provided at the end of the article.
Presented in part at the International Conference on Alzheimer's Disease, Chicago, IL, 2008.
Received August 22, 2008. Accepted in final form March 13, 2009.
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