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John C. Morris, MD; Martha Storandt, PhD; J. Phillip Miller; Daniel W. McKeel, MD; Joseph L. Price, PhD; Eugene H. Rubin, MD, PhD; Leonard Berg, MD

Arch Neurol. 2001;58:397-405.

Background  Mild cognitive impairment (MCI) is considered to be a transitional stage between aging and Alzheimer disease (AD).

Objective  To determine whether MCI represents early-stage AD by examining its natural history and neuropathologic basis.

Design  A prospective clinical and psychometric study of community-living elderly volunteers, both nondemented and minimally cognitively impaired, followed up for up to 9.5 years. Neuropathologic examinations were performed on participants who had undergone autopsy.

Setting  An AD research center.

Participants  All participants enrolled between July 1990 and June 1997 with Clinical Dementia Rating (CDR) scores of 0 (cognitively healthy; n = 177; mean age, 78.9 years) or 0.5 (equivalent to MCI; n = 277; mean age, 76.9 years). Based on the degree of clinical confidence that MCI represented dementia of the Alzheimer type (DAT), 3 subgroups of individuals with CDR scores of 0.5 were identified: CDR 0.5/DAT, CDR 0.5/incipient DAT, and CDR 0.5/uncertain dementia.

Main Outcome Measure  Progression to the stage of CDR 1, which characterizes mild definite DAT.

Results  Survival analysis showed that 100% of CDR 0.5/DAT participants progressed to greater dementia severity over a 9.5-year period. At 5 years, rates of progression to a score of CDR 1 (or greater) for DAT were 60.5% (95% confidence interval [CI], 50.2%-70.8%) for the CDR 0.5/DAT group, 35.7% (95% CI, 21.0%-50.3%) for the CDR 0.5/incipient DAT group, 19.9% (95% CI, 8.0%-31.8%) for the CDR 0.5/uncertain dementia group, and 6.8% (95% CI, 2.2%-11.3%) for CDR 0/controls. Progression to greater dementia severity correlated with degree of cognitive impairment at baseline. Twenty-four of the 25 participants with scores of CDR 0.5 had a neuropathologic dementing disorder, which was AD in 21 (84%).

Conclusions  Individuals currently characterized as having MCI progress steadily to greater stages of dementia severity at rates dependent on the level of cognitive impairment at entry and they almost always have the neuropathologic features of AD. We conclude that MCI generally represents early-stage AD.

From the Departments of Neurology (Drs Morris, Storandt, and Berg), Psychology (Dr Storandt), Pathology (Drs Morris and McKeel), Anatomy and Neurobiology (Dr Price), and Psychiatry (Dr Rubin), Division of Biostatistics (Mr Miller), and Alzheimer's Disease Research Center (Drs Morris, Storandt, McKeel, Price, Rubin, and Berg and Mr Miller), Washington University, St Louis, Mo.

Corresponding author and reprints: John C. Morris, MD, Alzheimer's Disease Research Center, Washington University School of Medicine, 4488 Forest Park Ave, Suite 130, St Louis, MO 63178.

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