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Altered PET Functional Brain Responses in Cognitively Intact Elderly Persons at Risk for Alzheimer Disease (Carriers of the 4 Allele)

Received August 20, 2003; revised January 13, April 16, 2004; accepted April 21, 2004. From the Cognitive Neuroscience Division of the Taub Institute for Research in Alzheimer's Disease and the Aging Brain (JF,AP,NS,CH,JH,AC,YS) and the Departments of Neurology (NS,YS), Psychiatry (GHP,MHT,DPD,YS) and Pathology (BT), College of Physicians and Surgeons of Columbia University, New York; and the Department of Psychiatry, University of Maryland, Baltimore, MD (KEA). Send correspondence to Nikolaos Scarmeas, M.D., Columbia University Medical Center; 622 West 168th St., PH 19th floor; New York, NY 10032. e-mail Note: ns257{at}columbia.edu
©2004 American Association for Geriatric Psychiatry

Objective: Few previous studies have investigated the association between APOE genotype and brain activation during performance of cognitive tasks in healthy middle-aged and elderly subjects, and the results have been mixed. The authors investigated APOE-mediated differential brain activation in a group of healthy elderly subjects. Methods: Using H₂¹⁵O positron emission tomography (PET), they imaged 32 healthy subjects (26 non-4 carriers and 6 4 carriers) performing a serial shape-recognition memory task under two conditions: Simple Demand (SD), in which one shape was presented in each study trial, and Titrated Demand (TD), in which study list length was adjusted so that each subject recognized words at approximately 75% accuracy. Multiple-regression analyses were performed, with the "activation" difference (TD–SD PET counts) as the dependent variable and the APOE genotype (presence versus absence of the 4 allele) as the independent variable. Results: Compared with non-carriers, 4 carriers exhibited significantly decreased TD–SD activation differences in the left superior temporal, right superior frontal, left postcental, left precuneus, and posterior cingulate gyrus because 4 carriers (versus non-carriers) showed increased activation during the SD and decreased activation during the TD condition. Conclusion: Patterns of brain activation during a nonverbal memory task differed as a function of APOE genotype and, therefore, of genetic risk for Alzheimer disease (AD). Differences in activation were not a reflection of task difficulty, but indicate memory-related altered cognitive processing. Brain regions with decreased activation in the 4 subjects may result from subclinical incipient AD pathology and/or APOE-related neurophysiologic heterogeneity.

Key Words: PET Studies • Neuroimaging • Genetic Studies • Cognition

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