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From The Laboratories for Molecular Neuroscience (Drs. Lai, Anderson, Chen, and Nixon), McLean Hospital, Belmont, MA; Departments of Neurology (Drs. Lai and Rebeck) and Psychiatry (Drs. Anderson, Chen, and Nixon), Harvard Medical School, Boston, MA; Neurology Service (Drs. Lai and Rebeck) and Medical Practices Evaluation Center (E. Kammann), Massachusetts General Hospital, Boston, MA; Biostatistics Department (E. Kammann), Harvard School of Public Health, Boston, MA; and Eunice Kennedy Shriver Center (Dr. Lai), Waltham, MA.
Address correspondence and reprint requests to Dr. Florence Lai, E002E, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114.
BACKGROUND: Alzheimer disease (AD) neuropathology is present in Down syndrome (DS) after age 35, but dementia onset varies from ages 40 to 70 years. Because of small sample sizes and nonuniform determination of dementia, previous studies produced differing results on the influence of APOE subtypes on AD in DS.
OBJECTIVE: To determine the influence of the APOE genotype and gender on development of AD in adults with DS to ascertain similarities with AD in the general population.
METHODS: A total of 100 adults with DS (ages 35 to 79 years), almost all of whom were longitudinally assessed by neurologists, underwent APOE genotyping. Dementia onset was determined using criteria applied from the Tenth International Classification of Mental and Behavioral Disorders. This cohort contains the largest number of DS subjects with dementia (n = 57) in a single study, thus increasing reliability of the results.
RESULTS: The 
2 allele frequency was 4% in those with dementia versus 13% in those without dementia (p = 0.03); 4 allele frequency was 18% in those with dementia versus 13% in those without dementia (p = 0.45). Using APOE-3/3 as the reference group, the risk ratio for the development of AD at any given time was 0.34 for the APOE-2/3 group (p = 0.04) and 1.44 for the APOE-(3/4,4/4) group (p = 0.25). Women were 1.77 times as likely to dement as men at any given point in time (p = 0.04).
CONCLUSIONS: The 2 allele confers a protective effect, and women with DS have an increased risk for AD, as in the general population. In this sample, 4 does not confer a significantly increased risk for AD in DS.
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