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Apolipoprotein E controls the risk and age at onset of Parkinson disease

From the Department of Medicine and Center for Human Genetics (Drs. Li, Hauser, Scott, Martin, Qin, Walter, Pericak-Vance, and Vance, and M.W. Booze), Duke University Medical Center, Durham, NC; Struthers Parkinson Center (Dr. Nance), Golden Valley, MN; Department of Neurology (Dr. Hubble), Ohio State University, Columbus; Department of Neurology (Dr. Koller), University of Miami School of Medicine, FL; Department of Neurology (Dr. Pahwa), University of Kansas Medical Center, Kansas City; Department of Neurology (Dr. Stern), University of Pennsylvania Health System, Philadelphia; Department of Neurology (Dr. Hiner), Marshfield Clinic, Marshfield, WI; Department of Neurology (Dr. Jankovic), Baylor College of Medicine, Houston, TX; Department of Neurological Sciences (Dr. Goetz), Rush-Presbyterian-St. Luke’s Hospital, Chicago, IL; Departments of Psychiatry & Biobehavioral Sciences and Neurology (Dr. Small), University of California, Los Angeles; Centre for Neuromuscular and Neurological Disorders (Dr. Mastaglia), University of Western Australia, Perth; and Center for Human Genetics Research (Dr. Haines), Vanderbilt University Medical Center, Nashville, TN.

Address correspondence and reprint requests to Dr. Yi-Ju Li, Center for Human Genetics, Duke University Medical Center, DUMC Box 3445, Durham, NC 27710; e-mail: yiju.li{at}duke.edu

Background: Similarities between Alzheimer disease (AD) and Parkinson disease (PD) suggest a possible role for apolipoprotein E (APOE) in PD. Most previous studies seeking to establish such a link used case-control datasets and results have been inconsistent.

Objective: To investigate APOE’s role in PD using family-based association analyses.

Methods: APOE functional polymorphisms were genotyped for 658 PD affected families, including 282 multiplex and 376 singleton families. The pedigree disequilibrium test (PDT) and the genotype-PDT were used to test the risk effect of APOE. The Monks-Kaplan test was used to evaluate the effect of APOE on age at onset of PD.

Results: APOE was significantly associated with risk of developing PD. Stratified analysis revealed that APOE was most strongly associated with families with a positive PD family history (global p = 0.003). Like AD, the APOE-4 allele increases disease risk while the APOE-3 allele decreases risk. We detected a positive association of APOE-3 (p = 0.019) and a negative association of APOE-4 (p = 0.015) with age at onset in PD.

Conclusions: The APOE-4 allele increases risk and decreases age at onset of PD, an association that may not be dependent upon cognitive impairment.

Received October 5, 2003. Accepted in final form January 23, 2004.

*These authors contributed equally to the manuscript.

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