BRIEF COMMUNICATIONS zyxw Modulation of the Age at Onset of Parhnson's Disease by Apolipoprotein E Genotypes Sepideh Zareparsi, MS,* Jeffrey Kaye, MD,t§ Richard Camicioli, MD,t Holly Grimslid, BS,* Barry Oken, MD,t Michael Litt, PhD,** John Nutt, MD,t Thomas Bird, MD,'" Gerard Schellenberg, PhD,S**tt and Haydeh Payami, PhD*t Parkinson's disease (PD) patients often develop demen- tia, and Alzheimer's disease zyxwvuts (AD) patients frequently de- velop parkinsonian signs. The apolipoprotein E ~4 allele is associated with increased risk and earlier onset of AD. We studied 137 unrelated white PD patients. Those with zyxwvut ~4 had the earliest onset (52.7 2 9.8 years), ~ 3 1 ~ 3 pa- tients had an intermediate onset (56.1 zyxwvuts & 11.1 years), and those with ~2 had the latest onset (59.1 zyxwvut f 13.4 years). The age at onset distribution for ~41~- was significantly earlier than for ~3/~3 and ~ 2 / ~ 3 . These preliminary re- sults suggest that apolipoprotein E genotypes modulate the age at onset of PD. Zareparsi S, Kaye J, Camicioli R, Grimslid H, Oken B, Litt M, Nutt J, Bird T, Schellenberg G, Payami H. Modulation of the age at onset of Parkinson's disease by apolipoprotein E genotypes. Ann Neurol 1997;42:655-658 Parkinson's disease (PD) and Alzheimer's disease (AD) are common neurodegenerative diseases. PD is a move- ment disorder whose symptoms include tremor, rigid- ity, and bradykinesia, and it affects 1 to 2% of the population older than 60 years of age [I]. In contrast, AD, which affects 2 to 10% of the population older than age 65 [2], is characterized by loss of memory and cognitive function. Patients with PD frequently de- velop dementia zyxwvutsrqp [3, 41, and conversely, AD patients of- ten exhibit parkinsonian features [5, 61. Autopsy re- ports show an increased frequency of Lewy bodies, the prime pathological feature of PD, in brains of patients From the Departments of *Molecular and Medical Genetics, tNeu- rology, and $Biochemistry and Molecular Biology, Oregon Health Sciences University, and $Portland Veterans Affairs Medical Center, Portland, OR and "Neurology Section, SGeriatric Research Educa- tion and Clinical Center, Veterans Affairs Puget Sound Health Care System, and "Departments of Neurology, **Medicine, and ttPhar- macology, University of Washington, Seattle, WA. Received Jan 21, 1997, and in revised form Apr 16. Accepted for publication Apr 23, 1997. Address correspondence to Ms Zareparsi, CDW-2, Oregon Health Sciences University, 745 SW Gaines Rd, Portland, O R 97201. with AD [7], and PD patients often display coinciden- tal AD pathology (ie, senile plaques and neurofibrillary tangles) [8]. PD is more frequent among first-degree relatives of AD patients [9], and similarly, dementia is more frequent among firsr-degree relatives of PD pa- tients [2]. The familial clustering of PD and AD sug- gests that the mechanism responsible for their clinical and neuropathological overlap may have a genetic basis. AD is genetically heterogeneous [lo). The vast ma- jority of AD is late onset (>GO years) and is associated with the allelic variants of the apolipoprotein E (ApoE) gene on chromosome 19. ApoE has three common al- leles, ~2, ~3, and ~4. In most AD patient populations, z ~4 frequency is elevated and ~2 frequency is reduced [lo]. ~4 Carriers have significantly earlier onset and the highest age-specific risk of developing AD, and ~2 car- riers have delayed onset and the lowest age-specific risk [ 10, 1 11. The role of ApoE in the pathogenesis of AD is still unknown. Recent studies suggest that PD also has a genetic component [12-141. We have previously shown that P D patients with a family history positive for P D have significantly earlier age at onset than patients without a positive family history [15], which is suggestive of a genetic influence on the age at onset of PD. In the present study, we questioned whether ApoE genotypes modulate the onset of PD in a manner similar to their effect on onset of AD, such that ~4 carriers would have the earliest onset, ~3 homozygotes would have an in- termediate onset, and ~2 carriers would have the latest onset. A common association of ApoE with AD and PD may explain the clustering of PD and AD in indi- viduals and families. Several studies have shown that ApoE allele frequencies are not altered in I'D [ 16-20]. However, the lack of a difference in allele frequencies does not negate an ApoE effect on age at onset [ 111. The aim of this study was to test the hypothesis that ApoE genotypes modulate the age at onset of PD. Patients and Methods The study population consisted of 105 unrelated white PD patients recruited from the Movement Disorder Clinic at Oregon Health Sciences University, Portland, and 32 unre- lated white PD patients from the University of Washington. All patients were evaluated by a neurologist and were diag- nosed with idiopathic PD, based on the presence of two or more of the cardinal features of I'D (tremor, rigidity, and bradykinesia), and the lack of other signs and history that could indicate alternative diagnoses or causes. Patients were not demented at the time of PD diagnosis; however, they were not followed-up for subsequent development of demen- tia. All subjects signed an informed consent, approved by the Institutional Review Board. Age at onset was defined as the age at which the patient noticed the first symptom indicative of PD. Patients with onset before 30 years of age were excluded to avoid con- Copyright 0 1997 by the American Neurological Association 655