Corresponding author: Dr. Yu-Min Kuo, Department of Cell Biology and Anatomy, National Cheng Kung University College of Medicine, 1 University Rd, Tainan 70101, Taiwan. Tel: +886-6-235-3535 ext 5294, Fax: +886-6-209-3007, E-mail:kuoym@mail.ncku.edu.tw Received: March 25, 2003; Revised: April 25, 2003; Accepted: April 30, 2003. Chinese Journal of Physiology 46(3): 111-115, 2003 111 The Association of a Cystatin C Gene Polymorphism with Late-Onset Alzheimer’s Disease and Vascular Dementia C. Lin 1 , S-T. Wang 2 , C-W. Wu 3 , L-J. Chuo 4 , and Y-M. Kuo 3, * 1 Department of Physiology China Medical College Taichung, Taiwan 2 Departments of Public Health 3 Departments of Cell Biology and Anatomy, College of Medicine National Cheng Kung University Tainan, Taiwan 4 Department Psychiatry Taichung Veterans General Hospital Taichung, Taiwan Abstract A polymorphism in the cystatin C (CST3) gene was suggested to associate with Alzheimer’s disease (AD). In the present study we attempted to determine the association between CST3 polymorphism and AD or vascular dementia (VD), and whether such effects are dependent of the APOE4 allele. The polymorphisms of CST3 genotype were determined using polymerase chain reactions (PCR) followed by gel electrophoresis in 124 AD, 70 VD, and 115 control individuals. No statistical difference in CST3B allele frequencies was observed among all three groups. Associations between CST3B/B genotype and AD patients older than 75-year-old, or VD patients younger than 75-year-old were evident. The APOE4 allele alone significantly increased the odds for the developing AD, but not VD. A logistic regression analysis revealed that either CST3 or its interaction with APOE4 were not significant predictors of AD. However, a synergistic association of CST3 and APOE4 alleles was observed in predicting VD patients. These results suggest that CST3 might interact with APOE4 on conferring vascular pathologies. Key Words: cystatin C, apolipoprotein E, polymorphism, Alzheimer’s disease, vascular dementia Introduction Alzheimer’s disease (AD) is the most frequent dementia in the elderly, accounting for more than half of all cases (11, 16). In the last decade, emerging evidence suggests the association of genetic risk factors and AD susceptibility. Previous genetic linkage analyses have demonstrated that familial AD is associated with specific mutations to the amyloid- β precursor protein, presenilin 1 and 2 proteins genes (9). In addition, the ε 4 allele of the apolipoprotein E ( APOE) gene is recognized as a major genetic risk factor for the development of sporadic AD (20). However, despite the clear significance of APOE4 allele to risk of AD development, only about 30% of patients carry this allele, suggesting the involvement of additional factors in the manifestation of this dementia. Vascular dementia (VD) is another commonly observed cognitive dysfunction of elderly individuals. Vascular dementia features a dementia syndrome with vascular lesions, white matter changes, hippocampal neuronal loss and some other clinical symptoms also found in AD (4, 23). Interestingly, APOE4 has also been shown to be associated with a greater risk for VD development (22). Clinically, AD and VD have been