Alpha-1-antichymotrypsin (ACT or SERPINA3) polymorphism may affect age-at-onset and disease duration of Alzheimer's disease

Kamboh, M. Ilyas; Minster, Ryan L.; Kenney, Margaret; Ozturk, Ayla; Desai, Purnima P.; Kammerer, Candace M.; DeKosky, Steven T.

doi:10.1016/j.neurobiolaging.2005.07.015

« Previous Next »Neurobiology of Aging
Volume 27, Issue 10 , Pages 1435-1439, October 2006

Alpha-1-antichymotrypsin (ACT or SERPINA3) polymorphism may affect age-at-onset and disease duration of Alzheimer's disease

M. Ilyas Kamboh
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Corresponding author. Tel.: +1 412 624 3066; fax: +1 412 383 7844.
Ryan L. Minster
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
Margaret Kenney
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
Ayla Ozturk
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
Purnima P. Desai
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
Candace M. Kammerer
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
Steven T. DeKosky
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Alzheimer's Disease Research Center, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA

Received 3 May 2005; received in revised form 11 July 2005; accepted 25 July 2005. published online 03 September 2005.

Abstract

In addition to genetic effects on disease risk, age-at-onset (AAO) of Alzheimer's disease (AD) is also genetically controlled. Using AAO as a covariate, a linkage signal for AD has been detected on chromosome 14q32 near the α1-antichymotrypsin (ACT) gene. Previously, a signal peptide polymorphism (codon −17A>T) in the ACT gene has been suggested to affect AD risk, but with inconsistent findings. Given that a linkage signal for AAO has been detected near ACT, we hypothesized that ACT genetic variation affects AAO rather than disease risk and this may explain the previous inconsistent findings between ACT genetic variation and AD risk. We examined the impact of the ACT signal peptide polymorphism on mean AAO in 909 AD cases. The ACT polymorphism was significantly associated with AAO and this effect was independent of the APOE polymorphism. Mean AAO among ACT/AA homozygotes was significantly lower than that in the combined AT+TT genotype group (p=0.019) and this difference was confined to male AD patients (p=0.002). Among male AD patients, the ACT/AA genotype was also associated with shorter disease duration before death as compared to the ACT/AT+TT genotypes (p=0.012). These data suggest that the ACT gene may affect AAO and disease duration of AD.