A new promoter polymorphism in the alpha-1-antichymotrypsin gene is a disease modifier of Alzheimer's disease.
Increased levels of alpha-1-antichymotrypsin (ACT), a protease inhibitor and an acute phase protein, have been found in the brain and peripheral blood of patients with Alzheimer's disease (AD). Patients from northern Italy with a clinical diagnosis of probable AD, and patients with early onset AD (EOAD) from UK with AD neuropathological diagnosis were genotyped for a new polymorphism in the promoter region of the ACT gene which has been shown to affect ACT expression. A subset of patients with clinical AD from northern Italy was also followed up for 2 years and monitored for cognitive decline. The ACT TT promoter genotype was associated with an increased risk of EOAD independently from the presence of the apolipoprotein E (APOE) epsilon 4 allele. After manifestation of the disease the ACT TT genotype was also associated with faster cognitive decline in patients with the APOE allele epsilon 4. The ACT gene appears to influence the early clinical development of the disease, and the interaction of the ACT and APOE genes affects clinical progression of AD.
Licastro
Federico
F
Department of Experimental Pathology, School of Medicine, University of Bologna, Via S. Giacomo 14, 40126 Bologna, Italy. licastro@alma.unibo.it
Chiappelli
Martina
M
Grimaldi
Luigi M E
LM
Morgan
Kevin
K
Kalsheker
Noor
N
Calabrese
Elena
E
Ritchie
Alistair
A
Porcellini
Elisa
E
Salani
Giuliana
G
Franceschi
Massimo
M
Canal
Nicola
N
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics; D016009:Chi-Square Distribution; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D016001:Confidence Intervals; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007558:Italy / Q000208:ethnology; D008297:Male; D008609:Mental Status Schedule; D009483:Neuropsychological Tests; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D000514:alpha 1-Antichymotrypsin / Q000235:genetics*
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D000514:alpha 1-Antichymotrypsin