A new promoter polymorphism in the alpha-1-antichymotrypsin gene is a disease modifier of Alzheimer’s disease

Abstract 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) e 4 allele. After manifestation of the disease the ACT TT genotype was also associated with faster cognitive decline in patients with the APOE allele e 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.