An increasing number of genes have been linked to Alzheimer disease over the past decade. Most recently, hyperhomocysteinemia and gene mutations suspected to cause hyperhomocysteinemia have been suggested as possible contributors to Alzheimer disease. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which is the major circulating form of folate and a cofactor in remethylation of homocysteine. Two different mutations, one at base position 677 (C to T transition that results in a """"""""thermolabile"""""""" variant of the MTHFR enzyme) and another at base pair 1298 (A to C transition), are now suspected to lead to increased homocysteine levels and increased risk of Alzheimer disease. In order to study the possible role of these gene mutations in Alzheimer disease, we developed practicable PCR-single-strand conformation polymorphism (PCR-SSCP) methods for their study in a large patient population. Both methods have been validated against conventional PCR-restriction fragment-length polymorphism (PCR-RFLP) assays and confirmed by DNA sequencing. In order to analyze the effect of both MTHFR gene mutations on plasma homocysteine, we are also measuring the plasma homocysteine and cysteine levels by an HPLC method in these patients. In another collaborative study, the possible pathogenic role of apolipoprotein(a) isoforms and alleles is being studied in a large cohort of patients with systemic lupus erythematosus. These patients often experience atherothrombotic events and finding reliable predictors for these events is of major clinical importance. Our preliminary findings indicate that apolipoprotetin isoforms/alleles may be such predictors.
