Studies looking for genetic variants across the genome that affect late-onset Alzheimer disease (LOAD) have had little success identifying genes other than APOE. Here, we use an expanded set of AD cases and controls to improve our power to detect genetic variants driving LOAD risk. Analyzing 483,399 genetic variants across the genome in a discovery dataset of 931 cases and 1,104 controls, we found a strong association to the marker rs11754661 on chromosome 6 in the gene MTHFD1L, in addition to the highly replicated chromosome 19 APOE association. We genotyped adjacent variants on chromosome 6 in these same cases and controls and found these variants were also associated with LOAD. We replicated the association with rs11754661 and additional SNPs in MTHFD1L in a combined dataset of cases and controls from our laboratory and from publicly available datasets. This finding is important because the gene is known to be involved in biological pathways influencing levels of homocysteine, a significant risk factor for AD.