Alterations in cholesterol homeostasis are associated with Alzheimer's disease (AD). The role played by specific fractions of serum lipoproteins in modifying the risk of AD, and the interaction with APOE genotype has not yet been investigated. We studied serum lipoprotein profiles using a gradient-density ultracentrifugation method in a cohort of lateonset sporadic AD patients without cerebrovascular lesions and in healthy elderly subjects. In the AD group the lipoprotein cholesterol distribution showed an increase in LDL cholesterol, reaching a significant difference with respect to controls in the LDL sub-fractions representing the transition between small dense-LDL (fraction 11, p=0.04) and normal-density LDL particles (fraction 12, p=0.03). APOE genotype and LDL cholesterol were independently associated with AD. The mean concentration of LDL in fractions 11 and 12 increased the risk of developing AD ( p=0.01 and p=0.025, respectively). These results confirm that an alteration of cholesterol homeostasis is associated with AD and that serum concentrations of LDL cholesterol are higher in AD patients without cerebrovascular pathology than in elderly normal subjects. The presence of the APOE ε4+ allele is a risk factor for AD independent of increased serum cholesterol or a modification of other vascular risk factors. Increased levels of specific sub-fractions of LDL cholesterol may be associated with increased risk of AD.