In elderly men as in elderly women, endogenous estradiol may play an important role in age-related cognitive impairment. To explore the relation between estradiol, cognition, dementia, and cerebral atrophy, Muller and Geerlings performed a systematic literature review. In their review, the authors found that most studies in elderly men do not report significant associations between estradiol levels and cognitive performance, cognitive decline, dementia, or brain atrophy. Some studies, however, do imply that higher estradiol levels are potentially detrimental, although to the extent that a relation may exist, the magnitude of risk is likely small. Given the long preclinical phase of Alzheimer's disease (AD), it is difficult to infer causality, even in longitudinal studies with long follow-up. Muller and Geerling indicated that the relation between estradiol and vascular risk merits further study with respect to AD. In addition, they provide evidence that sex hormone binding globulin (SHBG) levels and aromatase activity are relevant to questions of AD pathogenesis.