Cortisol: Mediator of association between Alzheimer's disease and diabetes mellitus?

Numerous epidemiologic studies have identified an independent association between Alzheimer's disease (AD) and diabetes mellitus (DM), which remains unexplained. This review contends that the association is mediated by mild hypercortisolemia that is manifested in AD by early stages, as empirical evidence indicates that hypercortisolemia is diabetogenic even at subclinical levels. Subclinical Cushing's syndrome is discussed as the paradigm. It is proposed that hypercortisolemia increases the risk of pre-diabetes and DM during early AD and the preceding decades. That hypercortisolemia is exhibited during the AD prodromal stage has yet to be determined, but may be inferred from concurrent metabolic parameters as documented in the literature. Studies refuting association between AD and DM also are evaluated, and the relationship between AD and DM is deduced to be more complex than directly causal, with DM of longstanding duration having a protective role. Association between DM and AD may require reappraisal by APOE ε4 carrier status, in view of newly identified roles of APOE ε4 in pre-diabetes. That association of APOE ε4 with DM in AD may have been underestimated in epidemiologic studies also is highlighted. At the core of arguments and mechanisms presented in this review is the circadian rhythm of cortisol secretion, which is the main determinant of glycemic control in humans. Alterations to that rhythm and to the hypothalamic-pituitary-adrenal axis occurring in AD are examined. Consequently the cause of hypercortisolemia in AD, and therefore of association between AD and DM, is proposed to be adrenal hyper-responsiveness to adrenocorticotropic hormone.