Alzheimer's disease drug development and the problem of the blood-brain barrier

Abstract

Alzheimer's disease (AD) drug development is limited by the presence of the blood-brain barrier (BBB). More than 98% of all small-molecule drugs, and approximately 100% of all large-molecule drugs, do not cross the BBB. Although the vast majority of AD drug candidates do not cross the BBB, the present-day AD drug-development effort is characterized by an imbalance wherein >99% of the drug-development effort is devoted to central nervous system (CNS) drug discovery, and <1% of drug development is devoted to CNS drug delivery. Future AD drug development needs a concerted effort to incorporate BBB sciences early in the CNS drug discovery process. This goal can be achieved by a reallocation of resources, and an expansion of research efforts in the pure science of BBB biology and the applied science of brain drug-targeting technology.

Figure 1

Whole body autoradiogram of a mouse sacrificed after the intravenous injection of a small molecule, histamine, which has a molecular weight of 111 Da. The histamine readily distributes to the extra-vascular space of all organs of the body, except for the brain and spinal cord. Histamine does not penetrate the CNS, owing to the presence of the BBB.