Bapineuzumab: anti-ß-amyloid monoclonal antibodies for the treatment of Alzheimer's disease.

In the last decade, new therapeutic approaches targeting ß-amyloid (Aß) have been discovered and developed with the hope of modifying the natural history of Alzheimer's disease (AD). The most revolutionary of these approaches consists in the removal of brain Aß via anti-Aß antibodies. After an active vaccine (AN1792) was discontinued in 2002 due to occurrence of meningoencephalitis in approximately 6% of patients, several other second-generation active Aß vaccines and passive Aß immunotherapies have been developed and are under clinical investigation with the aim of accelerating Aß clearance from the brain of AD patients. The most advanced of these immunological approaches is bapineuzumab, which is composed of humanized anti-Aß monoclonal antibodies that has been tested in two Phase II trials. Bapineuzumab has been shown to reduce Aß burden in the brain of AD patients. However, its preliminary cognitive efficacy appears uncertain, particularly in ApoE ε4 carriers, and vasogenic edema may limit its clinical use. The results of four ongoing large Phase III trials on bapineuzumab will provide answers regarding whether passive anti-Aß immunization is able to alter the course of this devastating disease.

Circulating biomarkers of cognitive decline and dementia.

Plasma and serum biochemical markers proposed for cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin and predementia syndromes (mild cognitive impairment and other related entities) are based on pathophysiologic processes such as lipoprotein metabolism (total cholesterol, apolipoprotein E, 24S-hydroxy-cholesterol), and vascular disease (homocysteine, lipoprotein(a)); SP formation (amyloid beta(Abeta)-protein, Abeta autoantibodies, platelet APP isoforms), oxidative stress (isoprostanes, vitamin E), and inflammation (cytokines). This review will focus on the current knowledge on circulating serum and plasma biomarkers of cognitive decline and dementia that are linked to cholesterol homeostasis and lipoprotein abnormalities, senile plaque formation and amyloid precursor protein (APP) metabolism, oxidative stress, and inflammatory reactions. Special emphasis will, however, be placed on biomarkers related to lipoprotein metabolism and vascular disease. Analytically, most plasma and serum proteins or metabolites lack reproducibility, sensitivity, or specificity for the diagnosis, risk and progression assessment, or therapeutic monitoring of AD and other dementing disorders. Measures linked to lipoprotein metabolism and vascular disease, APP metabolism, oxidative stress, or inflammation appear altered in AD relative to controls, but lack sufficient discriminatory power. Measures combining several biomarkers or incorporating a range of proteins in plasma and small molecule metabolites are promising approaches for the development of plasma or serum-based diagnostic tests for AD and other dementing disorders, as well as for predementia syndromes.