Editorial [Hot Topic:Active and Passive Aβ-Immunotherapy: Preclinical and Clinical Studies and Future Directions: Part I (Guest Editors: Michael G. Agadjanyan and David H. Cribbs)]

Alzheimer's disease (AD) is the leading cause of dementia among older people. An estimated 10% of Americans over the age of 65 and half of those over age 85 have Alzheimer's. More than four million Americans currently suffer from the disease, and the number is projected to balloon to 10-15 million over the next several decades. Alzheimer's is now the third most expensive disease to treat in the U.S., costing society close to $100 billion annually [1]. The clinical criteria for the diagnosis of AD include insidious onset and progressive impairment of memory and other cognitive functions; however a definitive diagnosis of AD can currently be made only at autopsy by examining brain tissue for amyloid plaques and neurofibrillary tangles. The extracellular amyloid plaques and intracellular neurofibrillary tangles represent examples of proteinopathies or proteopathies, which result from aberrant accumulation of misfolded or aggregated proteins that are believed to interfere with normal functions, and thereby either directly or indirectly contribute to disease pathogenesis. In addition to AD, misfolding or aberrant aggregation of proteins are central features of other neurodegenerative diseases as well, including tauopathies, Parkinson disease, amyotrophic lateral sclerosis, prion diseases, and the polyglutamine (polygln) diseases [2, 3]. Therapeutic strategies targeted at this class of diseases have focused on three areas: 1) reducing the production of the protein/peptide; 2) blocking the assembly of aberrant forms; or 3) promoting clearance [4]. The focus of this two volume series of reviews is on utilizing various types of immunotherapy to enhance clearance of the amyloid-beta (Aβ) peptide in the brain. The Aβ peptide has been targeted based on multiple lines of research, which have culminated in the amyloid hypothesis of AD, which assumes that the accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance [5]. The advent of anti-Aβ immunotherapy was initiated by the seminal report in Nature by Dale Schenk and his colleagues at Elan Pharmaceutical, where they showed that immunization of mice with the Aβ peptide prevented amyloid-plaque formation, neuritic dystrophy and astrogliosis, and that immunized older amyloid precursor protein (APP) transgenic (Tg) mice were able to clear preexisting forms of AD-like neuropathology [6]. Moreover, subsequent anti-Aβ immunization studies in APP/Tg mouse models of AD showed cognitive performance superior to that of the control transgenic mice and, ultimately, performed as well as non-transgenic mice [7, 8]. Additional studies using passive transfer of several monoclonal anti-Aβ antibodies identified antibodies as the principle therapeutic entity for clearance of CNS Aβ [9, 10]. However, the first immunotherapy clinical trial in AD patients, AN-1792, was halted when 6% of the Alzheimer's patients developed aseptic meningoencephalitis. Postmortem analysis of two cases with meningoencephalitis showed robust glial activation, T-cell infiltration and sporadic clearance of Aβ. Speculation on the cause(s) of the meningoencephalitis in patients that received the AN-1792 vaccine has focused on autoreactive anti-T Aβ and/or APP T cells and adjuvant-induced inflammation in the brain. The failure of the first clinical trial has encouraged the development of new approaches and alternative methods of immunotherapy for AD.