ElusiveAlzheimer'sDisease:CanImmune SignaturesHelpOurUnderstandingofThis ChallengingDisease?Part1:Clinicaland HistoricalBackgroundofAlzheimer'sDisease

Alzheimer's disease (AD) is the most com - mon form of dementia. Its most important patholog - ical hallmarks are profound neuronal loss, presence of intracellular neurofibrillary tangles, and extracel - lular deposition of beta-amyloid protein (A β) as beta-amyloid plaques. These latter aggregations result in neuronal degeneration in brain regions important not only for memory, but also for other cognitive functions. One of the most important risk factors for AD is age and with the increase of life- expectancy AD has thus become the most common form of dementia. It is now formally recognized by several new diagnostic criteria that AD is not a homogeneous disease. The current "Holy Grail" is to be able to diagnose variants of AD before they manifest clinically and before irreparable brain damage is done. To achieve this goal, robust and reli - able biomarkers that reflect the pathogenesis of AD have to be implemented. This is of paramount importance because such biomarkers may provide clues to pathways that can be targeted for interven - tions aimed at disease prevention or improvement. Although much attention has focused on A β as a major component of AD, A β may be a lesser attrac - tive target since an increasing amount of data has raised concerns about its causative role in AD. This review will be in two parts, this first part will deal with the current clinical knowledge and the questions raised by the A β cascade hypothesis in the pathogenesis of AD and the second part will aim to synthesize our current knowledge and to discuss new data that suggest how immune alterations may contribute to the development of AD and may there - fore provide beneficial targets in novel approaches for the treatment of AD. (Discovery Medicine 15(80):n-n, Janu ar y 2013)