Alzheimer’s disease: a challenge for modern neuropathobiology

Abstract

Springer-Verlag 2009 The clinical entity known as Alzheimer’s disease (AD) clearly existed before 1907, when Alois Alzheimer described the clinical course and changes in the brain of a 55-year-old woman dying after a 4-year history of progressive dementia [2, 4]. In his report of Auguste D, he demonstrated neurofibrillary tangles (NFT) using the newly developed Bielschowsky silver impregnation method, and observed cortical ‘‘miliary foci’’ of senile plaques (SP), described by Blocq and Marinesco [7] 15 years before. Examination of the histologic slides of Auguste D’s brain recovered 1992 in Munich revealed numerous NFTs and amyloid plaques in the upper parts of cerebral cortex, but no hippocampus was available. The genotype was determined ApoE e3/3 [14]. In the second case, Johann F, a male aged 56 years [3], numerous amyloid plaques but no NFTs were found in the neocortex, and DNA extraction revealed ApoE e3/3 without APP mutations [13]. Later studies suggested a familial form of the ‘‘plaque only type’’ of AD [19]. The case of Auguste D marks the beginning of research in Alzheimer’s disease (term introduced by Kraepelin in 1910 [20]), now recognized as the most common cause of dementia in the elderly—the disease/ epidemy of the twenty-first century, and the focus of intensive research during the past three centuries [17, 23]. Recently revised research and consensus criteria for the diagnosis of the major dementing disorders, in combination with modern (neuroimaging and cerebrospinal fluid) biomarkers improved the clinical diagnostic accuracy of AD from 65 to 92–96% [10]. Neuropathologic studies using immunohistochemistry, modern molecular biologic and genetic methods can achieve a diagnosis/classification, based on homogenous definitions, harmonized interlaboratory methods and standards for the assessment of nervous system lesions, in about 99%, without, however, being able to clarify the causes/etiology of most of these disorders, including AD. The current algorithms for the neuropathologic diagnosis of AD, based on (semi-) quantitative and topographic assessment of plaques and tangles, despite reasonable interrater agreements, only consider the classical