The Natural History of Alzheimer’s Disease: Minding the Gaps in Understanding the Mechanisms of Neurodegeneration

Alzheimer’s disease (AD) remains a formidable challenge despite advances in our understanding of many of the molecular events which surround its development. Studies over the past 20 years have focused on the role of Aβ amyloid in this disorder, with the aim of developing rational therapeutic strategies which can modify or prevent the disease process. This approach has been vindicated by the general acceptance of the “Aβ amyloid hypothesis,” which, among other concepts, has delivered the therapeutic targets of the β- and γ-secretases of the amyloid protein precursor (APP) which form the basis of the biogenesis of Aβ amyloid, the presenilins which are also intimate participants in the generation of Aβ, and other interacting proteins such as ApoE for which genetic evidence exists of linkage to the AD process. Despite this wealth of new knowledge, there remain many large gaps in our understanding of the pathogenesis of AD. These gaps include: 1) a full description of quantifiable levels of Aβ in relation to the progression of AD, and whether Aβ levels in biological fluids (plasma, CSF) can be used as reliable biological markers of the disease process; 2) whether currently available transgenic mouse models of AD sufficiently replicate the human disease, and whether the failure of these mice to develop neurofibrillary tangles is a major impediment; 3) the physical forms of Aβ which are pathologically relevant to the neurodegenerative process; 4) the intracellular compartments in which these etiologically relevant forms of Aβ are produced; 5) how extracellular forms of Aβ are processed and cleared from the brain, and whether either the intracellular or extracellular locations of Aβ can account for the peculiar topographic vulnerability of the brain in AD. Minding these gaps should lead to a more complete account of the natural history of AD and should also elucidate new therapeutic strategies.