A century of confusion in researching Alzheimer’s disease

Abstract

More than a century ago Alois Alzheimer published a case study that later evolved into the Amyloid Cascade hypothesis—which assumes that increasing proliferation of plaques and tangles in the brain cause dementia. However, studies involving the removal of plaques—amyloid-—in patients’ brains resulted in worse cognitive performance, suggesting that plaques cannot solely be the disease. The search then focused on tau misfolded protein. But the evidence is uncertain. This paper suggests a critical history approach to understanding this confusion in Alzheimer’s disease research. Confusion is related to variability in expression of the disease, inaccuracy of clinical diagnostic tools, the relationship to other diseases, and the increasing neurological variance among older adults. The final verdict is that there is an unclear relationship between the biology and the expression of the disease. Alzheimer’s disease may in fact be the expression of another, yet unknown, disease. An often overlooked component in Alzheimer’s disease is white matter in the brain. Although found to be negatively related to dementia and positively related to learning, white matter remains unexamined in most current research. Historical evidence suggests that this was not the case a century ago. This paper is grounded in historical observations that Alois Alzheimer and his contemporaries identified these criticisms a hundred years ago. By ignoring these criticisms today, we have ended in a research cul de sac. This paper argues for greater specificity of the definition of Alzheimer’s disease and a broadening of the research focus to include the possible role of epigenetic changes, variance within older ages and brain plasticity. Only by broadening the scope of research and addressing this confusion directly can we move out of this research cul de sac and move closer to a cure.