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-β-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.

Parting with the Concept of Alzheimer’s Disease in Senium

“…Alzheimer was aware of this fact and noted that there was no behavioral difference between the early-onset and late-onset Alzheimer´s dementia. His hesitation was apparent in his article of 1912, in which he stated, "The question, therefore, arises as to whether the cases of disease which I considered peculiar, are sufficiently different clinically or histologically for being distinguished from senile dementia or whether they should be included under that rubric" [2]. Moreover, Gaetano Perusini, Alzheimer´s pupil who played a role in popularizing the cases of presenile dementia, was aware of quite similar changes in the senile cases as well, which he stated in the following manner: "Fibrillary changes, which, in regard to morphology and localization, are identical with those which I have described, are also sporadically found in old men *3+."…”

Curing Alzheimer’s Disease: Myriad Causes and Myriad Cures Await

“…By comingling these clinical diseases together-AD and senile dementia-research in AD became unfocused and confused [19]. Over four decades later this confusion can be gauged by the unrelenting and consistent failure of pharmacological interventions to stop or slow the disease.…”

The pitfalls of crowdfunding Alzheimer's disease research

“…In particular, understanding how the brain protects itself from getting infected, and once infected has methods to cope with the infection is an important aspect of neuropathological development. Protective factors include cognitive reserve and the capacity of the brain to absorb trauma (maybe including education, multilingual, exercise, diet, enriched environment in infancy) [36,37]. While factors that worsen resilience possibly includes behavior (alcohol, cigarette smoking, recreational drugs, concussion), environmental elements (possibly aluminum), and emotional trauma (divorce, death of a loved one, sexual, physical and emotional abuse, and depression) [11].…”

“…Research remains disorganized, clinicians remain confused, and the public has become increasingly worried [36,47].…”