Additionally it is possible that this damaging effects of A are on cerebral vasculature (Malek-Ahmadi 2021), long before its accumulation in the brain parenchyma is evident. With 20-20 hindsight, there were four key vulnerabilities that pervaded the industry-led, amyloid-focused therapeutic programs (Table??1). human clinical trials data. Given this lack of pharmacological validity, input from geneticists in collaboration with neuroscientists is needed to establish criteria for valid models of Alzheimers disease. More generally, scientists using genetic model organisms as whole-animal bioassays can contribute to building the pathogenesis network map of Alzheimers disease. concluded that Big Pharma is usually losing a fortune trying to remedy Alzheimers (Kresge and Bloomfield 2017; see Web Resources). This was echoed two years later in with the headline, Alzheimers: A Trail of Disappointment for Big Pharma (Mukherjee 2019; see Web Resources). Nonetheless, in early June 2021, the U.S. Food and Drug Administration (FDA) granted a highly controversial approval for an investigational biologic that critics say shows little evidence of improving cognition in patients with Alzheimers disease Rabbit Polyclonal to PXMP2 has a high rate of serious adverse events (Carome 2021; see Web Resources). Thus, the primary educational challenge that I and other professors face is usually how to help aspiring scientists understand why, despite enormous investment and effort in basic and clinical research for the past four decades, there are still no safe-and-effective therapies that slow Alzheimers disease progression. As for explaining the FDAs unexpected decision, that will have to await the investigations currently underway by several government agencies (see below). I propose that discoveries in human genetics were misapplied to the pathogenesis of Alzheimers disease in a well-intentioned push to jump-start the discovery of therapeutic brokers. Several key interacting factors were (1) the publication timeline of key scientific discoveries; (2) the Mendelian genetics of familial dementias; and (3) the Batyl alcohol assumptions that underlie drug-development efforts based on the amyloid-cascade hypothesis. Alzheimers disease poses questions and challenges Alzheimers disease is an adult-onset, chronic, progressive condition characterized by cognitive decline, typically starting slowly and insidiously with short-term memory deficits. Many patients also manifest mood changes and dysfunctional behaviors that are difficult for caregivers to manage. Neurodegeneration eventually affects many cortical areas, causing gross atrophy, with prominent involvement of the most phylogenetically advanced regions, the neocortex. However, at the outset, it tends to show regional selectivity with cholinergic pathways and the hippocampus, an essential structure for memory formation, being particularly Batyl alcohol vulnerable. In many patients, hippocampal volume reduction can be detected by high-resolution MRI. That raises several big questionsBut these are relatively modern late-20th-century questions that required better understanding of normal cognitive aging and enough cellular and molecular-level advances to support the very idea that Alzheimers disease could plausibly be treatable. As with any neurodegenerative disease, the fundamental mystery is usually, The first clues came from autopsy histopathology, notably the work of Aloysius Alois Alzheimer and other clinician-pathologists working in early 20th century. Using Bielschowsky silver staining, light microscopy and camera lucida technologies, Alzheimer and his contemporaries, including Oskar Fischer and Gheorghe Marinescu, drew two types of abnormal structures seen in the postmortem brain sections of their elderly demented patients (reproduced in Ryan 2015; Broxmeyer 2017). Senile plaques are extracellular, circular Medusa-like arrays of tendrils surrounding a smooth center. (At the time, senile referred to old age; thus, senile dementia and presenile dementia distinguish age of onset. ) A rough English translation of Alzheimers writing at the time would be, Senile Batyl alcohol plaques have something to do with dementia. He also described a second abnormality translated as, peculiar fibrillary changes of the nerve cells, later named neurofibrillary tangles (NFTs). These intracellular structures have a characteristic flame shape, filling the neuronal cell body, with the tapered end extending into the apical dendrite. These were two tantalizing smoking guns, albeit in end-stage autopsy brain tissue (Physique??1). Open in a separate window Physique 1 Plaques and tangles: the classic neuropathology of Alzheimers disease. Bielschowsky silver-stained section of cerebral cortex from a patient with Alzheimers disease. Reproduced and annotated with permission from Massachusetts Medical Society.