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It seems that the tipping point has been reached in the Alzheimer’s research and development community, in the sense that it is becoming more widely accepted that new approaches are needed. The failure to produce significant benefits to patients via clearance of amyloid from the brain by immunotherapy has spurred a great deal of theorizing, and several new and promising lines of work. For example, working on restoring age-related declines in drainage of cerebrospinal fluid might remove all metabolic waste from the brain. Alternatively, a focus on neuroinflammation and the role of dysfunctional microglia is suggested, particularly by studies of senolytics showing benefits in mouse models resulting from removal of senescent microglia. The monolithic focus on amyloid is giving way to a period of greater experimentation and diversity in clinical development, and this can only be a good thing when it comes to making progress towards effective treatments for Alzheimer’s disease.
In the last five years, as several large clinical trials testing drugs for Alzheimer’s disease failed, the field came to a stark conclusion: These approaches did nothing to slow down – let alone reverse – the course of the disease once patients already exhibited symptoms of early dementia. The failed trials, along with the dawning realization that the disease unfolds over decades, have put the entire field on a reset-to develop and test interventions that can be used much earlier, to discover new targets beyond misfolded amyloid and tau proteins, and to fund large, interdisciplinary, big data collaborations.
Aging is by far the biggest risk factor for developing Alzheimer’s – if everyone lived to be 85, one in two people would develop dementia. The lion’s share of Alzheimer’s research and drug discovery to date has focused on misfolded amyloid and tau proteins, which aggregate to form plaques (amyloid) and tangles (tau) in the brain. But the body’s attempt to clear the sticky proteins might also be contributing to or causing the neurodegeneration. Drug trials have almost exclusively sought to use antibodies targeted toward these two proteins to try to attack and clear the misfolded forms or mop up soluble forms, or to inhibit enzymes responsible for generating the miscreant peptides.
New areas being explored include the vascular system, epigenetics, neuroprotection, synaptic health, immunity and inflammation, and metabolic dysfunction, among others. Neuroinflammation and proteostasis, or the management of proteins within cells, are trending areas of research. Another booming area of Alzheimer’s research is the development of biomarkers and diagnostic tests to monitor disease presence and progression. Radioactive positron emission tomography (PET) tracers enable physicians to image and measure amyloid and tau proteins in the brains of living patients. Other biomarkers can be measured precisely from collecting cerebral spinal fluid. However, both types of tests are invasive, and PET scans are expensive. “We need a blood test like the one we have for cholesterol that can be done in any doctor’s office quickly and inexpensively.”
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