Pathogenic Presenilin Mutations Generate Aβ43
Two new papers rekindle acrimonious debate about exactly what “loss-of-function” means when it comes to presenilin mutations in Alzheimer’s pathogenesis.
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Two new papers rekindle acrimonious debate about exactly what “loss-of-function” means when it comes to presenilin mutations in Alzheimer’s pathogenesis.
Presenilin 2 resides almost exclusively in late endosomes, multivesicular bodies, and lysosomes, where it generates a pool of aggregation-prone Aβ. Some PS-1 mutations phenocopy this intraneuronal distribution.
The EPOCH trial of verubecestat was halted for lack of efficacy. APECS trial in prodromal AD continues.
Researchers claim this failed drug allows Aβ to accumulate inside cells, while small peptides cleaved from the C-terminal end of APP become trapped in membranes.
Recent studies have identified rare loss-of-function variants that cause Alzheimer’s with nearly 100 percent penetrance. Now there are 17 more.
Binding occurs around lipid deposits in the choroid plexus, near Aβ deposits, and also in atherosclerotic plaques in blood vessels.
When the agency sent warning letters to 17 companies that falsely advertised cures and preventions for AD, most took down exaggerated claims. But can regulations stay ahead of the market?
GV-971, an oligosaccharide derived from marine kelp, was approved to treat AD in China. Preclinical studies suggest the drug soothes neuroinflammation by balancing the gut microbiome.
Researchers link age-related weakening of the barrier to TGFβ signaling, hyperexcitation, and cognitive problems. In rodents, TGFβ antagonists attenuate these effects, reducing seizures.
Acting downstream of TREM2, PLCγ2 facilitates phagocytic microglial behavior such as lipid processing. PLCγ2 also acts downstream of toll-like receptors, where it can throw a switch to inflammation.
Cognitive enrichment in early life correlated with less Alzheimer’s pathology, and slower cognitive decline, in late life.
Overexpressing the endosomal activator in neurons not only caused those organelles to swell, but also bungled synaptic transmission, goaded hyperphosphorylation of tau, and destroyed cholinergic neurons.
A person's blood phospho-tau level, combined with his or her APOE genotype and scores on executive function and memory tests, outperforms the clinician in predicting dementia within the next four years.
Industry analysts and watchdogs have heaped criticism on the FDA, while Alzheimer’s researchers remain divided over whether the decision helps or harms the field.
Trial data for aducanumab did not answer key questions, such as how long patients should stay on drug, leaving clinicians around the world to struggle with practical and ethical issues.