Current development of therapeutic strategies for Alzheimer's disease

Alzheimer's disease is an increasingly prevalent neurodegenerative cause of dementia. The prevailing model begins with neuronal deposits of beta-amyloid (Aβ42) (phase I), followed by intra-neuronal fibrillary tangles of p-tau (phase II) that recruit numerous effector pathways (phase III) leading to neuronal damage, synaptic loss and gliosis. Monoclonal anti-Aβ antibodies and tau substituent peptide-elicited anti-p-tau antibodies reduce brain loads of these pathogenic proteins. Anti-Aβ antibodies decreased cognitive loss by a mean of 26%, but anti-p-tau antibodies had no effect. Anti-p-tau antibodies were well-tolerated, but 30% of patients receiving anti-Aβ antibodies had brain areas of swelling and hemorrhages detected by imaging. Early studies of pharmacological alteration of phase III neuropathic effector mechanisms in humans and mouse models include inhibition of intersectin-1 to preserve mitophagy and synaptic vesicle recycling, melanin-concentrating hormone prevention of memory loss, chimeric (brain astrocyte) antigen-astrocyte reduction in Aβ load, PD-1 immune checkpoint inhibitor suppression of neuroinflammation, and reduction in oxidative stress by phytochemicals or MitoVitE. The many possible mechanisms of decreased resilience of neurons to effector attacks of Alzheimer's disease remain under investigation.