Over a century ago, a German doctor called Alois Alzheimer spotted anomalies in brain sections from a patient with dementia. Ever since, people have been studying the strange plaques and tangles that he saw in the hope that we could one day understand and cure what is now known as Alzheimer’s disease. Plaques are insoluble deposits of a peptide called amyloid beta, or Abeta. They’re formed when a protein called Amyloid Precursor Protein, is sequentially cleaved by two enzymes: beta and gamma secretase. Other molecules are generated by this cleavage and may play a role in the disease, but Abeta is the main culprit. Abeta tends to misfold and become sticky, eventually clumping together to form soluble oligomers. Some of these aggregate into large insoluble fibrils that deposit in the brain as plaques. The oligomers come in several forms, or species. We don’t know exactly which species are toxic, but research shows that they weaken communication and plasticity at synapses. This could be what stops the brain from forming or retrieving memories. Neurons aren’t the only cells affected in Alzheimer’s disease; astrocytes and microglia also play a role. Microglia are immune cells that clear out waste and prune synapses during development. Microglia take up Abeta, but, they also get activated by it, triggering the release of inflammatory cytokines that can damage neurons. The microglia also start to remove synapses by phagocytosis. As synapses start to malfunction and neurons die, abnormal patterns of activity emerge, and eventually, the brain can’t process and store information properly. Another key feature of Alzheimer’s disease is neuro-degeneration. Neuronal death and damage is triggered by Abeta, but some of Abeta’s effects seem to be mediated by another protein seen in the brains of patients: Tau, a component of tangles. In a healthy neuron, molecules are carried along the axon on a series of ‘tracks’ made of microtubules and stabilised by Tau. But in Alzheimer’s disease, Tau is modified, causing it to dissociate from the microtubules, adopt an abnormal shape and move from the axon to the cell body. Like Abeta, Tau comes in a variety of forms and we don’t know which ones contribute to the disease. And like Abeta, these forms either remain soluble, or stick together and deposit as the tangles that Dr Alzheimer saw. Eventually, these processes kill the neuron. Another problem seen in animal models is that misfolded Tau proteins can spread, across synapses, into healthy neurons. There they make healthy Tau proteins start to misfold as well, spreading pathology across the brain. The pattern of spreading through the different brain regions matches the changing symptoms from early to late stages of Alzheimer’s Disease. This pattern also reflects how certain neurons are more vulnerable than others to dying. Despite these advances in our understanding of Alzheimer’s disease, no cure exists. While drugs are being developed to target Amyloid Beta or Tau, it’s unclear whether they will eventually be successful in treating the disease. There’s only one certainty: continued support for basic and clinical research will enable us, one day, to diagnose and treat this devastating condition.