The brain of an Alzheimer’s patient looks shrunken and warped; massive cell death causes regions of the brain to contract, while fluid filled pockets inside the brain expand. Neurons must fight through a landscape of toxic aggregates of misfolded proteins. These aggregates form from accumulation of the small protein fragment β-amyloid (Aβ). Aβ begins as a small isolated fragment which then clumps together to form small aggregates called oligomers, and ultimately larger aggregates known as fibrils and plaques. Heightened levels of Aβ aggregates, and in particular the presence of oligomers, is thought by many to play a key causative role in Alzheimer’s disease (AD), disrupting complex networks of neuronal communication and triggering widespread cell death. Aβ has thus been the subject of intense research, but drugs specifically inhibiting Aβ aggregation have so far proven elusive.

To address this challenge, a team of scientists from the University of Cambridge, the University of Groningen in the Netherlands, and Lund University in Sweden, have developed a drug discovery pipeline to identify and characterise chemical compounds that target the formation of these toxic Aβ aggregates. Habchi and colleagues first screened a large set of chemical fragments to identify a library of compounds that interact with Aβ. Next, relying on a detailed chemical analysis of how Aβ aggregates form, they analyzed precisely how and where each selected candidate compound may interact with the Aβ aggregation pathway.

One promising compound is bexarotene, a drug approved years ago by the US Federal Drug Association and the European Medicines Agency for lymphoma. A 2012 study proposed that bexarotene helps get rid of excess Aβ by stimulating the production of another protein called apolipoprotein E (APOE), which promotes Aβ degradation. However, several groups failed to replicate this result, and its mechanism of action remained unclear.

Habchi and colleagues found through chemical kinetics analysis that bexarotene directly inhibits Aβ aggregation by delaying the first step in its production. Bexarotene dramatically slowed the initial joining of single Aβ monomers into the small groups that then form ‘seeds’ from which Aβ fibrils can grow. Bexarotene therefore delays aggregate formation significantly, but over time the number of aggregates creeps up anyway, ultimately reaching the same level as without the drug.

Armed with knowledge of bexarotene’s mechanism of action, the researchers proposed that bexarotene might serve as a ‘neurostatin’, a preventative drug analogous to statins prescribed for individuals with high risk of heart disease. Statins reduce cholesterol levels, lowering the risk of heart conditions. So, the analogy goes, neurostatins would be prescribed to seemingly healthy individuals at risk of AD. Delaying the initial aggregation of Aβ would in turn delay the onset of symptoms. Promisingly, in a worm model of Aβ-induced toxicity, bexarotene did just that. Worms normally develop paralysis as they age due to a build-up of toxic Aβ aggregates, so when they were given high doses of bexarotene at early larval stages they remained as motile as Aβ-free worms.

Alzheimer’s Disease International estimated that in 2015, there was a new AD case every three seconds. If bexarotene proves an effective preventative treatment, it could be instrumental in quelling this costly and perilous epidemic. Bexarotene delays Aβ aggregation, making it a promising prophylactic treatment, but drugs targeting later stages of the aggregation pathway could be even more powerful, for instance by decreasing the number of toxic Aβ aggregates instead of delaying their onset. The authors’ drug discovery and characterization pipeline provides a way to search for such compounds, perhaps offering hope that new drugs may soon be identified to aid sufferers and those at high risk of this disease.