Promising Treatment for Alzheimer's Disease

More than 55 million people worldwide were living with Alzheimer's disease in 2020, according to Alzheimer's Disease International. This figure is expected to almost double every 20 years, reaching 78 million in 2030 and 139 million in 2050. In 2021 the WHO Global Status Report estimated the annual worldwide cost of dementia as over $1.3 trillion and anticipated to rise to $2.8 trillion by 2030.

To date most drugs developed to treat Alzheimer's disease have failed, largely because they do not necessarily target the correct biomarkers and individuals already exhibiting signs of the disease. Once symptoms appear, however, many brain cells responsible for memory and cognition are likely already damaged and beyond repair. 

Professor Shai Rahimipour in the Chemistry Department at Bar-Ilan University in Israel has pioneered a different approach utilizing theranostics to pinpoint and treat the earliest, pre-symptomatic signs of Alzheimer's disease. Showing promise in stopping progression of the disease before onset of irreversible brain cell damage, Rahimipour's groundbreaking approach has garnered significant attention in the scientific world.   

In Alzheimer's disease, a small protein known as amyloid beta misfolds to intermediates that aggregate into larger macromolecular structures known as fibrils and plaques.

Although the exact cause of Alzheimer’s disease is still unknown, scientists long believed that amyloid plaques and fibrils, which are visible under a microscope, were the main pathogenic species leading to the damaging neurons in Alzheimer’s disease etiology. Many clinical trials and billions of dollars were invested over more than a quarter of a century to generate molecules and antibodies targeting and preventing formation of fibrils and plaques. Such treatments proved unsuccessful and caused intolerable side effects. Over time, fibrils and plaques themselves were deemed not really toxic, and instead earlier soluble intermediates known as oligomers are now considered the culprits in this insidious disease.

Recent clinical trials using antibodies to target oligomers have shown promising results, and the Biogen/Essai antibodies Aducanumab and Lecanemab have received US Food and Drug Administration (FDA) approval. Controversy over efficacy and notable side effects such as microhemorrhages and brain swelling highlight the need for better therapy and tools for early Alzheimer’s disease detection to improve standard of care. Moreover, most antibodies don't reach the brain sufficiently because the blood-brain barrier limits penetration of proteins and antibodies.

Rahimipour and his team have overcome these barriers by developing small abiotic and druggable cyclic peptides that was proven effective in diagnosing early pre-symptomatic stage of Alzheimer's and treating the disease by targeting oligomers. When these molecules were combined in a test tube with the small protein amyloid beta, the generation of oligomers was completely blocked, and no subsequent aggregation occurred. Instead, the cyclic peptides stabilized the early forms of amyloid beta before they converted to the toxic oligomers.

In the next stage, the researchers incubated human neurons with the toxic oligomers and the cyclic peptides. Most neurons remained alive, but those in the control group that were exposed to the oligomers without cyclic peptides were severely damaged and died.

With advanced research, the researchers successfully predetermined the onset of the disease before the formation of amyloid fibrils and plaques, and before the appearance of symptoms of Alzheimer's disease by detecting extremely low concentrations of early oligomers in the brain, using non-invasive imaging methods. Moreover, they showed for the first time that the pathology of Alzheimer’s disease starts at thalamus in the brain, an area that has often been overlooked in Alzheimer’s disease studies. Later, they were able to show that Alzheimer’s progression can be stopped in the very early stages of the Alzheimer’s disease animal model, by inhibiting the oligomer formation.

"We have, in effect, halted the disease in its early stages, even before oligomers are formed. One great advantage of our synthetic molecules, in contrast to natural antibodies, is that they are not immunogenic, and they remain in the body much longer, so fewer injections or applications are likely needed," says Prof. Rahimipour. "Our meticulous regime of experiments has shown no sign of toxicity and that, unlike antibodies, the molecules cross the blood-brain barrier very well," he adds.

Prof. Rahimipour's research was recently published in the journal Proceedings of the National Academy of Sciences, in collaboration with colleagues from the Université de Sherbrooke and the Université de Montréal in Canada. He is now working on the development of an appropriate drug toward pre-clinical and clinical trials.