Making Memories: The Search for a Cure to Alzheimer’s

by Emily Liu

It starts slowly, almost undetectably. You forget where you put your phone, even though you were just holding it a minute ago. You pause as you try to remember your niece’s name. You can’t recall what you said in the email you sent to your boss yesterday.

Then, more and more things start slipping away. You experience unusual shifts in your sleep patterns. On many occasions, you find yourself somewhere without knowing how you got there. You start to struggle with things like eating and walking, and finally, after just four to eight years, your life comes to a premature end.

This is Alzheimer’s disease.

Alzheimer’s is a neurodegenerative disease that leads to symptoms of dementia, the loss of cognitive and behavioral function that worsens to the point of interfering with daily life. As reported by the Alzheimer’s Association, about 5.8 million Americans are currently living with the disease, and this number is predicted to rise to almost 14 million by 2050. As of now, the progression of Alzheimer’s cannot be stopped or reversed, and it remains the sixth-leading cause of death in the United States. But according to a recent publication by the Nature and the Drug Target Review websites, there may be a new hope for those living with the disease.

On Feb. 10, The New York Times published an article about a study known as DIAN-TU. Over the course of five years, 194 participants tested two drugs — 52 took gantenerumab by Roche and another 52 took solanezumab by Eli Lilly. There were 40 participants that served as a control group and received no medication at all. All volunteers contained gene mutations for the overproduction of the protein amyloid, which is frequently found in clumps in the brains of patients with Alzheimer’s disease. Researchers observed that after Alzheimer’s patients developed these amyloid plaques, a protein known as tau started to appear in their brains, followed by neuron death. The two drugs specifically targeted amyloid plaques — scientists had hoped this would decisively point to amyloid as the culprit behind Alzheimer’s disease and prevent the devastating cognitive decline.

Up until now, the testing of anti-amyloid drugs has repeatedly brought back failed results. In 2011, patients testing the drug semagacestat only declined further, and the clinical trials of Biogen and Eisai’s drug aducanumab showed that it was extremely unlikely to have the intended effect. The DIAN-TU study was hardly any different — the data are still being analyzed, but the topline analysis showed that neither gantenerumab or solanezumab was effective in stopping Alzheimer’s. In light of this and similar studies, pharmaceutical companies began to grow skeptical of the correlation between accumulation of amyloid and development of Alzheimer’s disease, and many of them eventually reduced their efforts or gave up entirely.

Then, on Feb. 14, a discovery was made. At Tokyo Medical and Dental University, researchers identified a new target for future strategies: the YAP protein.

Neuron death is a crucial aspect of Alzheimer’s disease, but it is incredibly difficult to analyze in real time since dying cells cannot be stained through chemical means. Therefore, lead researcher Hikari Tanaka and his team used a biomarker to detect cell death, and as it turned out, neurons began dying much earlier than once thought.

At this early stage, Alzheimer’s patients were still only experiencing mild cognitive impairment (MCI). The researchers found that during MCI, neuronal death occurred at an even higher rate than it did during the full onset of Alzheimer’s. Upon taking a closer look, they found that a protein known as YAP decreased significantly in lab mice with Alzheimer’s and human patients with MCI. YAP served to increase the activity of the TEAD protein, and if the TEAD protein was too inactive, neuronal death would begin to occur. The deficiency of YAP was observed in the same amyloid plaques that have been under thorough examination in the past.

To test the effect of increased YAP activity on neuron health, the researchers injected the Alzheimer’s mice with a gene therapy vector expressing YAP analogue. As they’d hoped, the mice showed much less neuron loss and did not develop amyloid plaques. They concluded that further investigation is still needed, but medical intervention during MCI has the potential to prevent cognitive decline from ever developing into Alzheimer’s disease.

The Alzheimer’s Disease Research Center at the University of Pittsburgh is one of the leading research facilities contributing to the study of Alzheimer’s disease. The YAP protein is beginning to spark renewed interest in finding a cure to Alzheimer’s, and Pitt’s research center is recruiting patients for multiple clinical trials, including one to characterize all aspects of the disease starting from its earliest stages. Additionally, in the fall term of 2019, a group of Pitt students came together to start a chapter of the Youth Movement Against Alzheimer’s. The YMAA at Pitt currently works to raise awareness of Alzheimer’s disease among young age groups, raise funds towards studies like that surrounding the YAP protein and care for patients afflicted by the disease. As they continue welcoming new members to join them, they are steadily planning for new and better ways to contribute to this international cause.

Alzheimer’s disease has always been notoriously elusive, with no clear cause, treatment or cure as of yet. Progression of the disease has taken millions of lives, but the YAP study is a sign that we may soon save millions more. Even among the failed trials of the past, there is hope for the future, and although we still cannot predict what further research will find, we can put forth our best efforts knowing that they might someday lead us to a victory worth remembering.