Biotech companies are seeking new avenues for Alzheimer’s research after continued failures of several major treatment opportunities in the pipeline. With half a million new cases diagnosed in the US each year and no approved treatments to stop or slow progression, any clinical breakthroughs could have a profound impact on millions of lives. Recently, some key areas of interest for researchers have included APOE4 targeting and the use of CRISPR technologies. However, as some clinical trials continue to lack promising results, other potential causes are being looked into, such as a bacteria found in tooth decay. Through a brief survey of the research landscape, biotech companies can make informed partnerships and anticipate clinical trajectories as they formulate business strategies.

Alzheimer’s Disease (AD), the most prevalent form of dementia, is caused by multiple genetic, lifestyle, and environmental factors. The most common type of AD is late-onset, and its ties to the APOE4 gene means that a genetic risk factor test is available for this specific version. By examining patients’ brains with AD, scientists have observed increased levels of inflammation, mitochondrial dysfunction, slowed microglia responses, and neurodegeneration. In the past, researchers have zeroed in their efforts on targeting the spread of harmful amyloid-beta and tau proteins, the presence of which seem to correlate with disease progression.

Since the 1980s, billions of research dollars have been poured into treatments aimed at breaking down amyloid-beta protein plaques within the brain. In previous clinical trials, Novartis and Amgen had to stop Phase II and III trials involving BACE1 inhibitors after patient cognition worsened after treatment. Roche has also stopped their versions targeting amyloid plaque build-up as well. One study found that only 60% of patients exhibit this buildup of proteins, and that levels of this substance actually increases in other parts of the brain as the disease progresses.

Biogen is currently seeking FDA approval for antibody therapy aducanumab, with a decision anticipated by early March of 2021. This treatment would prevent rapid cognitive decline by targeting the amyloid beta plaque, slowing the process, which has shown potentially promising in clinical studies. However, FDA advisors considered the drug a failure and have recommended that the approval not go through, though their recommendation does not necessarily prevent the FDA from approving it. Biohaven Pharmaceuticals’ troriluzole drug has also recently failed, showing to not have much effect on brain function compared to the placebo in most cases, though it may have some promise for mildly affected patients pending further study.

Eli Lilly has been working on a drug called donanemab which targets the N3pG beta amyloid. Research and trials have performed well thus far, with discussion with regulators potentially ahead, since after 18 months donanemab has slowed memory and activity decline by 32% in participants as compared to placebo receivers. This could be the first time an Alzheimer’s drug showed positive Phase 2 clinical trial results if the research is verified. As theories and studies continue to develop, researchers can better understand that AD is a complex, polygenic disease that will require a more comprehensive strategy to truly address.
 
Strategy 1: APOE4 Targeting  
As previously mentioned, the presence of the APOE4 indicates high risk, and those with a single copy of the genetic marker may see their chances of developing the disease increase by four times. However, those with the APOE2 variant show a decreased risk of developing the disease, and scientists believe it’s related to how this locus controls the transportation of cholesterol and fats throughout the body. However, gene therapies in the past have focused primarily on monogenic diseases and addressing something as complex as Alzheimer’s using this technology is a fairly novel concept. Furthermore, finding the right dosage levels is a still a work in progress.

Strategy 2: CRISPR Technologies 
CRIPSR has been used to identify a STIM1 protein deficiency as a disease biomarker in sporadic and unknown origin cases, which helps researchers understand cases without a clear hereditary link. By using CRISPR to examine cell phenotypes, researchers found these STIM1 deficiencies in AD patients that slowed down calcium transportation among cells.

The difficulties in using CRISPR as a therapeutic are two-fold: Delivery into the cerebrum is difficult, and Alzheimer’s presents fewer well-defined molecular targets to aim for. On a positive note, one study used RNA-guided CRISPR-Cas9 in non-human models to reduce behavioral impairments and improve cognition with minimal off-target effects. Time will tell if the process can be replicated successfully in human patients.

Strategy 3: Looking Beyond Amyloid Targets  
Recent studies have indicated that the bacteria known as p gingivalis may be involved in Alzheimer’s development. This bacteria is found in tooth decay, and research showed that people with higher rates of tooth loss have a greater chance of having Alzheimer’s. P gingivalis is also found in Alzheimer’s patients’ brains, and the bacteria produces neuron-destroying enzymes that cause amyloid plaque to form to help target the infection of gingipain enzymes. Additionally, research has found that the gingipain enzymes can fragment ApoE proteins causing nerve damage. This can also trigger inflammation, and since inflammation is also tied to genetics, the idea that bacteria may cause Alzheimer’s does not contradict research showing that the disease is genetically linked. To follow this lead, Cortexyme is studying gingipain inhibitor atuzaginstat which will reach Phase 3 of clinical trials in December 2021.

In 2020, there were 121 unique Alzheimer’s therapies being tested across 136 clinical trials. By staying up-to-date on the latest areas of study, biotech companies can look for new partnership opportunities and forecast potential sources of revenue. As the American population ages, the percent of individuals with this debilitating disease will likely increase. Although the amyloid-beta approach is losing traction, labs are using cutting-edge treatments as they explore other ways to tackle Alzheimer’s.

Contributions by Courtney Loughran and Sabrina Zirkle