Alzheimer's Beyond Amyloid

Alzheimer’s is a neurodegenerative disease marked by the degeneration of brain neurons in the cerebral cortex, causing severe memory loss and overall impaired cognition. Although most candidate drugs have attempted to attack protein markers of the disease such as tau or beta-amyloid, there has been little success in these endeavors. In fact, since the year 2000, over 200 Alzheimer’s drugs have been tested but none prove to be a “silver bullet” (Park 1). It was not until quite recently that researchers like Dr. Krishna Bhirani have discovered the linkage brain-derived neurotropic factors have to Alzheimers and fueled the creation of a brand-new cocktail drug that is currently in the process of phase 2 trials and data analysis.

In the article “Serum pro-BDNF levels correlate with phospho-tau staining in Alzheimer’s disease”, Dr. Krishna Bharani et al. explore the relationship between brain-derived neurotrophic factors (BDNF) and the development of Alzheimer’s disease (AD). The researchers looked at various postmortem brain and fluid samples of patients with AD and compared them to control samples to examine any possible correlations with BDNF and AD. First, the researchers found lower precursor BDNF levels in the entorhinal and frontal cortices in AD brains as well as lower staining densities of TrkB (a BDNF receptor) in the hippocampus paired with greater Amylo-Glo and pTau staining in this region. Further, they discovered lower total BDNF levels correlated with lower Amylo-Glo training in the hippocampus, suggesting that the lower levels of BDNF levels in the brain may influence amyloid accumulation in the hippocampus (Krishna 1). Together, these results suggest a strong relationship between BDNF and Alzheimer’s, paving the pathway towards a potential treatment in the disease. 

One potential treatment that echoes research findings like Dr. Krishna’s is the drug LM11A-31, which is discussed in the TIME article “Alzheimer’s from a New Angle” by Alice Park. The company PharmatrophiX, led by the chairman of the department of neurology and neurological sciences at Stanford Dr. Frank Longo, has been working on the drug for many years and the company is currently proceeding with data analysis of their phase 2 trial (Longo 1). As previously mentioned, the countless drug candidates for Alzheimers focused on directly attacking amyloid or tau. What makes this approach inefficient is that “about 30% of people over 70 have amyloid in their brains but no signs of dementia. In other words, everyone with Alzheimer’s has amyloid, but not everyone with amyloid has developed Alzheimer’s” (Park 3). Thus, Alzheimer’s drug cannot only focus on amyloid accumulation because it is not a clean-cut indicator of Alzheimer’s. Targeting tau, which comes at later stages of Alzheimer’s, also proves to be a difficult task for drugs focusing only on this protein marker. 

This is where the new candidate drug comes in: instead of directly attacking amyloid or tau, it’s goal is to simply keep the brain cells strong at all possible stages of Alzheimer’s. In order to maintain neuronal strength, this drug is taking into account recent research that emphasizes the importance of growth factors that play roles in preserving and even regenerating connections between nerves by experimenting with various nerve-growth factors, including BDNF. The article cites that “having higher levels of factors like BDNF might give people cognitive reserve–the ability to counteract any damage that’s occurring and minimize its effects” (Park 3). For example, in a study with mice treated with the drug (which includes anti-amyloid, anti-tau as well as nerve-growth factors), beyond treating the markers of Alzheimer’s, the researchers even found some significant reversal of damage caused by the disease, highly crediting the role of nerve-growth factors. Although trials are still being conducted, LM11A-31 is showing some promise in being both a preventative treatment as well as a potential cure for Alzheimer’s.

As shown in Dr. Krishna’s article, BDNF is a key player in the mechanism of Alzheimer’s progression as it has strong relationship with protein markers of the disease such as amyloid and tau accumulation in the hippocampus. Research results like these are crucial in treating Alzheimer’s because they shed a new light on what previous drug candidates have been getting wrong. As seen in the TIME article by Alice Park, the drug LM11A-31 is taking the road less traveled by targeting amyloid and tau as well as implementing various nerve-growth factors such as BDNF in the treatment. Although trials and data analyses are still being run at this very moment, it acts as hope for light at the end of the tunnel.

Works Cited

Bharani, Krishna, et al. “Serum pro-BDNF Levels Correlate with Phospho-Tau Staining in Alzheimer’s Disease.” Neurobiology of Aging, 2020. 

Longo, Frank. Pharmatrophix, Inc., 2020, www.pharmatrophix.com/. 

Park, Alice. “Alzheimer's from a New Angle.” Time, Time, 11 Feb. 2016, time.com/magazine/us/4217023/february-22nd-2016-vol-187-no-6-u-s/.