WHAT IS THE STUDY ABOUT?
Phase 2 trials on an Alzheimer’s drug, Eli Lilly’s donanemab, has been carried out – and it has one of the most encouraging results ever in the history of the therapeutic treatment of Alzheimer’s. How does it work? The simple answer would be: donamemab clears amyloid plaques.
Of the 257 participants with early Alzheimer’s disease in the study, 131 received donanemab and 126 received placebo. The result was promising – donanemab successfully slowed down cognitive and functional decline of patients by 32% on the Integrated Alzheimer’s Disease Rating Scale (RC, BR, MA, & AM, 2021). On top of that, brain scans also revealed that donanemab effectively cleared amyloid from the brain in 68% of participants.
WHAT CAUSES ALZHEIMER’S DISEASE?
Before delving into the significance of this study, let us look at what Alzheimer’s disease is. There are two leading hypotheses of what causes Alzheimer’s disease – Amyloid hypothesis and infectious hypothesis.
Amyloid hypothesis (and tau hypothesis)
In the amyloid hypothesis, there are two main culprits responsible for causing Alzheimer’s – Beta-amyloid (Aβ) peptide and tau. Aβ is produced in many tissues, and it is small enough to sneak through the blood brain barrier and deposit around neurons to form plaques. These plaques interrupt nerve impulse transmission between synapses, either causing neuroinflammation and thus neuronal death (Parkins, 2021), or by triggering tau tangles. What is tau? Tau normally stabilizes neurons. Think of them as rubber bands you tie around your hair. When Aβ adds a phosphate group to them, these “rubber bands” not only let loose your hair, but also make everything all the more chaotic by forming tangles among themselves – these are what we call neurofibrillary tangles. These tangles will accumulate inside neurons and lead to cell death.
(Neural Regeneration Research, n.d.)
A strong evidence supporting the amyloid hypothesis is the discovery of APP gene. APP gene codes for APP protein, which is a precursor cut by β-secretase and γ-secretase into Aβ segments.
When there is a mutation on APP, the precursor is more likely to be cleaved into longer parts that can stick together to form plaques more easily. (Makin, 2018) Moreover, APP is on chromosome 21… sounds familiar? That’s because patients with Down’s syndrome are characterized by the extra copy of chromosome 21 (also known as trisomy 21). The fact that up to 50% of Down’s syndrome patients in their 60s develop Alzheimer’s dementia (Down syndrome and alzheimer's disease n.d.) is another strong proof for amyloid hypothesis. When there is an extra copy of APP, there is an overproduction of Aβ to form amyloid plaques, thereby increasing the risk of Alzheimer’s disease.
The treatment for Alzheimer’s disease is simple, if we only consider the amyloid hypothesis – We just have to inhibit the β- and γ-secretase, or directly eradicate the amyloid plaques.
As β-secretase and γ-secretase also play an important role in other biological functions, inhibiting them may risk disrupting our overall metabolism. Hence, most researchers are working on eradicating amyloid plaques. However, due to multiples failures in drugs that target amyloid plaques over the past two decades, such as aducanumab by Biogen, verubecestat by Merck, just to name a few, people have started to cast doubt on the veracity of the hypothesis.
Another flaw in the amyloid hypothesis is that Alzheimer’s symptoms are more closely related to the “number and location of tau tangles” than they are to Aβ. (Parkins, 2021) While supporters of the amyloid hypothesis may suggest that amyloid causes tau, there is no direct evidence proving so. Instead, some studies in mice have shown that tau tangles do not necessarily form when there are amyloid plaques, while other studies show that tau are found in patients with mild dementia but not amyloid plaques. And this is why some people believe in the “tau hypothesis”, meaning that tau is the main cause of Alzheimer’s Disease and occurs independently of amyloid plaques. Nonetheless, the tau hypothesis is underdeveloped, and it is still a mainstream belief that tau tangles are induced by amyloid plaques.
Infectious hypothesis
Infectious hypothesis suggests that pathogens, in particular a herpesvirus called HSV-1, are the main cause of Alzheimer’s disease. One of the strongest supporting evidence comes from a study in 2002, which revealed that several types of herpesviruses, including HSV-1, are found more commonly in patients with Alzheimer’s disease (Lin WR;Wozniak MA;Cooper RJ;Wilcock GK;Itzhaki RF, n.d.) . According to the National Health Insurance Research Database in Taiwan, those who have been infected with HSV had a 2.56 increased risk of developing dementia, suggesting a positive correlation between HSV and neurodegeneration. Moreover, those who took antiviral drugs to treat HSV infection have shown a 90% reduced risk of further dementia compared to those who did not take any medication. In fact, some studies also show that flu shots (Verreault, Laurin, Lindsay, & De Serres, 2001) and pneumonia vaccines (Flu, pneumonia Vaccinations tied to lower risk of ALZHEIMER'S DEMENTIA: Aaic 2020: Alzheimer's Association n.d.) may reduce the risk of developing Alzheimer’s disease, though dietary behaviors of participants have not been well-controlled. Could common vaccines be used to combat Alzheimer’s disease? The answer to this question remains a mystery.
Back to the infectious hypothesis: how exactly does infection lead to Alzheimer’s disease? The actual mechanism is not known but it is believed that infection accelerates the deposit of Aβ into amyloid plaques. Since Aβ actually has anti-microbial properties that allow it to “entrap pathogens and disrupt cell membranes” (SR, 2018), some scientists believe that Aβ are attracted to the site of infection. So, it can be argued that Aβ offers neuroprotective effects in response to damage, rather than being the cause of neurodegeneration.
On the other hand, it is also suggested that viruses can directly interact with proteins, thereby making Aβ more likely to aggregate into plaques (Ezzat K; Pernemalm M et al. 2019) This does not contradict the amyloid hypothesis, but instead, it provides an explanation to why Aβ deposits, while supporting the role of Aβ in the development of Alzheimer’s disease.
The list of hypotheses for Alzheimer’s disease goes on – neuroinflammation hypothesis, synapse hypothesis, mitochondria hypothesis… Search them up if you’re interested!
WHAT IS THIS STUDY IMPORTANT? WHY SHOULD YOU CARE?
It has been nearly 20 years since the FDA approved a new drug to treat the disease. (Marvar, 2021) In other words, the success of donanemab’s phase 2 trial marks an important milestone in the development of treatment against Alzheimer’s disease. Furthermore, it also affirms that treatment aimed at amyloid can slow down development of Alzheimer’s disease.
So, what makes donanemab different from other drugs targeting amyloid plaques? Prior to the success of donanemab, the drug that has come closest to backing up the amyloid hypothesis is Biogen’s aducanumab, which failed in phase 3 trials. Like many other potential Alzheimer’s drugs, aducanumab targets Aβ oligomers, which has not yet formed amyloid plaques, thereby preventing deposition of new Aβ on existing plaques (Budd Haeberlein S et al., 2017), whereas donanemab targets amyloid plaques directly, effectively clearing away existing plaques (MC et al., n.d.).
WHY DID SO MANY ALZHEIMER’S DISEASE DRUGS FAIL? WHY IS THE DEVELOPMENT SO SLOW?
First described 115 years ago, by Alois Alzheimer, the disease is still a mystery. Over the past 18 years, the game-changing drug to Alzheimer’s disease has always been “just around the corner” but never seems to arrive.
One reason is the conflicting hypotheses for Alzheimer’s Disease. Apart from amyloid hypothesis and infectious hypothesis, there are still more theories about, for example, how faulty mitochondria creates oxidative stress, resulting in neuronal damage (Guo, Sun, Chen, Zhang, 2013). Without knowing the underlying cause of Alzheimer’s disease, it is difficult to know where and what to target.
However, the “most-cited explanation” is that the patients are treated too late in the development of Alzheimer’s disease. (Parkins,2021) It may take up to 20 to 30 years for symptoms to appear for an Alzheimer’s patient. “The general view is these are the right drugs, but they’re too late,” says John Hardy, a neurogeneticist and a pioneer of amyloid hypothesis. (Parkins, 2021) On the bright side, new blood tests have been developed in 2019 that can predict the disease ten years before onset of symptoms with around 80% accuracy. (Palmqvist S et al., 2020) Therefore, earlier intervention and diagnosis are made possible, and drugs can be applied to patients at an earlier stage.
One even bigger issue is that there are too many variants in Alzheimer’s disease. The two biggest classes are the early-onset and late-onset. You may think that they would only differ by the time of symptom onset, but that’s not true. They are two entirely different entities, in terms of genetics, clinical symptoms, and even pathogenesis. Early-onset Alzheimer’s are found to be more aggressive – there are more plaques (Ho GJ et al., 2002), more tau tangles (DeTure & Dickson, 2019), and greater volume of brain loss in early-onset than late-onset (Lancet, 2003). Early-onset causes up to 2-3% brain loss compared to 0.8% of late-onset. Moreover, the region of brain atrophy is different – early-onset is characterized by loss of frontal lobe, while late-onset is loss of hippocampus. This may explain why early-onset patients suffer from greater impairment in executive functions, languages and attention (Tellechea et al., 2018); whereas late-onset patients find it difficult to form new memories. (Sperling et al., 2010)
So, maybe there really is no one-size-fits-all treatment – There is too much variance and complications. “Alzheimer’s Disease” is just an umbrella term for a number of specific diseases. If participants of a study do not have the same type of Alzheimer’s, let alone the same underlying causes, it is difficult for the drug to succeed.
CONCLUSION
The promising results of donanemab’s phase 2 trial has shed some light onto Alzheimer’s disease. While it has successfully met the primary endpoints by slowing down cognitive decline, the performance in secondary endpoints is not statistically significant. In particular, it failed to meet the datapoint on a widely accepted dementia assessment known as CDR-SB. Some other scientists have cast doubt on the careful screening involved in patient enrollment – could donanemab be applied to the majority of patients with Alzheimer’s disease in the future? Or would it only cater the needs of those in the strict enrollment criteria? Questions have also been raised about the drug’s safety – despite meeting the safety standards, “amyloid-related side effects” have been recorded.
Nonetheless, Eli Lilly is aiming to replicate the results and carry on with a larger study involving 1000 participants, starting by the end of this year. While the success of donanemab is something worth celebrating, there is a greater pressure on Eli Lilly to demonstrate in the coming trials that they will meet the CDR-SB threshold.
Even though the exact mechanism of Alzheimer’s disease is still unknown, this is the closest time in history to finding a cure for it. This study in particular has encouraged scientists in the field to continue working on the amyloid plaques. In the future, tau, oxidative stress and neuroinflammation are next in line for us to tackle, thanks to the rapid advancement in science and medicine. After all, a great leap in humanity takes concerted efforts, one step at a time.
REFERENCES
RC, P., BR, R., MA, M., & AM, W. (n.d.). Donanemab confirms: Clearing Plaques Slows Decline-By a bit. Retrieved April 03, 2021, from https://www.alzforum.org/news/conference-coverage/donanemab-confirms-clearing-plaques-slows-decline-bit
Parkins, K. (2021, April 01). Alzheimer's trials: BIOGEN AND Lilly's Amyloid-targeting drugs race for FDA approval. Retrieved April 03, 2021, from https://www.clinicaltrialsarena.com/analysis/alzheimers-biogen-eli-lilly-amyloid-targeting-therapy-fda-approval/
Makin, S. (2018, July 25). The amyloid hypothesis on trial. Retrieved April 03, 2021, from https://www.nature.com/articles/d41586-018-05719-4
Down syndrome and alzheimer's disease. (n.d.). Retrieved April 03, 2021, from https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/down-syndrome#:~:text=According%20to%20the%20National%20Down,their%2060s%20have%20Alzheimer's%20dementia.
Lin WR;Wozniak MA;Cooper RJ;Wilcock GK;Itzhaki RF;. (n.d.). Herpesviruses in brain and alzheimer's disease. Retrieved April 03, 2021, from https://pubmed.ncbi.nlm.nih.gov/12115887/
Verreault, R., Laurin, D., Lindsay, J., & De Serres, G. (2001, November 27). Past exposure to vaccines and subsequent risk of alzheimer's disease. Retrieved April 03, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC81665/
Flu, pneumonia Vaccinations tied to lower risk of ALZHEIMER'S DEMENTIA: Aaic 2020: Alzheimer's Association. (n.d.). Retrieved April 03, 2021, from https://www.alz.org/aaic/releases_2020/vaccines-dementia-risk.asp#:~:text=Flu%2C%20Pneumonia%20Vaccinations%20Tied%20to%20Lower%20Risk%20of%20Alzheimer's%20Dementia,-%C2%AB%20Back%20to%20All&text=CHICAGO%2C%20JULY%2027%2C%202020%20%E2%80%94,%C2%AE%20(AAIC%C2%AE)%202020
SR;, G. (n.d.). Alzheimer's amyloid-β is an antimicrobial peptide: A review of the evidence. Retrieved April 03, 2021, from https://pubmed.ncbi.nlm.nih.gov/29504537/
Ezzat K;Pernemalm M;Pålsson S;Roberts TC;Järver P;Dondalska A;Bestas B;Sobkowiak MJ;Levänen B;Sköld M;Thompson EA;Saher O;Kari OK;Lajunen T;Sverremark Ekström E;Nilsson C;Ishchenko Y;Malm T;Wood MJA;Power UF;Masich S;Lindén A;Sandberg JK;Lehtiö J;Spetz AL. (2019). The viral protein corona directs viral pathogenesis and amyloid aggregation. Retrieved April 03, 2021, from https://pubmed.ncbi.nlm.nih.gov/31133680/
Marvar, A. (2021, March 13). Does Eli Lilly's Alzheimer's Drug Donanemab WORK? Key new data released. Retrieved April 03, 2021, from https://www.beingpatient.com/eli-lilly-alzheimers-trailblazer-trial-does-donanemab-work/
Budd Haeberlein S;O'Gorman J;Chiao P;Bussière T;von Rosenstiel P;Tian Y;Zhu Y;von Hehn C;Gheuens S;Skordos L;Chen T;Sandrock A;. (n.d.). Clinical development Of Aducanumab, an Anti-Aβ human monoclonal antibody being investigated for the treatment of Early Alzheimer's disease. Retrieved April 03, 2021, from https://pubmed.ncbi.nlm.nih.gov/29181491/#:~:text=Aducanumab%20(BIIB037)%20is%20a%20human,soluble%20oligomers%20and%20insoluble%20fibrils
MC, I., SL, L., AM, W., RB, D., JH, R., & T, H. (n.d.). Donanemab. Retrieved April 03, 2021, from https://www.alzforum.org/therapeutics/donanemab
Palmqvist S;Janelidze S;Quiroz YT;Zetterberg H;Lopera F;Stomrud E;Su Y;Chen Y;Serrano GE;Leuzy A;Mattsson-Carlgren N;Strandberg O;Smith R;Villegas A;Sepulveda-Falla D;Chai X;Proctor NK;Beach TG;Blennow K;Dage JL;Reiman EM;Hansson O;. (2020). Discriminative accuracy of Plasma PHOSPHO-TAU217 for Alzheimer Disease vs other neurodegenerative disorders. Retrieved April 03, 2021, from https://pubmed.ncbi.nlm.nih.gov/32722745/
Ho GJ;Hansen LA;Alford MF;Foster K;Salmon DP;Galasko D;Thal LJ;Masliah E;. (2002). Age at onset is associated with disease severity in Lewy Body variant and Alzheimer's disease. Retrieved April 03, 2021, from https://pubmed.ncbi.nlm.nih.gov/12395133/
DeTure, M., & Dickson, D. (2019, August 02). The neuropathological diagnosis of alzheimer's disease. Retrieved April 03, 2021, from https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-019-0333-5
Tellechea, P., Pujol, N., Esteve-Belloch, P., Echeveste, B., García-Eulate, M., Arbizu, J., & Riverol, M. (2018, May 01). Early- and late-onset alzheimer disease: Are they the same entity? Retrieved April 03, 2021, from https://www.elsevier.es/en-revista-neurologia-english-edition--495-articulo-early-late-onset-alzheimer-disease-are-S217358081630133X
Sperling, R., Dickerson, B., Pihlajamaki, M., Vannini, P., LaViolette, P., Vitolo, O., . . . Johnson, K. (2010, January 13). Functional alterations in memory networks in early alzheimer's disease. Retrieved April 03, 2021, from https://link.springer.com/article/10.1007/s12017-009-8109-7
