Diseases and Disorders

Amyloid Beta in Alzheimer's Disease

Lasya Kambhampati


Amyloid beta has long been recognized as the most prominent molecular feature of Alzheimer's disease, along with tau tangles. In this paper, we will explore Alzheimer's disease by studying amyloid beta. We will discuss the history of amyloid beta and its role in Alzheimer's disease, as well as explore its properties, what makes it so toxic, and the evidence that verifies its role in Alzheimer's disease. Furthermore, we will explore the relationship between Amyloid beta, Alzheimer's, and the lipid membrane. Finally, we will discuss possible avenues of treatment and current areas of research. 


What is Alzheimer's Disease? 

Alzheimer’s disease is a neurodegenerative disease in which brain cells that process, store and retrieve information degenerate and die. It causes progressive memory impairment and loss of cognitive function. Symptoms include mental confusion, forgetfulness, loss of basic cognitive abilities, and on a more molecular level, aggregates of amyloid beta protein plaques and tau tangles on blood vessels and neurons [1]. Scientists believe that oligomers cause amyloid toxicity and are working on preventing aggregation of amyloid beta. An oligomer is a chain of a few repeating units. Researchers are also creating more accurate models to study the molecular changes that amyloid beta and potential treatments cause. As of right now, there is no cure or prevention for Alzheimer’s disease. 


What is Amyloid Beta? 

Amyloid beta oligomers are the most prominent aspect in the molecular pathology of Alzheimer’s. An amyloid beta oligomer is part of a larger protein, known as amyloid precursor protein, that extends from the inside of brain cells to the external environment [2]. Later, it is cut into separate pieces when activated and, in some situations, a beta-amyloid is produced.

In Alzheimer’s, amyloid beta gathers around synapses, disrupting communication between neurons, leading to their death. The oligomers are more toxic if they are small and soluble[2]. The amyloid hypothesis assumes that problems in production, accumulation, or disposal of this protein lead to the symptoms. The mechanism behind the toxicity of these oligomers is believed to be destabilization of homeostasis through the formation of new ion channels in lipid bilayers. Scientists still don’t know the exact mechanism behind these changes which could help develop new treatments. 


What is the evidence for amyloid beta relation to Alzheimer’s? 

Scientists have been able to prove that amyloid beta is directly linked to Alzheimer’s. Looking at families across the globe, scientists have been able to pinpoint specific genes that nearly always guarantee development of Alzheimer’s disease. One example is the APP gene which codes for amyloid beta. These mutations are all associated with amyloid beta production. Furthermore, in experiments with genetically engineered mice, scientists found that mutations in only the amyloid beta gene lead to Alzheimer's symptoms. In addition, those with Down syndrome, who have three copies of the APP gene, almost invariably develop Alzheimer's disease. 


The Dynamics of Plaque Formation

One of the biggest reasons that amyloid beta causes so many problems is that it is chemically “stickier” than other fragments produced when APP is broken. The protein clumps into clusters known as oligomers. As the disease progresses, the oligomers link together, becoming fibrils. Fibrils join together to form beta-sheets, which can join together to form plaques[2]. The plaques are most prominently seen in pictures and contain clumps of various systems. 

What is the Relation Between Amyloid beta, Alzheimer’s and Lipid Membranes?

Not only does beta-amyloid play a significant role in Alzheimer’s disease, changes in the lipid membrane also play a part. There are changes in the phospholipid bilayer to sphingomyelin and gangliosides. Sphingomyelin has been consistently shown to decrease in Alzheimer's disease [3]. Gangliosides, however, has conflicting results. Some studies show that it increases and others say it decreases; similarly, studies are conflicted on whether or not it decreases or increases the probability of plaques and tangles forming [4][5]. Although some lipids have produced conflicting results, on the whole researchers have found the lipid concentrations and Alzheimer's (specifically damage to neuronal membranes) are linked and can be used as an indicator [5]. 

These changes in lipid composition of neuronal membranes affect properties such as membrane fluidity, permeability, and domains. These all affect the way amyloid binds in the brain and, therefore, the course of Alzheimer's disease. At the time, there are no models in the literature that can accurately model healthy and AD membranes. In order to study the changes that happen to the lipid membranes and their effects on AD, scientists have, in the past, used a simple lipid model [6]. Oftentimes the results from such studies can not be directly related to the human body or actual animal subjects as they don’t represent the cell accurately enough. Scientists have begun to pick aspects of the membrane and feature them prominently in the model in order to create a more representative model. Some areas of focus are the DPPC, POPC, sphingomyelin, cholesterol, and ganglioside GM1. [7] In this way, the resulting experiment’s results could be used to mimic healthy and diseased states of real neurons. 

To explore the specific changes in the neuronal model with the new model, researcher Elizabeth Drolle designed an experiment. There were three experimental groups: normal, decreased GM1 (ganglioside), decreased GM1 and SM (sphingomyelin)[7]. These specific lipid changes were picked because they were observed in vivo most often. Drolle measured the morphology and electrical surface potential of the neurons using BLM (Black Lipid Membrane), POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and AFM (a type of imaging to view topography of a model). The results showed that the changes in lipid membrane content changed the membrane permeability - throwing the neuron out of homeostasis[7]. Since ion concentration is essential neuronal signaling, these membrane changes caused damage to normal cell function. Particularly in AD cells, these changes also allow amyloid beta to penetrate further into the cell, further increasing its toxicity. This discovery opens up a new avenue for treatment research. 

In addition to these changes, Drolle’s results lead her to a new hypothesis regarding amyloid’s toxicity. This theory postulates that amyloid has protective roles in the brain to fight against the bacteria and microbes without affecting the host cell. AMP’s (antimicrobial peptides) such as amyloids are able to recognize bacterial membranes using electrostatic interactions[7]. These changes in the neuronal membranes prevent amyloid beta from performing its normal function and cause amyloid beta plaques to build up. If we were able to prevent this, we could prevent mass cell death. 


What are potential avenues of treatment? 

Scientists have been looking for a treatment for Alzheimer's disease for decades. However, until the drug known as aducanumab, there was no large-scale successful therapy discovered. It was the first drug that was shown to have a positive effect in studies on Alzheimer's disease by binding to amyloid beta and reducing the rate of cognitive decline. The drug is currently in clinical trials but it opened up new avenues for scientists to study treatments. Some directions are outlined below: 


Decreasing Production: 

Current research aims to change the behavior of the enzymes and proteins that break amyloid precursor proteins into smaller fragments. These proteins are known as secretases, with beta and gamma secretases being the most prominent [9]. Scientists are either trying to change the interactions the enzymes have with APP (i.e. to create fragments other than APP) or create drugs that block the secretases. 


Preventing Aggregation: 

Scientists are also exploring drugs that can prevent the formation of the fibrils, mats, and plaques discussed above as some studies indicate that the toxic effects of beta-amyloid begin before the separate molecules begin to interact. Some methods include “mobilizing the immune system to produce antibodies to attack beta-amyloid, administering laboratory-produced antibodies to beta-amyloid and administering natural agents with anti-amyloid effects”[9]. 



There are two types of antibodies being studied: active and passive vaccines. Active vaccines have a virus or protein that has amyloid beta attached. Theoretically, this should prompt the body to produce antibodies in response and reduce levels of amyloid beta in the brain. Passive vaccines, on the other hand, are predetermined doses of antibodies that can be produced in the laboratory. In this way, the vaccine doesn’t rely on the body to produce antibodies but directly supplies them. In addition, some researchers are looking into natural agents with anti-amyloid properties such as IVIG, intravenous immunoglobulin in the plasma of human donors [9]. It has been shown to contain natural antibodies that could reduce amyloid beta levels.


  1. Puglielli L, Tanzi RE, Kovacs DM. (2003). Alzheimer's disease: the cholesterol connection. Nat Neurosci. https://www.ncbi.nlm.nih.gov/pubmed/12658281.

  2. Hertel C., Terzi E., Hauser N., Jakob-Rotne R., Seeling J. and Kemp J.A. (19/08/1997). Inhibition of the electrostatic interaction between β-amyloid peptide and membranes prevents β-amyloid-induced toxicity. PNAS. https://www.pnas.org/content/94/17/9412.

  3. He X, Huang Y, Li B, Gong CX, Schuchman EH. (2010). Deregulation of sphingolipid metabolism in Alzheimer's disease. Neurobiol Aging. https://www.ncbi.nlm.nih.gov/pubmed/18547682/.

  4. Mlinac, K., Bognar, S.K. (2010). Role of gangliosides in brain aging and neurodegeneration. Translational Neuroscience. https://doi.org/10.2478/v10134-010-0043-6.

  5. Svennerholm L1, Gottfries CG. (1994). Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type I) and demyelination in late-onset form (type II). J Neurochemistry. https://www.ncbi.nlm.nih.gov/pubmed/8113790/.

  6. Mouritsen OG1, Jørgensen K. (1998). A new look at lipid-membrane structure in relation to drug research. Pharm Res. https://www.ncbi.nlm.nih.gov/pubmed/9794491/.

  7. Drolle, Elizabeth. (2017). Changes in lipid membranes may trigger amyloid toxicity in Alzheimer's disease. PLoS One. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540602/.

  8. Michalowski, Jennifer. (15/11/2017). Plaques, Proteins, and the Causes of Alzheimer's Disease. Brain Facts. https://www.brainfacts.org/diseases-and-disorders/neurodegenerative-disorders/2017/alzheimers-111017.

  9. (2017). Beta-amyloid and the amyloid hypothesis. Alzheimer’s Association. https://www.alz.org/national/documents/topicsheet_betaamyloid.pdf.

Lasya Kambhampati

Lasya Kambhampati

Lasya is a senior at Blue Valley North. She is planning on majoring in neuroscience or biomedical engineering. She first got involved in the IYNA after participating (and placing 7th) at the National Brain Bee. She is now the Director of Chapters and is focusing on helping extend the impact the IYNA has. Lasya also runs a neuroscience blog to help students prepare for the Brain Bee and just learn more about the nervous system. She hopes to help students of all ages and backgrounds learn about the amazing organ that runs our whole lives. In the future, Lasya hopes to be a neurosurgeon and research the molecular mechanisms behind memory. Outside of neuroscience-related activities, she loves to write, read, and play the violin/piano.