Alzheimer’s Disease and Promising Treatments
Alzheimer’s disease is a neurological disease caused by an abnormal buildup of
misfolded or unfolded proteins. Alzheimer’s affects around 6 million people in America and
about 50 million people worldwide. When the diseased cell has the mutated gene that does not
code correctly for a gene, the translated protein misfolds. Plaques and tangles formed from
protein aggregations disrupt the signaling and neurotransmitters of nerve cells. Therefore, the
brain cells die and the brain shrinks.
Misfolded proteins aggregate as hydrophobic cores of the proteins form London
dispersion forces. The hydrophobic residues are exposed, promoting misfolded protein
aggregates. The insoluble misfolded proteins form long linear or fibrillar aggregates known as
amyloid deposits. When Amyloid and Tau proteins form toxic misfolded aggregates in the brain,
causing brain cell death. Plaques form when there is a buildup of amyloids. These plaques can
kill neurons in multiple ways. Amyloid plaques can trigger an immune response. Tangles form
when the misfolded Tau protein builds up within the neurons. Plaques and tangles can isolate
neurons in a way that might not allow neurons to receive nutrients for survival and communicate
with surrounding neurons. With Alzheimer’s, Acetylcholine levels are decreased. The plaques
and tangles cause an increase in the levels of acetylcholinesterase, which breaks down
acetylcholine. As a result, Alzheimer’s patients experience progressive decline in memory,
thinking, learning and organizing skills. Alzheimer’s is influenced by inherited genes in
combination with diet and environmental factors. Risk factors are mainly age and genetics.
However, not all Alzheimer’s patients have a genetic history of hte disease. Every person inherits
two copies of hte ApoE gene that comes with three allele versions: E2 (protective), E3 (most
common type and reference point for other alleles), and E4 (deleterious). Acquiring two copies
of the E4 gene would pose the highest risk. The ApoE protein is important because it shuttles
lipids between cells by attaching to cell-surface receptors.
The most common medications for Alzheimer’s are cholinesterase inhibitors and
memantine. Cholinesterase inhibitors preserve ACh in synapse between neurons, improve
communication between neurons by preserving ACh, and enhance behavioral symptoms like
agitation or depression. Memantine blocks the effects of glutamate (sends messages between
nerves) and slows the buildup of glutamate between neurons, which slows Alzheimer’s
progression symptoms.
The latest research discovered promising treatments that can be used for Alzheimer’s.
Lecanemab is a monoclonal antibody that binds to soluble amyloid-beta (Aβ) protofibrils (toxic
to neurons) with high affinity. It reduced the markers of amyloid in Alzheimer’s and reduced the
progression of disease cognition symptoms. Lecanemad has been approved by the FDA in
January of 2023. BIIB080 (/IONIS-MAPTRx) is an nntisense oligonucleotide that silences the
expression of Tau protein. It stops mRNA from producing the tau protein (microtubule
stabilizer), which decreases buildup of Tau protein. The drug was promising and showed more
than 50% reduction in total Tau protein and phosphorylated Tau accumulation.
Carla Botros (1)
References:
Fernandez CG, Hamby ME, McReynolds ML and Ray WJ (2019) The Role of APOE4 in
Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Alzheimer’s
Disease. Front. Aging Neurosci. 11:14. doi: https://doi.org/10.3389/fnagi.2019.00014
Andrew M. Stern, Yang Yang, Shanxue Jin, Keitaro Yamashita, Angela L. Meunier, Wen Liu,
Yuqi Cai, Maria Ericsson, Lei Liu, Michel Goedert, Sjors H.W. Scheres, Dennis J. Selkoe.
Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer’s
disease brains. Neuron, 2023; DOI: 10.1016/j.neuron.2023.04.007
Catherine J. Mummery, Anne Börjesson-Hanson, Daniel J. Blackburn, Everard G. B. Vijverberg,
Peter Paul De Deyn, Simon Ducharme, Michael Jonsson, Anja Schneider, Juha O. Rinne, Albert
C. Ludolph, Ralf Bodenschatz, Holly Kordasiewicz, Eric E. Swayze, Bethany Fitzsimmons,
Laurence Mignon, Katrina M. Moore, Chris Yun, Tiffany Baumann, Dan Li, Daniel A. Norris,
Rebecca Crean, Danielle L. Graham, Ellen Huang, Elena Ratti, C. Frank Bennett, Candice Junge,
Roger M. Lane. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a
phase 1b, randomized, placebo-controlled trial. Nature Medicine, 2023; DOI:
10.1038/s41591-023-02326-3
Although I already knew a fair bit about Alzheimer's, I had no idea that it was caused by the brain literally shrinking. If one of the main causes of Alzheimer's is genetics, I wonder if we are not far away from being able to detect warning signs in genetic code in early life, so that treatment plans can help prevent symptoms before they happen.
ReplyDeleteBefore I read about Alzheimer’s, I also thought that Alzheimer’s does not cause brain shrinkage. Misfolding of proteins like Tau causes the formation of aggregates in neuronal synapses that can hinder communication and transport of nutrients. The misfolding of these proteins causes neuronal cell death, which leads to degeneration. The genetic code can actually tell us who is at a higher risk of AD. Each person carries two copies of the ApoE gene, which shuttles lipids between cells by attaching to cell-surface receptors, and comes with three allele versions-E2, E3, and E4. The E2 version is protective; the E3 version is the most common type, the reference point for othe alleles, and has a neutral effect; and the E4 version is deleterious. The E4/E4 genotype poses the highest risk followed by the E3/E3 genotype, then the E3/E4 genotype.
Delete-Carla Botros
Could you explain the normal function of Tau protein? I am confused as to why specifically it is Tau protein that is the culprit. I think its exciting that we are making progress in the treatment of Alzheimer's. - Calvin Keating
ReplyDeleteTau is a microtubule stabilizer found in the central nervous system neurons and is responsible for the assembly and stability of microtubules for the transport of proteins and organelles in neurons. Having stable microtubules in neurons is crucial to moving molecules in neuronal cells and to neuron function. Phosphorylating Tau changes its conformation and causes it to dissociate from the microtubule, affecting the neuron’s function. Therefore, proteins and organelles will not be properly transported in axons and dendrites. Tau can also form aggregates called tangles, which can form between neurons and cut off communication in neuron synapses, causing neuronal cell death.
Delete-Carla Botros
Hi Carla. Alzheimer's is an interesting disease and the process that you described on how the brain degenerates is intriguing. Lecanemab has been recently approved by the FDA and sounds like a really great treatment. What are some side effects of the treatment? How easily accessible is the treatment?
ReplyDelete- Lorena Soldevilla
Lecanemab is a drug used to slow down the progression of mild Alzheimer's disease by reducing amyloid-beta proteins in the brain. It has been found that taking lecanemab over 18 months slows cognitive decline in people with early symptomatic Alzheimer's disease. However, it is not yet known if the drug can help in other ways or prevent the development of Alzheimer's in people without memory loss symptoms. According to Mayo Clinic, Lecanemab is administered through IV infusion every two weeks and is closely monitored for side effects such as dizziness, headache, visual changes, worsening confusion, swelling or bleeding in the brain, brain shrinkage, and very rarely, death. This drug is not effective for those with full cognitive function or in later stages of Alzheimer's. Those with a history of cancer, bleeding in the brain, or taking anticoagulant drugs may be prevented from taking lecanemab. Each person carries two copies of the ApoE gene, which shuttles lipids between cells by attaching to cell-surface receptors, and comes with three allele versions-E2, E3, and E4. The ApoE E4 version gene is deleterious and may have a higher risk of serious side effects and should be tested before starting treatment. Prior to starting treatment with Lecanemab, a brain MRI is required, and regular MRI scans are necessary to monitor for brain bleeds.
Delete-Carla Botros