First, what is the APOE gene?
Certain genes make you more likely to develop Alzheimer's, but there are many other genetic and environmental factors involved in disease initiation. The APOE gene provides instructions for making a protein called apolipoprotein E(APOE). This protein combines with fats (lipids) in the body to form molecules called lipoproteins. Lipoproteins are responsible for packaging cholesterol and other fats and carrying them through the bloodstream. Maintaining normal levels of cholesterol is essential for the prevention of disorders that affect the heart and blood vessels (cardiovascular diseases), including heart attack and stroke. APOE is thought to be responsible for the transportation of lipids within the brain, maintaining structural integrity of the microtubule within the neuron, and assisting with neural transmission. APOE is also intricately involved in the innate immune response in the body and the brain. There are three types of the APOE gene, called alleles: APOE2, E3 and E4. Everyone has two copies of the gene and the combination determines your APOE "genotype. The APOE4 allele, present in approximately 10-15% of people, increases the risk for late onset Alzheimer's and lowers the age of onset. Late-onset Alzheimer's disease, the subset of the disorder occurring in people age 65 and over, affects more than give million Americans, and is characterized by progressive memory loss and dementia. The early-onset form of AD (younger than 65 years old) is predominantly familial and most often linked to single mutations in the genes encoding APP, presenilin 1 (PSEN1) or presenilin 2 (PSEN2). Ninety percent of patients with dementia have an idiopathic form, which is considered an interplay between genes and the environment. Note that having one copy of E4 (E3/E4) can increase your risk of disease occurrence by two to three times while two copies (E4/E4) can increase the risk by as many as 12 times. How does the APO4 E gene increase the risk of cognitive decline? The APOE4 gene locus has been discussed as a possible mediator of cognitive impairment as it is associated with the evolution of dementias like Alzheimer’s disease. Outside the brain, APOE4 can increase the risk of atherosclerosis (hardening of the arteries) and stroke, which may explain why APOE4 is a risk factor for vascular causes of cognitive impairment and dementia. APOE is thought to be involved in repairing neuronal injury, synapse formation, and scavenging of toxins. APOE in the brain is primarily expressed by astrocytes and microglia, cell types that are now widely appreciated to play key roles in the pathogenesis of AD. Data has emerged that shows APOE4 disrupts normal glial cell biology and impairs the metabolic activity of the human microglia. If microglia are compromised then widespread neuro-inflammation can spread like a wildfire out of control, toxic waste products like amyloid and tau cannot be cleared and the risk of cognitive decline is amplified. Recent study findings In this recently published study in Neurology®, Neuroimmunology & Neuroinflammation, the researchers sought to understand the impact of APOE polymorphisms on parameters of cognitive function in a large multicenter, prospectively collected German data set of untreated patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS). In this study, 552 newly diagnosed MS patients in Germany were followed. 25.2% of the patients were carriers of the APOE ε4 allele. Ten of these (1.8%) were homozygotes (e.g. they had two copies of the APOE4 gene.) Along with parameters of a higher disease burden, APOE ε4 homozygosity was identified as a potential predictor of cognitive performance in this large cohort of patients with CIS and RRMS. Other factors that were associated with worse cognition were higher expanded disability status scale (EDSS) scores and higher lesion volume on MRI. Previous studies in smaller cohorts of patients with MS with mean disease durations of 8.328 and 13 years reported an association of APOE ε4 with dysfunction in some cognitive domains including verbal fluency and memory.1 The role of microglia as both “angels” and “assassins.” As the resident immune cells in the central nervous system, microglia are also involved in: synaptic organization; trophic neuronal support during development; phagocytosis of apoptotic cells in the developing brain; myelin turnover; control of neuronal excitability; and phagocytic debris removal as well as brain protection and repair. Microglia seem to drive synapse loss in neurodegenerative diseases through out-of-control and misguided synaptic pruning. Acting as the brain’s clean-up crew, microglia maintain a vigilant watch for injury or infection, clearing away pathogens, malformed proteins, and dead cells. However, it is possible that activated microglia can set off chronic neuroinflammation and subsequent neurodegeneration due to the release of pro-inflammatory cytokines, chemokines, and other inflammatory impacts along with reactive oxygen species (ROS) and reactive nitrogen species (RNS). Just this month, researchers at Yale University, School of Medicine, Grutzendler Lab for the first time captured images of the process of brain cell death at the level of a single neuron, showing how specialized brain cells coordinate the removal of neuronal corpses and dendrites from the central nervous system.2 This is both a remarkable accomplishment and fascinating to see exactly how this process takes place. For more information regarding microglia, you may also want to read “The Angel and the Assassin: The Tiny Brain Cell That Changed the Course of Medicine” by Donna Jackson Nakazawa. She details how once-healthy microglia can in a toxic environment actually destroy the brain and become its untimely “assassin.” As discussed in our numerous blogs and scientific articles, we know anything that affects the behavior of the microglia may set the stage for the development of one of many neurodegenerative and neuropsychiatric diseases. So clearly, microglia can be either our best friend or worst enemy. All factors leading to decline of brain function need to be considered in MS and other neurodegenerative diseases. It could be that the APOE 4 genotype may be a biomarker in MS and may also influence other neurological conditions such as those that occur with traumatic brain injury and Parkinson's disease. And undoubtedly more studies are needed to fully understand the role of genetic influences. But, it’s equally critical to remember that genes are just one part of the equation and that lifestyle and environmental factors also contribute to disease initiation. We cannot change our genes, but we definitely can change many things about how we live to give ourselves the best chance at a healthier life. In hope and healing, Dr. Suzanne Gazda References: 1 Is APOE ε4 associated with cognitive performance in early MS? Sinah Engel, Christiane Graetz, Anke Salmen, Muthuraman Muthuraman, Gerrit Toenges, Björn Ambrosius, Antonios Bayas, Achim Berthele, Christoph Heesen, Luisa Klotz, Tania Kümpfel, Ralf A. Linker, Sven G. Meuth, Friedemann Paul, Martin Stangel, Björn Tackenberg, Florian Then Bergh, Hayrettin Tumani, Frank Weber, Brigitte Wildemann, Uwe K. Zettl, Gisela Antony, Stefan Bittner, Sergiu Groppa, Bernhard Hemmer, Heinz Wiendl, Ralf Gold, Frauke Zipp, Christina M. Lill, Felix Luessi, for the German Competence Network of Multiple Sclerosis Neurol Neuroimmunol Neuroinflamm Jul 2020, 7 (4) e728; DOI: 10.1212/NXI.0000000000000728 https://nn.neurology.org/content/7/4/e728.abstract?etoc 2 Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo BY EYIYEMISI C. DAMISAH, ROBERT A. HILL, ANUPAMA RAI, FUYI CHEN, CARLA V. ROTHLIN, SOURAV GHOSH, JAIME GRUTZENDLER SCIENCE ADVANCES26 JUN 2020 : EABA3239 https://advances.sciencemag.org/content/6/26/eaba3239 Additional references and reading: Christopher Carlin, BSc, Lilian Murray, PhD, David Graham, PhD, FRCPath, David Doyle, MD, James Nicoll, MD, FRCPath, Involvement of Apolipoprotein E in Multiple Sclerosis: Absence of Remyelination Associated with Possession of the APOE ε2 Allele, Journal of Neuropathology & Experimental Neurology, Volume 59, Issue 5, May 2000, Pages 361–367, https://doi.org/10.1093/jnen/59.5.361 https://academic.oup.com/jnen/article/59/5/361/2609860 Liu G, Hannon T. Reasons for the prevalence of childhood obesity - Genetic predisposition and environmental influences. ENDOCRINOLOGIST. 2005;15:49-55. https://journals.lww.com/theendocrinologist/Abstract/2005/01000/Reasons_for_the_Prevalence_of_Childhood_Obesity_.11.aspx Michaelson DM. APOE ε4: the most prevalent yet understudied risk factor for Alzheimer's disease. Alzheimers Dement. 2014;10(6):861-868. doi:10.1016/j.jalz.2014.06.015 Nathoo, N., Chetty, R., van Dellen, J. R., & Barnett, G. H. (2003). Genetic vulnerability following traumatic brain injury: the role of apolipoprotein E. Molecular pathology : MP, 56(3), 132–136. https://doi.org/10.1136/mp.56.3.132 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1187307/ Safieh, M., Korczyn, A.D. & Michaelson, D.M. ApoE4: an emerging therapeutic target for Alzheimer’s disease. BMC Med 17, 64 (2019). https://doi.org/10.1186/s12916-019-1299-4 https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1299-4 Shi J, Tu JL, Gale SD, et al. APOE epsilon4 is associated with exacerbation of cognitive decline in patients with multiple sclerosis. Cogn Behav Neurol 2011;24:128–133. Bachiller, S., Jiménez-Ferrer, I., Paulus, A., Yang, Y., Swanberg, M., Deierborg, T., & Boza-Serrano, A. (2018). Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response. Frontiers in cellular neuroscience, 12, 488. https://doi.org/10.3389/fncel.2018.00488 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305407/ NA ZHAO, OLIVIA N. ATTREBI, YINGXUE REN, WENHUI QIAO, BERKIYE SONUSTUN, YUKA A. MARTENS, AXEL D. MENESES, FUYAO LI, FRANCIS SHUE, JIAYING ZHENG, ALEXANDRA J. VAN INGELGOM, MARY D. DAVIS, AISHE KURTI, JOSHUA A. KNIGHT, CYNTHIA LINARES, YIXING CHEN, MARION DELENCLOS, CHIA-CHEN LIU, JOHN D. FRYER, YAN W. ASMANN, PAMELA J. MCLEAN, DENNIS W. DICKSON, OWEN A. ROSS, GUOJUN BU. SCIENCE TRANSLATIONAL MEDICINE05 FEB 2020 APOE4 exacerbates α-synuclein pathology in a synucleinopathy mouse model, and APOE4 genotype associates with increased α-synuclein pathology in humans. https://stm.sciencemag.org/content/12/529/eaay1809.abstract Liu G, Hannon T. Reasons for the prevalence of childhood obesity - Genetic predisposition and environmental influences. ENDOCRINOLOGIST. 2005;15:49-55. https://journals.lww.com/theendocrinologist/Abstract/2005/01000/Reasons_for_the_Prevalence_of_Childhood_Obesity_.11.aspx
1 Comment
|
Authorby Suzanne Gazda M.D. Archives
August 2021
Categories |
RSS Feed