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0ROLE OF APOE IN AB METABOLISM
ELGUJA TSITLIDZE
Faculty of Natural Sciences and Health Care of Batumi Shota Rustaveli State University
Batumi, Georgia
Abctract. APOE-e4 is the first risk gene identified for Alzheimer's disease (AD) and remains the most influential gene in certain populations. Testing positive for APOE-e4 does not uniformly indicate Alzheimer's risk across all racial and ethnic groups, with estimates suggesting 40-65% of diagnosed individuals carry the allele. The APOE-e4 allele may also correlate with an earlier onset of symptoms compared to those without it. While the exact relationship between APOE-e4 and Alzheimer's risk remains unclear, research indicates a connection to increased amyloid plaque accumulation in the brains of affected individuals. This buildup can lead to neuronal death and the progression of Alzheimer's symptoms.
It is crucial to note that possessing the APOE-e4 allele increases the risk of developing Alzheimer's, but does not guarantee it. Understanding the roles of Aft and ApoE in AD pathogenesis is essential for developing targeted interventions that can improve clinical outcomes for at-risk patients.
Keywords: APOE-e4, Alzheimer's disease (AD), Amyloid plaques, Neuronal death, Genetic
risk.
Introduction
APOE-e4 is the first risk gene identified and remains the gene with the strongest impact on risk for some populations. Testing positive for APOE-e4 may not mean the same for Alzheimer's risk across all racial and ethnic groups. Researchers estimate that between 40-65% of people diagnosed with Alzheimer's have the APOE-e4 gene. [6], [7]. [8].
APOE-e4 is one of three common forms of the APOE gene; the others are APOE-e2 and APOE-e3. We all inherit a copy of some form of APOE from each parent. Those who inherit one copy of APOE-e4 from their mother or father have an increased risk of developing Alzheimer's. Those who inherit two copies from their mother and father have an even higher risk, but not a certainty. In addition to raising risk, APOE-e4 may tend to make symptoms appear at a younger age than usual, which adds to the complexity of understanding how APOE may contribute to a person's risk. . [1], [2]. [3]. The APOE gene provides instructions for making a protein called apolipoprotein E. 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. . [4], [5]. [9].
There are at least three slightly different versions (alleles) of the APOE gene. The major alleles are called e2, e3, and e4. The most common allele is e3, which is found in more than half of the general population The e4 version of the APOE gene increases an individual's risk for developing late-onset Alzheimer's disease. . [6], [7]. [10]. Alzheimer's disease is a degenerative disease of the brain that causes dementia, which is a gradual loss of memory, judgment, and ability to function. The late-onset form of the condition occurs in people older than age 65.
People who inherit one copy of the APOE e4 allele have an increased chance of developing the disease; those who inherit two copies of the allele are at even greater risk. The APOE e4 allele may also be associated with an earlier onset of memory loss and other symptoms compared to individuals with Alzheimer's disease who do not have this allele. The e4 version of the APOE gene increases an individual's risk for developing late-onset Alzheimer's disease. Alzheimer's disease is a degenerative disease of the brain that causes dementia, which is a gradual loss of memory, judgment, and ability to function. The late-onset form of the condition occurs in people older than age 65. People who
inherit one copy of the APOE e4 allele have an increased chance of developing the disease; those who inherit two copies of the allele are at even greater risk.
The APOE e4 allele may also be associated with an earlier onset of memory loss and other symptoms compared to individuals with Alzheimer's disease who do not have this allele. It is not known how the APOE e4 allele is related to the risk of Alzheimer's disease. However, researchers have found that this allele is associated with an increased number of protein clumps, called amyloid plaques, in the brain tissue of affected people. A buildup of amyloid plaques may lead to the death of nerve cells (neurons) and the progressive signs and symptoms of Alzheimer's disease. . [1], [3]. [4].
It is important to note that people with the APOE e4 allele inherit an increased risk of developing Alzheimer's disease, not the disease itself. Not all people with Alzheimer's disease have the APOE e4 allele, and not all people who have this allele will develop the disease
Apolipoprotein E (ApoE) is critical in Ap dynamics, influencing its metabolism, aggregation, and deposition.
1. Isoform-Dependent Effects: The effectiveness of ApoE in clearing Ap from the brain is isoform-dependent:
o ApoE s4: The least efficient at mediating Ap clearance and is associated with
increased risk for AD.
o ApoE s3: Provides a moderate effect on Ap clearance.
o ApoE s2: The most effective at promoting Ap clearance and confers protective effects
against AD.
2. Cholesterol Regulation: ApoE also regulates cholesterol levels, impacting y-secretase activity and subsequently Ap production. Dysregulation in cholesterol metabolism can lead to increased Ap deposition.
3. Clearance Mechanisms:
o ApoE-Knockout Studies: Research indicates that ApoE-knockout mice clear Ap
more efficiently than control mice, suggesting that ApoE may hinder Ap clearance. The absence of ApoE allows for enhanced Ap removal mechanisms to function optimally.
o Liver X Receptors (LXRs) and Retinoid X Receptors (RXRs): Stimulation of these
receptors can enhance ApoE levels and facilitate Ap clearance, indicating potential therapeutic avenues.
o ABCA1 Transporter: The ATP-binding cassette transporter A1 (ABCA1) is crucial
for lipid transport to ApoE. Deficiencies in ABCA1 impair Ap clearance, particularly in ApoE4 carriers, suggesting that effective Ap clearance relies on sufficient ABCA1 activity.
Clinical Implications of Ap Aggregation
The aggregation of Ap into insoluble forms leads to the formation of senile plaques, a hallmark of AD. The presence of amyloid plaques correlates with cognitive decline in patients, making understanding Ap dynamics essential for developing therapeutic strategies.
APOE and Cognitive Decline
APOE s4 as a Major Risk Factor
The APOE s4 allele is the most significant genetic risk factor for AD, with numerous studies confirming its association with both early-onset and late-onset AD. Key points include:
• Individuals with one s4 allele have a risk increase of 2.6 to 3.2 times compared to those with s3 alleles.
• Those with two s4 alleles face a staggering 14.9 times increased risk.
• APOE s4 carriers often develop AD at a younger age, with 91% of s4 homozygotes developing AD by age 68.
Cognitive Decline in Healthy Individuals
Healthy individuals carrying the APOE s4 allele show signs of cognitive decline around ages 55-60, indicating that pathological changes can occur long before clinical symptoms manifest. Interestingly, younger APOE s4 carriers may initially perform better cognitively, highlighting a phenomenon known as antagonistic pleiotropy, where early advantages can lead to later decline.
Prediction of Alzheimer's Disease in Mild Cognitive Impairment (MCI)
MCI serves as a transitional stage between normal aging and dementia. Patients with amnesic MCI (aMCI) progress to AD at a rate of 10-15% per year, substantially higher than the rate in healthy elderly individuals. The presence of APOE s4 is linked to a more rapid cognitive decline, lower cerebrospinal fluid (CSF) Ap42 levels, and higher tau levels, indicating greater neurodegeneration.
1. Amnesic MCI (aMCI): Characterized primarily by memory problems.
2. Dys-executive MCI: Involves difficulties with executive functions rather than memory.
APOE and Other Types of Dementia
Lewy Body Disease (LBD)
LBD, which includes Parkinson's disease and dementia with Lewy bodies, shows a nuanced relationship with APOE:
• While there is little association between APOE s4 and Parkinson's disease, s4 increases the risk of dementia with Lewy bodies, correlating with higher Lewy body deposition in these patients.
Frontotemporal Dementia (FTD)
Research suggests that APOE s4 may also be a risk factor for FTD, although further investigation is needed to understand its role fully.
Huntington's Disease and Amyotrophic Lateral Sclerosis
Current evidence indicates that APOE genotypes do not significantly influence the risk of Huntington's disease or amyotrophic lateral sclerosis.
Conclusion
The multifaceted roles of Ap and ApoE in Alzheimer's disease pathogenesis highlight the complexity of the disease. The progression from soluble to insoluble Ap forms, influenced by ApoE isoforms, underpins the neurodegenerative process observed in AD. Understanding these mechanisms is vital for developing targeted interventions that may modulate Ap dynamics and improve clinical outcomes for patients at risk for Alzheimer's disease.
REFERENCES
1. Wang H, Kulas JA, Wang C, Holtzman DM, Ferris HA, Hansen SB (August 2021). "Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol". Proceedings of the National Academy of Sciences of the United States of America. 118 (33): 2020.06.18.159632. Bibcode:2021PNAS..11802191W. bioRxiv 10.1101/2020.06.18.159632. do i:10.1073/pnas.2102191118. PMC 8379952. PMID 34385305. S2CID 220044671.
2. Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (February 2013). "Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy". Nature Reviews. Neurology. 9 (2): 106118. doi:10.1038/nrneurol.2012.263. PMC 3726719. PMID 23296339.
3. Yin C, Ackermann S, Ma Z, Mohanta SK, Zhang C, Li Y, et al. (March 2019). "ApoE attenuates unresolvable inflammation by complex formation with activated C1q". Nature Medicine. 25 (3): 496-506. doi:10.1038/s41591-018-0336-8. PMC 6420126. PMID 30692699.
4. Babin PJ, Thisse C, Durliat M, Andre M, Akimenko MA, Thisse B (August 1997). "Both apolipoprotein E and A-I genes are present in a nonmammalian vertebrate and are highly expressed during embryonic development". Proceedings of the National Academy of Sciences of the United States of America. 94 (16): 86228627. Bibcode: 1997PNAS...94.8622B. doi:10.1073/pnas.94.16.8622. PMC 23048. PMID 92380 27.
5. Huebbe P, Rimbach G (August 2017). "Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors". Ageing Research Reviews. 37: 146-161. doi:10.1016/j.arr.2017.06.002. PMID 28647612. S2CID 3758905.
6. McIntosh AM, Bennett C, Dickson D, Anestis SF, Watts DP, Webster TH, et al. (2012). "The apolipoprotein E (APOE) gene appears functionally monomorphic in chimpanzees (Pan troglodytes)". PLOS ONE. 7 (10): e47760. Bibcode:2012PLoSO...747760M. doi:10.1371/journal.pone.0047760. PMC 3480407. P MID 23112842.
7. Phillips MC (September 2014). "Apolipoprotein E isoforms and lipoprotein metabolism". IUBMB Life. 66 (9): 616623. doi:10.1002/iub.1314. PMID 25328986. S2CID 6159310.
8. Eisenberg DT, Kuzawa CW, Hayes MG (September 2010). "Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history". American Journal of Physical Anthropology. 143 (1): 100-111. doi:10.1002/ajpa.21298. PMID 20734437.
9. Jump up to:a b Baars HF, van der Smagt JJ, Doevandans PA (2011). Clinical Cardiogenetics. London: Springer. ISBN 978-1849964715.
10. Ghebranious N, Ivacic L, Mallum J, Dokken C (October 2005). "Detection of ApoE E2, E3 and E4 alleles using MALDI-TOF mass spectrometry and the homogeneous mass-extend technology". Nucleic Acids Research. 33 (17): e149. doi:10.1093/nar/gni 155. PMC 1243648. PMID 16204452.
