Alzheimer’s Disease: The Role of Apolipoprotein E

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Alzheimer’s Disease: The Role of Apolipoprotein E

21 September 2019

Alzheimer’s Disease: The Role of Apolipoprotein E

Since 2012, September has been devoted to raising awareness of Alzheimer’s disease (AD) with Alzheimer’s Day on 21st September each year. Dementia is the medical name attributed to a set of symptoms affecting the brain, including: difficulties with problem solving, thinking, language and memory loss. AD is the most common form of dementia accounting for 60 – 80% of cases and it is believed that half of patients with Alzheimer’s dementia (dementia due to AD) have Alzheimer’s disease 1, 2.

About Alzheimer’s Disease (AD)

AD is one of the most devastating and complex diseases characterised by:

. Neurodegeneration resulting in memory loss 2

. Neurofibrillary tangles composed of tau amyloid fibrils which associates with synapse loss 2

. Accumulation of β-amyloid (Aβ) plaques 2

. Other cognitive functions 2

It is believed that AD is expected to begin 20 years prior to symptom onset, as the small changes in the functioning of the brain are unnoticeable to the person affected. Overtime, the symptoms progress and begin to interfere with the patient’s ability to perform everyday tasks. The final stages of AD leaves the patient bed-bound, requiring 24/7 care. Ultimately, AD is fatal. Age has been identified as a risk factor for AD with 10% of people over the age of 65 affected. Moreover, AD has been recognised as a leading cause of morbidity and the sixth leading cause of mortality, but the fifth leading cause of death in over 65’s in the US 3.

Figure 1: Alzheimer’s Disease Demographic, 2019 3

Physiological Significance of Apolipoprotein E

Apolipoprotein E (Apo E) is a lipoprotein composed of 299 amino acids with a molecular weight of 34kDa.  Apo E is responsible for the regulation of homeostasis through the mediation of lipid transport from and to bodily cells and tissues. Apo E comprises of three common isoforms: apo E2, apo E3 and apo E4. The apo E isoforms differ due to differences in either the 112 and 158 amino acids, whether either arginine (ARG) or cysteine (CYS) is present 4.

Apo E3 is the parent form of apo E and is responsible for the clearance of triglyceride-rich lipoproteins. Apo E3 is associated with normal lipid plasma concentrations. Apo E2 is the rarest of the apo E isoforms and differs slightly compared to the apo E3 isoform through the substitution of a single amino acid, ARG158Cys, located near the low-density lipoprotein receptor (LDLR) recognition site. Apo E2 displays impaired binding to the receptor, prohibiting the clearance of triglyceride-rich lipoprotein remnant particles. Apo E2 is strongly associated with type-III hyperlipoproteinemia. Apo E3 also differs from apo E4, again through the substitution of a single amino acid, Cys112Arg. The main difference between apo E3 and apo E4 is that apo E4 is unaffected by the binding of the isoform to LDLR. However, apo E4 is strongly associated with dyslipidemia 5. Fig. 2 provides a visual representation of the variations in the Apo E isoforms.

Figure 2: Variations in the Apo E Isoforms 4

Apo E is expressed in numerous bodily organs with the liver presenting with the highest expression followed by the brain. Astrocytes and, to a lesser extent, microglia are the major cells responsible for the expression of apo E in the brain. In the brain, apo E, apo J and apo A-1 are predominantly expressed on distinct high-density-like lipoprotein particles. Whilst apo A-1 is the major apolipoprotein of high-density lipoproteins (HDL), in the central nervous system (CNS), apo E is the predominant apolipoprotein of HDL-like lipoproteins. HDL-like lipoproteins are the only lipoproteins present in the CNS. It is believed that the cholesterol released from apo E supports synaptogenesis 6.

Clinical Significance of Apolipoprotein E in Alzheimer’s Disease

Whilst apo E3 is the most abundant of the three isoforms, apo E4 has been known for decades to be the most significant genetic risk factor for late-onset AD. Inheriting the one copy of the apo E4 gene increases the risk of AD 2-3-fold, whilst inheriting two copies increases the risk of AD up to 12-fold 7. Whilst the underlying mechanism of apo E’s contribution to AD risk is still unclear and debatable, apo E has been identified as promoting amyloid β (Aβ) deposition and clearance as well as neurofibrillary tangles in the brain. Interestingly, Aβ-independent pathways exist for apo E in AD, which led to the unearthing of the new roles of apo E including the most recent, iron metabolism and mitochondria dysfunction 8, 9. Captivatingly, sex-related hormones may play a role in AD in apo E4 carriers as AD has been recognised to be more pronounced in women 10. Apo E4 has also been identified as impairing lipid transport, microglial responsiveness, glucose metabolism, synaptic plasticity and integrity, and cerebrovascular function and integrity. Some of these pathogeneses are independent of Aβ pathways. Furthermore, therapeutic strategies are aiming to modulate the quantity, lipidation, structural properties, Aβ interaction and receptor expression of Apo E 11.

Key Features of the Randox Apolipoprotein E Assay

Randox are one of the only manufacturers to offer the apo E assay in an automated clinical chemistry format. Utilising the immunoturbidimetric method, the Randox apo E assay is available in a liquid ready-to-use format. Not only does the Randox apo E suffer from limited interferences from bilirubin, haemoglobin, intralipid® and triglycerides for truly accurate results, it has an excellent measuring range of 1.04 – 12.3mg/dl for the comfortable detection of clinically important results. Moreover, apolipoprotein calibrator and controls are available for a complete testing package. Applications are available detailing instrument-specific settings for the convenient use of the Randox apo E assay on a wide range of clinical chemistry analysers.

Biochip Technology – Alzheimer’s Array

Utilising the Biochip Technology, Randox have developed an array to identify the risk of Alzheimer’s disease in just 3 hours with one effective test. In addition to a rapid and accurate diagnosis, this also introduces both cost and time-saving benefits. The apo E4 array is a research use only product developed for the Evidence Investigator, a semi-automated benchtop immunoassay analyser which can process up to 2376 test per hour as well as up to 44 analytes screened per biochip. The apo E4 array measures both total apo E protein levels and apo E4 protein levels directly from plasma samples as well as using a ratio, it can classify patients as negative or positive for apo E4. In turn, we can then assess their risk for the development of Alzheimer’s disease.

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In vitro diagnostics is the heart and soul of the healthcare system as healthcare professionals not only rely on diagnostic tests to diagnose and treat patients, but also to rule out the different contributing causes of a disease state. The implementation of superior performance & unique tests can aid in the early and accurate diagnosis of disease states, enabling the appropriate and effective implementation of a personalised treatment plan 1.

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All our superior performance & unique diagnostic reagents are validated against gold-standard methods, offering low CV’s and excellent precision giving you the confidence that you are sending out accurate patient results.

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Lp(a)

The Randox Lp(a) assay is calibrated in nmol/l and traceable to the WHO/IFCC reference material (IFCC SRM 2B) and provides an acceptable bias compared with the Northwest Lipid Metabolism Diabetes Research Laboratory (NLMDRKL) gold standard. A five-point calibrator with accuracy-based assigned target values (in nmol/l) is available, accurately reflecting the heterogeneity of the apo(a) isoforms.

Bile Acids

The Randox bile acids test utilises an advanced enzyme cycling method which displays outstanding sensitivity and precision when compared to traditional enzymatic based tests. The Randox 5th Generation Bile Acids test is particularly useful in paediatrics where traditional bile acids tests are affected by haemolytic and lipaemic samples.

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A superior assay from Randox, the vanadate oxidation method offers several advantages over the diazo method, including less interference by haemolysis and lipaemia, which is particularly evident for infant and neonatal populations.

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Adiponectin has been identified as having pleiotropic functions widely associated with anti-atherogenic, anti-diabetic, cardioprotective and anti-inflammatory effects. Adiponectin levels inversely correlate with insulin levels, BMI, triglyceride levels, insulin resistance (IR), glucose, and most importantly, visceral fat accumulation.

sTfR

Soluble transferrin receptor (sTfR) is a marker of iron status. In iron deficiency anaemia, sTfR levels are significantly increased, however remain normal in the anaemia of inflammation. Consequently, sTfR measurement is useful in the differential diagnosis of microcytic anaemia.

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CVD
  • Cardiovascular Disease (CVD)

    CVD accounts for 45% of all deaths in europe and 37% of all deaths in the EU. Atherogenesis is a circulatory disease whereby atheromas are formed (plaque build-up) within the artery.  Plaque is a combination of cholesterol, fat, calcium, lipids and other substances within the blood stream.  As time progresses, the plaque hardens, narrowing the arteries.  This is known as atherosclerosis. Consequently, blood flow through the narrowed artery is reduced, limiting the supply of blood to vital organs and bodily tissues.  As atherogenesis can affect any artery within the body, different diseases may develop based on the artery that is affected.  Such diseases include: coronary heart/artery disease, carotid artery disease, peripheral artery disease and chronic kidney disease 2, 3, 4.

  • Type 2 Diabetes Mellitus (T2DM)

    425 million people are living with type 2 diabetes mellitus (T2DM) and 352 million are at risk of developing T2DM. T2DM is a serious condition whereby blood glucose levels are elevated (hyperglycaemia). T2DM is characterised by insulin resistance or insulin deficiency. T2DM is the most common form of diabetes, accounting for 90% of cases. The key to T2DM is control. Implementing lifestyle changes, oral medication and in more severe cases, insulin, a diabetic can take control of their disease, keeping glucose levels stable. When glucose levels are not monitored and controlled, associated complications may arise including: diabetic nephropathy, CVD and renal impairment 5, 6.

  • Chronic Kidney Disease (CKD)

    Worldwide 1/5 of men and 1/4 of women between 65 and 74 years of age have Chronic kidney disease (CKD). CKD is an umbrella term encompassing a wide range of renal conditions from commonly prevalent sub-clinical, asymptomatic to rare end-stage renal disease requiring dialysis or a transplant to sustain life. Kidney disease is ranked in stages from stage 1 (very mild damage) through to stage 5 (kidney failure) 7. Symptoms are commonly expressed in the later stages of renal impairment, however, at this point dangerous levels of fluid, electrolytes and waste products can build up inside the body. The aim of CKD treatment is to slow the progression of the disease, thus early intervention is vital 8.

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Extensive study confirms the benefit of testing apolipoproteins E, C-II and C-III to assess cardiac risk

A study published on 21st February 2017 in the Journal of the American College of Cardiology has found that measuring apolipoproteins E, C-II and C-III can offer earlier detection of cardiovascular risk in comparison to routine apolipoprotein A-I and B tests.1

The lead author of the study, Professor Manuel Mayr, from King’s College London has said, “We directly compared the association of a broad panel of apolipoproteins to new onset of cardiovascular disease over a 10-year observation period, and found that while apoB was predictive, other apolipoproteins, namely apoE, apo C-II and apo C-III, were even better”. Professor Mayr further implied that the findings provide support that expanding current cardiac screening tests to include apolipoproteins could reduce risk of cardiovascular diseases.2


What are apolipoproteins?

Apolipoproteins are proteins that bind to lipids to form lipoproteins. Lipoproteins are made of proteins and fats, and serve the function of transporting insoluble fats, such as cholesterol and triglycerides, to be used by different cells. 3

There are six major types of apolipoprotein: A, B, C, D, E and H and the lipoproteins within these categories can vary in size, density and lipid composition. The study found that apolipoproteins E, C-II and C-III are linked to very low-density lipoproteins (vLDL) and have a stronger association with cardiovascular diseases in comparison to apolipoprotein A-I and apolipoprotein B.4

vLDL is strongly associated with the development of atherosclerosis, the build-up of fatty material inside the arteries, which is a major risk factor of cardiovascular diseases as it can lead to angina, heart attack, stroke or peripheral arterial disease.5


Why measure apo C-II, apo C-III and apo-E?


As highlighted by the authors of the study, cardiovascular risk assessment is commonly associated with only a few lipids within established lipoprotein classes, such as LDL.1 This emphasises the importance of carrying out detailed lipid testing to identify all subgroups to provide a complete cardiovascular risk assessment, as traditional biomarkers for lipids may only provide a limited overview. This can then allow for effective treatment to be provided at an earlier stage, which could subsequently reduce the risk of death by cardiovascular diseases.

Randox offer a range of routine and novel cardiac assays to provide a complete cardiac risk assessment, including: Apolipoprotein C-II / C-III / E / A-I / A-II /  B, Adiponectin, HDL Cholesterol, HDL3 Cholesterol, LDL Cholesterol, sLDL Cholesterol, Total Cholesterol, TxBCardio™, H-FABP, Homocysteine, hsCRP, Lipoprotein (a), sPLA2-IIA, and Triglycerides. For more information, email: reagents@randox.com.


References

1. Mayr, M. et al., Very-low-density lipoprotein-associated apolipoproteins predict cardiovascular events and are lowered by inhibition of APOC-III., Journal of the American College of Cardiology. Vol. 69, No. 7, 2017.

2. NIHR Biomedical Research Centre at Guy’s and St Thomas’ and King’s College London, Discovery could help doctors to spot cardiovascular disease at an earlier stage: Advanced technologies provide researchers with new insights into the warning signs for cardiovascular disease, ScienceDaily (2017) Available from: https://goo.gl/XkC23R [Accessed: 21 February 2017]

3. Kingsbury, K. J., Understanding the Essentials of Blood Lipid Metabolism, Medscape, (2017) Available from: https://goo.gl/AApW6S [Accessed: 23 February 2017]

4. Wallace, A., New technique could aid in earlier diagnosis of heart disease, UPI, (2017) Available from: https://goo.gl/xzxLdf [Accessed: 23 February 2017]

5. British Heart Foundation, Atherosclerosis, (2017) Available from: https://goo.gl/1qHxpk [Accessed: 23 February 2017}

Apolipoproteins may offer earlier detection of CVDs


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