{"id":21365,"date":"2024-05-28T09:02:02","date_gmt":"2024-05-28T09:02:02","guid":{"rendered":"https:\/\/clinlabint.com\/?p=21365"},"modified":"2024-05-28T06:29:09","modified_gmt":"2024-05-28T06:29:09","slug":"apoe-genotype","status":"publish","type":"post","link":"https:\/\/clinlabint.com\/apoe-genotype\/","title":{"rendered":"APOE genotype"},"content":{"rendered":"
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\r\n\"Bio-Rad<\/a>\r\n<\/p>\n<\/div><\/section><\/div>

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APOE genotype<\/h1>\/ in Featured Articles<\/a> <\/span><\/span><\/header>\n<\/div><\/section>
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By Dr Jacqueline Gosink<\/em><\/p>\n

A risk factor for adverse effects from anti-amyloid therapy in Alzheimer\u2019s disease<\/h3>\n

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The apolipoprotein E (APOE) genotype influences the development of Alzheimer\u2019s disease and has recently been found to be a risk factor for side effects from new disease-modifying therapies. Carriers of the APOE \u03b54 allele have the highest risk, especially if they are homozygous. APOE genotyping is therefore increasingly relevant for risk assessment prior to the use of anti-amyloid drugs.<\/h4>\n

Alzheimer\u2019s disease<\/h3>\n

Alzheimer’s disease is the most common age-related cause of dementia and is a major global health concern. The number of cases is rising rapidly and is projected to continue growing over the coming decades, causing a massive societal and economic burden. Most cases of Alzheimer\u2019s disease are late onset, occurring in people over 65. The prevalence doubles with about every five years of age, from just over 1% in the age group 65\u201369 to more than 25% in those over 90 years old [1]. Early-onset Alzheimer\u2019s disease, which can occur in people in their 40s or 50s, is much rarer, constituting about 5% of Alzheimer\u2019s cases. The main pathologic feature of Alzheimer\u2019s disease is aggregation of amyloid-beta in the brain which drives the rest of the disease process, such as the neurofibrillary tau tangles that result from an imbalance between amyloid-beta production and clearance [2]. In the last few years, novel disease-modifying drugs that clear the toxic amyloid deposits have appeared on the market. However, in some individuals they induce severe side effects that are linked to the APOE genotype.<\/p>\n

Apolipoprotein E<\/h3>\n

Apolipoprotein E (Apo-E) is a lipid transporter that delivers cholesterol and phospholipids throughout the body. Apo-E plays a role in Alzheimer\u2019s disease by interacting with amyloid-beta and regulating its aggregation and clearance. Apo-E also contributes to Alzheimer\u2019s pathogenesis via various other amyloid-beta-related and -independent pathways: for example, by modulating brain synaptic plasticity, glucose metabolism, neuronal signalling, oxidative stress, neuroinflammation, mitochondrial function and cholesterol transportation [3].<\/p>\n

APOE alleles<\/h3>\n

There are three clinically relevant APOE alleles, which are denoted \u03b52, \u03b53 and \u03b54. Depending on the allele, three different isoforms of the Apo-E protein are produced, which differ in the amino acids\u00a0 at positions 112 and 158. E2 contains cysteine at both positions, E3 contains cysteine and arginine respectively, and E4 contains arginine at both positions.<\/p>\n

Variant \u03b53 is the most frequent of the three alleles. \u03b53\/\u03b53 is considered the normal genotype and is carried, for example, by 63% of the population. The \u03b54 allele is associated with an increased risk of developing Alzheimer\u2019s disease. This variant occurs at frequencies of 21% for the heterozygous \u03b53\/\u03b54 form, 2% for the combination \u03b52\/\u03b54, and 2% for the homozygous \u03b54\/\u03b54 form. The \u03b52 allele, on the other hand, is neuroprotective for Alzheimer\u2019s disease. Eleven percent of the population carry the heterozygous \u03b52\/\u03b53 form and 1% the homozygous \u03b52\/\u03b52 form [4].<\/p>\n

The \u03b54 allele is found around three times more frequently in Alzheimer\u2019s disease patients than in the cognitively normal population, corresponding to about 38% compared to 14%, respectively [5]. In contrast, the \u03b52 allele occurs in just 3.9% of Alzheimer\u2019s patients compared to 7% of cognitively normal persons. Furthermore, the \u03b54 gene dosage impacts both
\nthe disease risk and the age at which late-onset Alzheimer\u2019s disease manifests. The relative risk of developing late-onset Alzheimer\u2019s disease with respect to the genotype is in ascending order: \u03b52\/\u03b52, \u03b52\/\u03b53, \u03b52\/\u03b54, \u03b53\/\u03b53, \u03b53\/\u03b54 and \u03b54\/\u03b54. The average age of disease onset amounts to 84 years for non-\u03b54 carriers, 76 years for heterozygote carriers and 68 years for homozygous carriers [6]. In the early-onset familial form of Alzheimer\u2019s disease, numerous mutations in other genes are implicated, including genes for amyloid precursor protein and presenilin 1 and 2.<\/p>\n

Alzheimer\u2019s diagnostics<\/h3>\n

Early diagnosis of Alzheimer\u2019s disease is important for effective therapy management and patient support. Diagnosis of Alzheimer\u2019s disease is based on clinical evaluation, imaging methods such as positron emission tomography (PET), and analysis of biomarkers in cerebrospinal fluid (CSF). APOE genotyping alone does not play a major role in diagnosis of Alzheimer\u2019s disease, as its predictive value is limited. CSF analysis is considered the most sensitive diagnostic method, detecting pathologic changes many years before disease onset [7]. The most important CSF biomarkers are the amyloid-beta 1\u201342 to 1\u201340 ratio, phosphorylated tau and total tau. These markers can be measured, for example, by ELISA
\nor chemiluminescence immunoassay (ChLIA). A portfolio of ELISA and ChLIA assays* developed by EUROIMMUN in collaboration with ADx Neurosciences demonstrate robust
\nand highly reproducible measurements. The assays use highly specific monoclonal antibodies for precise detection of each analyte.<\/p>\n

A new era of therapy<\/h3>\n

Although Alzheimer\u2019s disease cannot be cured, the last few years have witnessed the introduction of disease-modifying therapies, which can delay disease progression in patients with early-stage Alzheimer\u2019s disease [8]. These monoclonal antibody-based treatments reduce amyloid-beta plaques in the brain, slowing cognitive and functional decline. To be effective,
\nanti-amyloid therapies must be implemented in the prodromal stage of mild cognitive impairment.<\/p>\n

The first drug on the market, aducanumab (Aduhelm), received FDA approval in 2021 under the accelerated approval pathway. A second drug, lecanemab (Leqembi), received traditional approval in 2023 for treatment of patients in the early stage of Alzheimer\u2019s disease with confirmed amyloid pathology as demonstrated by PET or CSF testing. Authorization of lecanemab by the European Medicines Agency (EMA) is expected in spring 2024 [9]. Donanemab is also expected to be approved soon in the USA.
\nMany further promising anti-amyloid drugs are in the pipeline.<\/p>\n

Side effects of amyloid modification therapies<\/h3>\n

In some cases, anti-amyloid treatments can induce side effects, including amyloid-related imaging abnormalities (ARIA) with edema and\/or effusion (ARIA-E) or hemorrhagic changes (ARIA-H) [2,10]. These are thought to be expressions of increased vascular fragility and leakage of proteinaceous fluid and erythrocytes caused by the antibody treatments. Although mainly asymptomatic, ARIA may cause additional symptoms such as headache, confusion, visual changes, dizziness, nausea, gait difficulty and seizures. In a few cases, the side effects have even been fatal. If ARIA are detected, the treatment is usually suspended until improvement or discontinued completely. The risk of developing ARIA is greater in carriers of the \u03b54 allele, with homozygous carriers considered at highest risk. The rate of ARIA amounted to 5.4% in \u03b54 non-carriers, 10.9% in heterozygotes and 32.6% in homozygotes. Rates of symptomatic ARIA were 1.4%, 1.7% and 9.2%, respectively [11].<\/p>\n

Significance of APOE genotyping<\/h3>\n

The determination of APOE gene variants associated with Alzheimer\u2019s disease is increasingly recommended as a screening tool prior to anti-amyloid therapy to assess the risk of negative consequences. Information about the increased risk of ARIA for \u03b54 carriers compared to other genotypes can be included in patient management decisions. In patients receiving lecanemab, post-treatment monitoring is directed principally at detecting ARIA, and heightened vigilance for ARIA is recommended in \u03b54 carriers, especially homozygotes [11].<\/p>\n

PCR-based genotyping test<\/h3>\n

A real-time PCR test to determine the APOE genotype has been developed by EUROIMMUN. The multiplex EURORealTime APOE simultaneously detects the APOE \u03b52, \u03b53 and \u03b54 alleles and deduces the six possible genotypes \u03b52\/\u03b52, \u03b52\/\u03b53, \u03b52\/\u03b54, \u03b53\/\u03b53, \u03b53\/\u03b54 and \u03b54\/\u03b54. Only one reaction is required per patient sample. The test is performed on genomic DNA (gDNA) isolated from EDTA blood samples. The assay processing can be automated on established instruments, and results are evaluated, documented and archived using the EURORealTime Analysis Software. The EURORealTime APOE will be launched soon.*<\/p>\n

Conclusion<\/h3>\n

With the advent of disease-modifying therapies for Alzheimer\u2019s disease, the use of APOE genotyping has become relevant for supporting patient management. For clinicians treating Alzheimer\u2019s patients, APOE genotyping will grant additional patient information and will enable a more personalized approach in anti-amyloid treatment.<\/p>\n

* Regulatory status, precise intended use and product availability must be verified for the user\u2018s individual jurisdiction<\/p>\n<\/div><\/section>
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Illustration of amyloid plaques forming between neurons (Shutterstock.com)<\/em><\/p>\n<\/div><\/section>
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<\/span><\/span><\/div>
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The author<\/strong><\/em><\/p>\n

Jacqueline Gosink PhD<\/em>
\nEUROIMMUN, 23560 L\u00fcbeck, Germany<\/em><\/p>\n

For further information see: <\/em>www.neuro-company.com<\/em><\/a><\/p>\n

References<\/strong><\/em><\/p>\n

1. Ghebremedhin E, Deller T. Risikofaktoren der Alzheimer-Krankheit: was verraten uns die Gene? [Risk factors for Alzheimer\u2019s disease: what do the genes reveal?] Forschung Frankfurt 2007;2:90\u201393\u00a0 (https:\/\/www.forschung-frankfurt.uni-frankfurt.de\/36050533\/forschung-frankfurt-ausgabe-2-2007-risikofaktoren-der-alzheimerkrankheit-was-verraten-uns-die-gene.pdf<\/a>; In German).<\/em>
\n2. Agarwal A, Gupta V, Brahmbhatt P et al. Amyloid-related imaging abnormalities in Alzheimer disease treated with anti-amyloid-\u03b2 therapy. Radiographics 2023;43(9):e230009 <\/em>
\n(https:\/\/pubs.rsna.org\/doi\/10.1148\/rg.230009<\/a>).<\/em>
\n3. Sun YY, Wang Z, Huang HC. Roles of ApoE4 on the pathogenesis in Alzheimer’s disease and the potential therapeutic approaches. Cell Mol Neurobiol 2023;43(7):3115\u20133136 <\/em>
\n(https:\/\/link.springer.com\/article\/10.1007\/s10571-023-01365-1<\/a>).<\/em>
\n4. Wang YY, Ge YJ, Tan CC et al. The proportion of APOE4 carriers among non-demented individuals: a pooled analysis of 389,000 community-dwellers. J Alzheimers Dis 2021;81(3):1331\u20131339 (https:\/\/content.iospress.com\/articles\/journal-of-alzheimers-disease\/jad201606<\/a>).<\/em>
\n5. Alzgene \u2013 meta-analysis of all published ad association studies (case-control only) APOE_E2\/3\/4. Alzforum (www.alzgene.org\/meta.asp?geneID=83<\/a>).<\/em>
\n6. Corder EH, Saunders AM, Strittmatter WJ et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;261(5123):921\u2013923 (https:\/\/www.science.org\/doi\/10.1126\/science.8346443<\/a>).<\/em>
\n7. Jia J, Ning Y, Chen M et al. Biomarker changes during 20 years preceding Alzheimer\u2019s disease. N Engl J Med 2024;390(8):712\u2013722 (https:\/\/www.nejm.org\/doi\/10.1056\/NEJMoa2310168<\/a>).<\/em>
\n8. van Dyck CH, Swanson CJ, Aisen P et al. Lecanemab in early Alzheimer\u2019s disease. N Engl J Med 2023;388:9\u201321 (https:\/\/www.nejm.org\/doi\/10.1056\/NEJMoa2212948<\/a>).<\/em>
\n9. Morbus Alzheimer: FDA z\u00f6gert Zulassung von Donanemab hinaus [Alzheimer’s disease: FDA delays approval of donanemab]. \u00c4rzteblatt 12 March, 2024 (www.aerzteblatt.de\/nachrichten\/149893; in German<\/a>).<\/em>
\n10. Filippi M, Cecchetti G, Spinelli EG et al. Amyloid-related imaging abnormalities and \u03b2-amyloid-targeting antibodies: a systematic review. JAMA Neurol 2022;79(3):291\u2013304 (https:\/\/jamanetwork.com\/journals\/jamaneurology\/article-abstract\/2788269<\/a>).<\/em>
\n11. Cummings J, Apostolova L, Rabinovici GD et al. Lecanemab: appropriate use recommendations. J Prev Alzheimer\u2019s Dis 2023;10(3):362\u2013377 (https:\/\/link.springer.com\/article\/10.14283\/jpad.2023.30<\/a>).<\/em><\/p>\n<\/div><\/section>
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