Apolipoprotein E (APOE) Genotyping, Alzheimer Disease Risk

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Apolipoprotein E (APOE) Genotyping, Alzheimer Disease Risk Incidence of AD Indications for Ordering • 65-74 years – 1/500 • Supports a clinical diagnosis of Alzheimer disease (AD) in • 75-84 years – 1/76 symptomatic individuals • ≥85 years – 1/25 • NOT recommended for predicting risk for AD in APOE allele frequencies asymptomatic individuals • e2 – 10% • NOT performed on individuals <18 years or on fetal • e3 – 75% specimens • e4 – 15% 30-60% of individuals with AD have at least one e4 allele Test Description o o e4/e4 is found in Polymerase chain reaction and fluorescence monitoring using . ~13% of AD population hybridization probes for APOE gene . 20% of familial AD population • Variants tested . 1-2% of general population o c.388T>C (rs429358, p.Cys130Arg) Age of onset – typically >65 years c.526C>T (rs7412, p.Arg176Cys) o Symptoms • Alleles • Cognitive decline o e2 allele (cysteine at codons 130 and 176) o Progressive memory loss o e3 allele (cysteine at codon 130, arginine at codon 176) o Confusion and disorientation o e4 allele (arginine at codons 130 and 176) o Personality changes Tests to Consider o Problems with executive function • Neurological findings Primary test o Seizures APOE Apolipoprotein E ( ) Genotyping, Alzheimer Disease Risk o Parkinsonism 2013341 o Psychiatric disturbance • Determines APOE genotype in context of evaluation for • Progression of symptoms can last 8-25 years AD • Death typically occurs due to malnutrition, pneumonia, or • See 2013337 below for cardiovascular risk assessment secondary infections • Genetic counseling and informed consent are strongly Diagnostic issues recommended prior to ordering and posttest to discuss results • Diagnosing AD in symptomatic individuals o Probable diagnosis of AD can be made based on Related test combination of clinical findings, neuroimaging, and Apolipoprotein E (APOE) Genotyping, Cardiovascular Risk exclusion of other causes of dementia 2013337 . An antemortem diagnosis of AD is correct 80-90% of • Provides supporting evidence for a diagnosis of type III the time hyperlipoproteinemia for evaluation of premature . Presence of e4/e4 APOE genotype increases diagnostic coronary heart disease certainty to ~97% • Use for cardiovascular disease risk assessment only o Diagnosis is confirmed postmortem by neuropathologic examination Disease Overview o APOE genotyping can be used to support the clinical Prevalence of AD diagnosis of AD in symptomatic individuals if one or • ≥65 years – 1/9 more e4 alleles are present, but e4 is neither necessary • ≥85 years – 1/3 nor sufficient to diagnose AD

• Predicting AD risk in asymptomatic individuals Test Interpretation o APOE genotyping is not recommended for predictive testing in asymptomatic individuals due to Sensitivity/specificity . Low sensitivity and specificity • Analytical sensitivity/specificity – 99% . Lack of preventive options Results . Difficulty quantifying individual risk • APOE e2/e2 AD risk is multifactorial o o Not associated with increased risk for AD, but has been . Determined by multiple genes, age, gender, ethnicity, associated with increased risk for type III family history, and environment hyperlipoproteinemia o In rare cases of early onset familial AD, presymptomatic • APOE e3/e3 and e2/e3 testing is possible if the familial variant is known o Not associated with increased risk for AD, but does not . APP, PSEN1, and PSEN2 genes, which are associated exclude a diagnosis of AD with early onset AD, are not included in this test • APOE e4/e4 Pathophysiology o Adds substantial support to a clinical diagnosis of AD in symptomatic individuals Etiology of AD is largely unknown • APOE e2/e4 and e3/e4 • Symptoms are thought to be caused by abnormal Adds support to a clinical diagnosis of AD in accumulation of beta-amyloid plaques and neurofibrillary o symptomatic individuals tangles of tau protein in the brain that cause neuronal damage and death Limitations • Presence of one or more APOE e4 alleles is considered a Genetics risk factor but is not diagnostic for AD APOE Gene – APOE o e4 is neither necessary nor sufficient to diagnose AD Inheritance of AD – multifactorial • Other APOE alleles and variants in other genes associated Inheritance of APOE e4 – semidominant with AD are not analyzed • Diagnostic errors can occur due to rare sequence Penetrance – incomplete and age dependent variations Variants • APOE e2 References o Associated with decreased risk for AD • Alzheimer’s Association. 2015 Alzheimer’s disease facts • APOE e3 and figures (www.alz.org/facts/) o Most common APOE allele in the general population • Bird TD. Alzheimer Disease Overview. 1998 Oct 23 • APOE e4 [Updated 2015 Sept 24]. In: Pagon RA, Adam MP, Ardinger o Associated with increased risk for AD HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016 (www.ncbi.nlm.nih.gov/books/NBK1161/)