Alzheimer disease is an irreversible, progressive brain disease. It is characterized by the development of amyloid plaques and neurofibrillary tangles; the loss of connections between nerve cells, or neurons, in the brain; and the death of these nerve cells. [1, 2]
The expanded definition of Alzheimer disease includes 2 new phases of the disease—
presymptomatic and mildly symptomatic but predementia—along with dementia caused by Alzheimer disease. This reflects current thinking that Alzheimer disease begins creating distinct and measurable changes in the brains of affected people years before onset. [1, 2, 3]
Types of Alzheimer disease
There are 2 types of Alzheimer disease—early-onset and late-onset (LOAD). Early-onset disease occurs in people 30-60 years of age. It is rare, representing less than 5% of all people who have Alzheimer disease. Some cases of early-onset disease have no known cause, but most cases are inherited, a type known as familial Alzheimer disease (FAD). Familial Alzheimer disease is caused by any one of a number of different single-gene mutations, such as mutations on chromosome 21, which cause the formation of abnormal amyloid precursor protein (APP). A mutation on chromosome 14 causes the production of abnormal presenilin 1, and a mutation on chromosome 1 leads to production of abnormal presenilin 2. [4, 5, 6, 7]
Most cases of Alzheimer disease are the late-onset form, which develops after 60 years of age. The causes of late-onset Alzheimer disease are not yet completely understood, but they likely include a combination of genetic, environmental, and lifestyle factors that influence a person's risk for developing the disease. Inheritable risk in LOAD is 60-80%, but genetics and environmental factors equally contribute to the onset, progression, and severity of disease. [3, 4, 5, 6, 7]
Currently, the APOE gene (located on chromosome 19) is the only gene identified that is related to LOAD, and it also runs in families, although its relation to the occurrence of LOAD is weak. APOE at the molecular level helps in the synthesis of apolipoprotein E, which is a cholesterol carrier in the brain, helping in amyloid aggregation and the clearing of deposits from the parenchyma of the brain. In the absence of function of this gene, excessive beta-amyloid deposits occur in the brain, which is one of the findings in patients with LOAD. There are different forms, or alleles, of APOE, with the 3 most common ones being APOE ε2, APOE ε3, and APOE ε4. The 5 common genotypes are 2/3, 3/3, 2/4, 3/4, and 4/4. [3, 4, 5, 6, 7, 8, 9, 10, 11, 12]
APOE ε2 is a relatively common variant but is rarely seen in the population and may provide some protection against the disease. APOE ε3, the most common allele, is believed to play a neutral role in the disease—neither decreasing nor increasing risk. [3, 5, 12, 13]
APOE ε4 is present in about 25-30% of the population and in about 40% of all people with LOAD. People who develop Alzheimer disease are more likely to have an APOE ε4 allele than people who do not develop the disease. APOE ε4 is called a risk-factor gene because it increases a person's risk of developing the disease; however, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer disease. [9, 11] Although research supports the relation of the APOE ε4 variant and the occurrence of LOAD, the full mechanism of action and the pathophysiology are not known. It has also been documented that the risk of LOAD is much higher in patients with the double variant of the APOEε4 gene than in those with the single variant; the risk of LOAD increases 10-fold with double-variant alleles for APOE ε4. A stronger correlation is found in Asian andEuropeanpatients. [9, 11]
The molecular mechanism that supports the role of APOE ε4 in pathogens is that of LOAD. [9, 11] Research showed differential coexpression correlation network analysis of the APOE ε4, and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these mediators—including APBA2, FYN, RNF219, and SV2A—encode known or novel modulators of LOAD-associated amyloid-beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset.  These data implicate an APOE ε4 – associated molecular pathway that promotes LOAD but with weak clinical correlation.
Although a blood test can identify which APOE alleles a person has, it cannot predict who will or will not develop Alzheimer's disease.  It is unlikely that genetic testing will ever be able to predict the disease with 100% accuracy, because too many other factors may influence its development and progression, such as environmental factors, ethnicity, and other comorbidities (eg, hypertension, diabetes, obesity, high cholesterol, and head trauma).  One of the biggest limitations of genetic testing is the psychological impact that positive results can have on patients who might have the disease in the future. However, the impact of delivering a positive result was studied by the REVEAL trial, which didn’t show any significant long-term psychological impact, depression, or anxiety in patients tested positive for the APOE ε4 gene. [3, 13, 14, 15]
At present, APOE ε4 testing is used in research settings to identify study participants who may have an increased risk of developing Alzheimer disease. This knowledge helps scientists look for early brain changes in participants and compare the effectiveness of treatments for people with different APOE ε4 profiles. [1, 2, 3, 8, 13] Most researchers believe that APOE ε4 testing is useful for studying the risk of Alzheimer disease in large groups of people but not for determining any one person's specific risk.
Pediatric testing for AD should not occur. Prenatal testing for AD is not advised if the patient intends to continue a pregnancy with a mutation.
Genetic testing for AD should only occur in the context of genetic counseling (in-person or through videoconference) and support by someone with expertise in this area.
Symptomatic patients: genetic counseling for symptomatic patients should be performed in the presence of the individual’s legal guardian or family member.
Asymptomatic patients: a protocol based on the International Huntington Association and World Federation of Neurology Research Group on Huntington’s Chorea Guidelines is recommended.
Direct to consumer (DTC) APOEε4 testing is not advised.
A 3-generation (or more) family history should be obtained, with specific attention paid to the age of onset of any neurologic and/or psychiatric symptoms, type of dementia, and method of diagnosis, along with current ages, ages at death (especially unaffected relatives), and causes of death. 
Patients should be informed that currently there are no proven pharmacologic or lifestyle choices that reduce the risk of developing AD or stop its progression.
A risk assessment should be performed by pedigree analysis to determine whether the family history is consistent with EOAD or LOAD and with autosomal dominant (with or without complete penetrance), familial, or sporadic inheritance.
Psychological analysis and referral should be given before and after genetic testing.
Discuss the risk that inheriting a mutation from a parent affected with autosomal dominant AD is 50%. In the absence of identifying a mutation in apparent autosomal dominant families, risk to offspring could be as high as 50% but may be less.
For families in which an autosomal dominant AD gene mutation is a possibility, testing is recommended in patients with symptomatic family members with EOAD or more than 2 family members/generations affected with EOAD or patients who are PSEN/APP gene positive.
For families in which autosomal dominant AD is unlikely, genetic testing for susceptibility loci (eg, APOE) is not clinically recommended because of limited clinical utility and poor predictive value. If a patient wishes to pursue testing despite genetic counseling and recommendations to the contrary, testing may be considered at the clinician’s discretion. Such individuals should get psychological referral and counseling before and after they get their genetic testing done. [3, 8, 14]
After the REVEAL study,  in European countries APOE ε4 gene testing is offered as a direct to consumer (DTC) test, with informed medical consent and informed disclosure/denial to test results. Patients are followed up to monitor various psychological reactions after disclosure of positive results and long-term effects and occurrence of LOAD in positive patients. In doctors' offices and other clinical settings, genetic testing is used for people with a family history of early-onset Alzheimer disease.  No clear guidelines have been elucidated regarding APOE ε4 testing in patients at risk of developing LOAD.
MRI and PET scans can demonstrate the changes of Alzheimer disease. Repeated scanning in patients with APOE ɛ4 has revealed a potential correlation between genetic variation and MRI findings of atrophic hippocampal volume in MRI markers, increased cerebral amyloid deposition, and cerebral hypometabolism. [3, 17] Such associations may indicate the potential role of the APOE gene in the pathophysiology of Alzheimer disease, but the studies have been performed on small cohorts and therefore may not be applicable to the general population.
Recent phase 3 trials of immunotherapy have shown that bapineuzumab, an antibody that targets the N terminus of Aβ, prevents Aβ deposition in the brains of APOE ε4 carriers with mild or moderate Alzheimer disease, but not noncarriers. Bapineuzumab also lowers levels of phosphorylated tau in the CSF of both APOE ε4 carriers and noncarriers. These reports suggest that Aβ immunotherapy is useful to eliminate Aβ from the brains of patients with Alzheimer disease and that its effect is likely to depend on Apo E isoforms. [3, 5, 6, 7, 12] Major adverse effects of bapineuzumab—namely, vasogenic cerebral edema and microhemorrhage—occur more frequently in APOE ε4 carriers than in noncarriers. Although bapineuzumab failed to prevent cognitive and functional decline in these clinical trials, a combination of Aβ immunotherapy and an Apo E targeted approach might lead to more effective therapeutic strategies.
Although the presence of APOE ε4 does not necessarily entail disease development, this genetic isoform probably accelerates the rate of disease conversion and progression. Thus, understanding the potential pathogenic link between APOE ε4 and cognitive function might enable earlier identification of people at increased risk of Alzheimer disease. In combination with other putative biomarkers—such as MRI scans, PiB-PET, and measurements of CSF Aβ and tau—APOE allele status could add predictive value to clinical diagnosis and evaluation of treatment efficacy. [3, 5, 6, 7, 12]