Alzheimer's disease (AD) is a neurodegenerative disorder of the brain that is progressive, irreversible and typically characterized by development of abnormal memory loss, along with deterioration of other higher cognitive abilities, including language, judgement, and perception. Behavioral and psychiatric manifestations can also occur during the disease's course. AD is the most common form of dementia accounting for approximately 70% of all adult cases in industrialized countries.1 It is estimated that four million people in the U.S. are affected by AD and that by the middle of this century as many as 14 million could also be affected.2
Risk factors for AD include age, Down syndrome, family history, and ApoE genotype. In demented individuals, the most prevalent known genetic risk factor for AD is Apolipoprotein E (ApoE) genotype. ApoE is a susceptibility gene that contributes to the risk of developing AD after age 65 in demented individuals. Three isoforms of ApoE exist: E2, E3, and E4. A demented patient harboring two ApoE4 alleles has a 91% chance of developing AD by age 803, whereas a demented patient harboring one E4 allele has a 47% chance of developing the disease by age 80.3 ApoE genotyping is useful both as an adjunct to help confirm a suspected clinical diagnosis of AD, as well as a tool to help differentiate AD from atypical presentations of dementia.4
ApoE is an integral part of the physiological pathway of acetylcholine in the brain. The relationship of ApoE and acetylcholine helps to explain parts of the neuropathological progression of Alzheimer's disease. Depending on which variant of ApoE is inherited, the amount of acetylcholine may be normal or reduced and the likelihood of developing AD may be affected. According to Soininen et al., "AD patients carrying the epsilon 4 [E4] allele have a more severe cholinergic deficit than the AD patients without the epsilon 4 allele."5
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Among other investigators, Mayeux et al., have demonstrated how ApoE, when used as an adjunct to a clinical diagnosis, improves confidence in the diagnosis of AD.7 This study showed that the clinical diagnosis alone misdiagnosed 45% of patients, who did not have AD, as AD patients. However, when ApoE was used with the clinical diagnosis, only 16% of patients without AD were diagnosed as having AD.7 According to Clark et al., the Mini-Mental Status Exam (MMSE), a test that is routinely used to diagnose AD, is inaccurate: "Although it [the MMSE] is insensitive in patients with mild cognitive impairment and lacks diagnostic specificity, the test remains popular." 8 The addition of ApoE genotyping to a clinical diagnosis can reduce false positives and add confidence to a diagnosis of AD. 7
Knowing the ApoE genotype of a patient can also help to develop a prognosis. Although previous studies have not supported a relationship between cognitive decline and ApoE, Craft et al., correlated cognitive decline and ApoE using the Dementia Rating Scale (DRS). A patient's ApoE genotype can help guide a physician as to how fast a patient with AD may decline: ". . . ApoE-e4 homozygotes had the fastest rate of decline . . . e2/e3 genotypes had the slowest rate of decline."9 This data is shown in Figure 1, below.
Figure 1
Figure 1 Predicted annual rate of decline for each genotype group at Dementia Rating Scale (DRS) scores of 80, 105, and 130. Rate of decline is expressed in DRS points per year; thus, larger values reflect greater rate of decline. At DRS scores of 105, the covariate-adjusted mean slope for the e4/4 group is significantly greater than the slope for the e2/3 group (p<0.003), with a similar trend noted in comparisons with the e3/3 (p<0.076) and the e3/4 (p<0.055) groups. At DRS scores of 80, even larger differences are observed among genotypes; the e4/4 group again had an increased rate of decline relative to the e2/3 (p<0.0006), e3/4 (p<0.021), and e3/3 (p<0.174) groups. The e2/3 group had a significantly slower rate of decline than all other groups at DRS scores of 80 or 105.
Establishing ApoE genotype can help improve patient management. By adding confidence to the diagnosis and helping to establish an early diagnosis, knowing a patient's ApoE status may lead to earlier, and more effective, therapeutic intervention. ApoE genotype also can help identify which patients are likely to have a more aggressive course of the disease. Accordingly, these individuals may be monitored more closely, be seen more often, and assessed more intensely. As summarized in a recent article, "Information on the rate of change is valuable for assessing the results of therapeutic interventions, predicting the severity of cognitive decline, and planning for long-term healthcare." 8
