ClinVar Genomic variation as it relates to human health

Weisgraber et al. (1981), Das et al. (1985), and Paik et al. (1985) identified the apolipoprotein E4 (apoE4) isoform, in which there is a cys112-to-arg (C112R) substitution. This variant is found in 6 to 37% of individuals from different populations. Individuals carrying the apolipoprotein E4 allele display low levels of apolipoprotein E and high levels of plasma cholesterol, low density lipoprotein-cholesterol, apolipoprotein B, lipoprotein (a), and are at higher risk for coronary artery disease than other individuals. Saunders et al. (1993) reported an increased frequency of the E4 allele in a small prospective series of possible-probable AD patients presenting to the memory disorders clinic at Duke University, in comparison with spouse controls. Corder et al. (1993) found that the APOE*E4 allele is associated with the late-onset familial and sporadic forms of Alzheimer disease. In 42 families with the late-onset form of Alzheimer disease (AD2; 104310), the gene had been mapped to the same region of chromosome 19 as the APOE gene. Corder et al. (1993) found that the risk for AD increased from 20 to 90% and mean age of onset decreased from 84 to 68 years with increasing number of APOE*E4 alleles. Homozygosity for APOE*E4 was virtually sufficient to cause AD by age 80. Myers et al. (1996) examined the association of apolipoprotein E4 with Alzheimer disease and other dementias in 1,030 elderly individuals in the Framingham Study cohort. They found an increased risk for Alzheimer disease as well as other dementias in patients who were homozygous or heterozygous for E4. However they pointed out that most apoE4 carriers do not develop dementia and about one-half of Alzheimer disease is not associated with apoE4. Tang et al. (1996) compared relative risks by APOE genotypes in a collection of cases and controls from 3 ethnic groups in a New York community. The relative risk for Alzheimer disease associated with APOE4 homozygosity was increased in all ethnic groups: African American RR = 3.0; Caucasian RR = 7.3; and Hispanic RR = 2.5 (compared with the RR with APOE3 homozygosity). The risk was also increased for APOE4 heterozygous Caucasians and Hispanics, but not for African Americans. The age distribution of the proportion of Caucasian and Hispanics without AD was consistently lower for APOE4 homozygous and APOE4 heterozygous individuals than for those with other APOE genotypes. In African Americans this relationship was observed only in APOE4 homozygotes. Differences in risk among APOE4 heterozygous African Americans suggested to the authors that other genetic or environmental factors may modify the effect of APOE4 in some populations. In a longitudinal study of 55 patients with Alzheimer disease, Mori et al. (2002) determined that the rate of hippocampal atrophy was significantly greater in those with an APOE4 allele, and that the rate became more severe as the number of E4 alleles increased. However, their data did not support the findings of previous studies that the E4 allele is associated with an increased rate of cognitive decline. In a cohort of 180 asymptomatic individuals with a mean age of 60 years, Caselli et al. (2004) found that carriers of an E4 allele showed greater declines in memory performance over a median period of 33 months compared to those without an E4 allele. Among 494 individuals with mild cognitive impairment, Farlow et al. (2004) found an association between the E4 allele and worse scores on cognition tests as well as smaller total hippocampal volume. Among 6,202 Caucasian middle-aged individuals (47 to 68 years), Blair et al. (2005) found that carriers of the E4 allele had greater cognitive decline over a 6-year period compared to those without an E4 allele. Results for 1,693 African American patients were inconclusive. Enzinger et al. (2004) noted that decreases in brain size and volume in patients with multiple sclerosis (126200) are related to neuroaxonal injury and loss, and are a useful surrogate marker of tissue damage and disease progression. In a study of 99 patients with MS, the authors found that patients who carried an E4 allele had more relapses during the study period and had a 5-fold higher rate of annual brain volume loss compared to patients without the E4 allele. Over time, E4 carriers also had an increase in individual lesions on MRI, termed 'black holes.' Among all genotype groups, the lowest annual loss of brain volume occurred in patients with an E2 allele. Among 76 patients with relapsing-remitting MS, de Stefano et al. (2004) found that carriers of the E4 allele showed significantly lower total brain volumes compared to MS patients without the E4 alleles. There was no difference in lesion volume between the 2 groups. The authors suggested that the E4 allele is linked to impaired mechanisms of cell repair and severe tissue destruction in MS. Among 89 patients with head injury, Teasdale et al. (1997) found that patients with the E4 allele were more likely than those without the E4 allele to have an unfavorable outcome 6 months after head injury. The authors discussed the role of the apoE protein in response to acute brain injury. In a prospective study of 69 patients with severe blunt trauma to the head, Friedman et al. (1999) found an odds ratio of 5.69 for more than 7 days of unconsciousness and 13.93 for a suboptimal neurologic outcome at 6 months for individuals with an APOE4 allele compared to those without that allele. In 110 patients with traumatic brain injury (TBI), Crawford et al. (2002) tested memory and other cognitive variables and found that patients with the APOE4 allele had more difficulty with memory than matched patients without the E4 allele. In those with the E4 allele, performance was poor regardless of severity of injury, whereas in those without the E4 allele, performance worsened with more severe injury. Crawford et al. (2002) noted that TBI may result in greater damage to the medial temporal lobe structures involved in memory and suggested a role for the APOE protein in neuronal repair. In 87 patients with mild to moderate TBI, Liberman et al. (2002) used neuropsychologic testing to examine whether the APOE4 genotype affected short-term recovery. At 6 weeks, E4-positive patients had lower mean scores on 11 of 13 tests, but the differences from the E4-negative group were smaller than the differences observed at 3 weeks. Although Liberman et al. (2002) stated that the findings are consistent with delayed recovery among E4-positive TBI patients, perhaps due to interactions with beta-amyloid, they cautioned against the generalizability of the results. Among 60 patients with TBI with a mean follow-up of 31 years, Koponen et al. (2004) found that presence of the E4 allele increased the risk for dementia, but there was no association between the E4 allele and development of other psychiatric illnesses, including depression, anxiety, psychosis, or personality disorders. Montagne et al. (2020) showed that individuals bearing APOE4 were distinguished from those without APOE4 by breakdown of the blood-brain barrier in hippocampus and medial temporal lobe. This finding was apparent in cognitively unimpaired APOE4 carriers and was more severe in those with cognitive impairment, but it was not related to amyloid-beta or tau pathology measured in cerebrospinal fluid or by positron emission tomography. High baseline levels of soluble PDGFR-beta (PDGFRB; 173410), a blood-brain barrier pericyte injury biomarker, in cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in noncarriers, even after controlling for amyloid-beta and tau status, and correlated with increased activity of the blood-brain barrier-degrading cyclophilin A (PPIA; 123840)-matrix metalloproteinase-9 (MMP9; 120361) pathway in cerebrospinal fluid. Montagne et al. (2020) concluded that breakdown of the blood-brain barrier contributes to APOE4-associated cognitive decline independently of Alzheimer disease pathology and might be a therapeutic target in APOE4 carriers. (less)