Alternative titles; symbols
SNOMEDCT: 230267005; ORPHA: 1020; DO: 0110035;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.32 | Alzheimer disease 2 | 104310 | Autosomal dominant | 3 | APOE | 107741 |
A number sign (#) is used with this entry because of the association between late-onset Alzheimer disease-2 (AD2) and the apolipoprotein E (107741) E4 allele.
For a general phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease, see 104300.
Using positron emission tomography (PET), Reiman et al. (1996) found that 11 cognitively normal subjects aged 50 to 65 years who were homozygous for the APOE4 allele had reduced glucose metabolism in the same regions of the brain as patients with probable Alzheimer disease. The affected areas included temporal, parietal, posterior cingulate, and prefrontal regions. These findings provided preclinical evidence that the presence of the APOE4 allele is a risk factor for Alzheimer disease. Reiman et al. (1996) suggested that PET may offer a relatively rapid way of testing treatments to prevent Alzheimer disease in the future.
Reiman et al. (2001) found that 10 cognitively normal apoE4 heterozygotes aged 50 to 63 years also had abnormally low measurements of the cerebral metabolic rate for glucose in the same regions as AD patients. Over a period of 2 years, the E4 heterozygotes had declines in several regions, including temporal, posterior cingulate, prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus. These declines were significantly greater than those of 15 non-E4 carriers.
Using PET scans, Reiman et al. (2004) found that 12 young adult volunteers, ranging in age from 20 to 39 years, who were heterozygous for the apoE4 allele had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Reiman et al. (2004) concluded that carriers of the E4 allele have brain abnormalities in young adulthood, several decades before the possible onset of dementia.
Rippon et al. (2006) examined potential modifying risk factors for familial AD in a Latino population comprising 778 AD patients from 350 families. The population was primarily from the Dominican Republic and Puerto Rico and had been previously studied by Romas et al. (2002). The APOE E4 allele was associated with a nearly 2-fold increased risk of AD, a history of stroke (601367) was associated with a 4-fold increase, and a statistical interaction between APOE E4 and stroke was observed. Women with the E4 allele who were on estrogen replacement therapy did not have an increased risk of AD, but in women with a history of stroke, estrogen therapy was a deleterious effect modifier. Among risk factors, diabetes mellitus, myocardial infarction, head injury, hypertension, and smoking were not associated with AD.
Among 100 patients with AD, van der Flier et al. (2006) found an association between presence of the E4 allele and the typical amnestic phenotype, characterized by initial presentation of forgetfulness and difficulties with memory. Those with the memory phenotype were 3 times more likely to carry an E4 allele compared to AD patients who displayed a nonmemory phenotype, with initial complaints including problems with calculation, agnosia, and apraxia. The memory phenotype was almost exclusively observed in homozygous E4 carriers.
Borroni et al. (2007) also reported an association between the memory phenotype of AD and presence of the E4 allele. Among 319 late-onset AD patients, 77.6% of E4 allele carriers presented with the memory phenotype compared to 64.6% of noncarriers.
Wolk et al. (2010) compared the phenotypes of 67 AD patients carrying at least 1 APOE E4 allele to 24 AD patients without an E4 allele. Both groups of patients had a cerebrospinal fluid profile consistent with AD. E4 carriers had significantly greater impairment on measures of memory retention, whereas noncarriers were more impaired on tests of working memory, executive control, and lexical access. E4 carriers also had greater atrophy of the medial temporal lobe and smaller hippocampal volumes on neuroimaging, whereas noncarriers had greater frontoparietal atrophy. The findings suggested that APOE genotype may influence selective regional brain pathology, which in turns reflects phenotypic variation in the specific cognitive symptoms of AD.
Kunz et al. (2015) found that young adults at genetic risk for AD (APOE-E4 carriers) exhibit reduced grid cell-like representations and altered navigational behavior in a virtual arena. Both changes were associated with impaired spatial memory performance. Reduced grid cell-like representations were also related to increased hippocampal activity, potentially reflecting compensatory mechanisms that prevent overt spatial memory impairment in APOE-E4 carriers. Kunz et al. (2015) concluded that their results provided evidence of behaviorally relevant entorhinal dysfunction in humans at genetic risk for AD, decades before potential disease onset.
Pericak-Vance et al. (1988) excluded linkage to the AD1 locus on chromosome 21 (104300) in 13 families with FAD. Pericak-Vance et al. (1989, 1990) presented evidence for linkage to 2 markers on chromosome 19. When analysis was limited to the affecteds only, a lod score of 2.5 at theta = 0 was obtained for linkage with BCL3 (109560). Pericak-Vance et al. (1991) found evidence of linkage to chromosome 19 in their late-onset FAD families, and to chromosome 21 in their early-onset FAD families. When only affected persons were used in the analysis, a high lod score was obtained also with ATP1A3 (182350), which maps to 19q12-q13.2.
In a study of 48 kindreds with multiple cases of Alzheimer disease in 2 or more generations and with family age-at-onset means ranging from 41 to 83 years, Schellenberg et al. (1991) found negative lod scores for those families with onset after age 60, those families with onset before age 60, and for Volga German families with mean age of onset of 56. The early-onset non-Volga German families with onset before age 60 had low positive lod scores. Schellenberg et al. (1991) concluded that the AD gene on chromosome 21 is not responsible for late-onset FAD nor for the early-onset FAD represented by the Volga German kindreds.
Of 23 families with FAD, Schellenberg et al. (1992) excluded linkage to 19q in early-onset families, but small positive lod scores were obtained for late-onset families. Specific linkage to the APOC2 locus (608083) was excluded in all families.
Sillen et al. (2006) conducted a genomewide linkage study on 188 individuals with AD from 71 Swedish families, using 365 markers (average intermarker distance 8.97 cM). They performed nonparametric linkage analyses in the total family material as well as stratified the families with respect to the presence or absence of APOE4. The results suggested that the disorder in these families was tightly linked to the APOE region (19q13). The next highest lod score was to chromosome 5q35, and no linkage was found to chromosomes 9, 10, and 12.
Harold et al. (2009) undertook a 2-stage genomewide association study of Alzheimer disease involving 16,000 individuals, which they stated was the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), they replicated the established association with the APOE locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)).
Corder et al. (1993) found that the risk for late-onset AD increased from 20 to 90% and mean age of onset decreased from 84 to 68 years with increasing number of APOE*E4 alleles (107741.0016) in 42 families with late-onset AD. Onset was early in 4 other families tested; 2 had chromosome 21 APP (104760) mutations and 2 showed linkage to chromosome 14, thus representing AD1 (104300) and AD3 (607822), respectively. The frequency of APOE*E4 was not elevated in these families or in 12 other early-onset families. Homozygosity for APOE*E4 was virtually sufficient alone to cause AD by age 80.
Bray et al. (2004) applied highly quantitative measures of allele discrimination to cortical RNA from individuals heterozygous for the APOE E2, E3, and E4 alleles. A small, but significant, increase in the expression of E4 allele was observed relative to that of the E3 and E2 alleles (P less than 0.0001). Similar differences were observed in brain tissue from confirmed late-onset Alzheimer disease subjects, and between cortical regions BA10 (frontopolar) and BA20 (inferior temporal). Stratification of E4/E3 allelic expression ratios according to heterozygosity for the -219G-T promoter polymorphism (107741.0030) revealed significantly lower relative expression of haplotypes containing the -219T allele (P = 0.02). Bray et al. (2004) concluded that, in human brain, most of the cis-acting variance in APOE expression may be accounted for by the E4 haplotype, but there are additional small cis-acting influences associated with the promoter genotype.
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.
Romas et al. (2002) found that both early-onset and late-onset familial AD occurs in Caribbean Hispanics. In contrast to sporadic AD, late-onset familial AD among Caribbean Hispanics was strongly associated with APOE4.
Borroni, B., Di Luca, M., Padovani, A. The effect of APOE genotype on clinical phenotype in Alzheimer disease. Neurology 68: 624 only, 2007. [PubMed: 17310043] [Full Text: https://doi.org/10.1212/01.wnl.0000258354.96336.97]
Bray, N. J., Jehu, L., Moskvina, V., Buxbaum, J. D., Dracheva, S., Haroutunian, V., Williams, J., Buckland, P. R., Owen, M. J., O'Donovan, M. C. Allelic expression of APOE in human brain: effects of epsilon status and promoter haplotypes. Hum. Molec. Genet. 13: 2885-2892, 2004. [PubMed: 15385439] [Full Text: https://doi.org/10.1093/hmg/ddh299]
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., Pericak-Vance, M. A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261: 921-923, 1993. [PubMed: 8346443] [Full Text: https://doi.org/10.1126/science.8346443]
Edwards, J. H. Exclusion mapping. J. Med. Genet. 24: 539-543, 1987. [PubMed: 3669048] [Full Text: https://doi.org/10.1136/jmg.24.9.539]
Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., Jones, N., Thomas, C., and 74 others. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genet. 41: 1088-1093, 2009. Note: Erratum: Nature Genet. 41: 1156 only, 2009. Erratum: Nature Genet. 45: 712 only, 2013. [PubMed: 19734902] [Full Text: https://doi.org/10.1038/ng.440]
Kunz, L., Schroder, T. N., Lee, H., Montag, C., Lachmann, B., Sariyska, R., Reuter, M., Stirnberg, R., Stocker, T., Messing-Floeter, P. C., Fell, J., Doeller, C. F., Axmacher, N. Reduced grid-cell-like representations in adults at genetic risk for Alzheimer's disease. Science 350: 430-433, 2015. [PubMed: 26494756] [Full Text: https://doi.org/10.1126/science.aac8128]
Montagne, A., Nation, D. A., Sagare, A. P., Barisano, G., Sweeney, M. D., Chakhoyan, A., Pachicano, M., Joe, E., Nelson, A. R., D'Orazio, L. M., Buennagel, D. P., Harrington, M. G., and 15 others. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature 581: 71-76, 2020. [PubMed: 32376954] [Full Text: https://doi.org/10.1038/s41586-020-2247-3]
Pericak-Vance, M. A., Bebout, J. L., Gaskell, P. C., Jr., Yamaoka, L. H., Hung, W.-Y., Alberts, M. J., Walker, A. P., Bartlett, R. J., Haynes, C. A., Welsh, K. A., Earl, N. L., Heyman, A., Clark, C. M., Roses, A. D. Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am. J. Hum. Genet. 48: 1034-1050, 1991. [PubMed: 2035524]
Pericak-Vance, M. A., Bebout, J. L., Haynes, C. A., Gaskell, P. C., Jr., Yamaoka, L. A., Hung, W.-Y., Alberts, M. J., Walker, A. P., Bartlett, R. J., Welsh, K. A., Earl, N. L., Heyman, A., Clark, C. M., Roses, A. D. Linkage studies in familial Alzheimer's disease: evidence for chromosome 19 linkage. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A194 only, 1990.
Pericak-Vance, M. A., Yamaoka, L. H., Bebout, J., Gaskell, P. C., Clark, C., Haynes, C. S., Earl, N., Welch, K., Hung, W.-Y., Alberts, M. J., Heyman, A., Roses, A. D. Linkage studies in familial Alzheimer's disease. (Abstract) Cytogenet. Cell Genet. 51: 1058-1059, 1989.
Pericak-Vance, M. A., Yamaoka, L. H., Haynes, C. S., Speer, M. C., Haines, J. L., Gaskell, P. C., Hung, W.-Y., Clark, C. M., Heyman, A. L., Trofatter, J. A., Eisenmenger, J. P., Gilbert, J. R., Lee, J. E., Alberts, M. J., Dawson, D. V., Bartlett, R. J., Earl, N. L., Siddique, T., Vance, J. M., Conneally, P. M., Roses, A. D. Genetic linkage studies in Alzheimer's disease families. Exp. Neurol. 102: 271-279, 1988. [PubMed: 3197787] [Full Text: https://doi.org/10.1016/0014-4886(88)90220-8]
Reiman, E. M., Caselli, R. J., Chen, K., Alexander, G. E., Bandy, D., Frost, J. Declining brain activity in cognitively normal apolipoprotein E epsilon-4 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proc. Nat. Acad. Sci. 98: 3334-3339, 2001. [PubMed: 11248079] [Full Text: https://doi.org/10.1073/pnas.061509598]
Reiman, E. M., Caselli, R. J., Yun, L. S., Chen, K., Bandy, D., Minoshima, S., Thibodeau, S. N., Osborne, D. Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon-4 allele for apolipoprotein E. New Eng. J. Med. 334: 752-758, 1996. [PubMed: 8592548] [Full Text: https://doi.org/10.1056/NEJM199603213341202]
Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M., Hardy, J. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc. Nat. Acad. Sci. 101: 284-289, 2004. [PubMed: 14688411] [Full Text: https://doi.org/10.1073/pnas.2635903100]
Rippon, G. A., Tang, M.-X., Lee, J. H., Lantigua, R., Medrano, M., Mayeux, R. Familial Alzheimer disease in Latinos: interaction between APOE, stroke, and estrogen replacement. Neurology 66: 35-40, 2006. [PubMed: 16401842] [Full Text: https://doi.org/10.1212/01.wnl.0000191300.38571.3e]
Romas, S. N., Santana, V., Williamson, J., Ciappa, A., Lee, J. H., Rondon, H. Z., Estevez, P., Lantigua, R., Medrano, M., Torres, M., Stern, Y., Tycko, B., Mayeux, R. Familial Alzheimer disease among Caribbean Hispanics: a reexamination of its association with APOE. Arch. Neurol. 59: 87-91, 2002. [PubMed: 11790235] [Full Text: https://doi.org/10.1001/archneur.59.1.87]
Schellenberg, G. D., Boehnke, M., Wijsman, E. M., Moore, D. K., Martin, G. M., Bird, T. D. Genetic association and linkage analysis of the apolipoprotein CII locus and familial Alzheimer's disease. Ann. Neurol. 31: 223-227, 1992. [PubMed: 1349467] [Full Text: https://doi.org/10.1002/ana.410310214]
Schellenberg, G. D., Pericak-Vance, M. A., Wijsman, E. M., Moore, D. K., Gaskell, P. C., Jr., Yamaoka, L. A., Bebout, J. L., Anderson, L., Welsh, K. A., Clark, C. M., Martin, G. M., Roses, A. D., Bird, T. D. Linkage analysis of familial Alzheimer disease, using chromosome 21 markers. Am. J. Hum. Genet. 48: 563-583, 1991. [PubMed: 1998342]
Sillen, A., Forsell, C., Lilius, L., Axelman, K., Bjork, B. F., Onkamo, P., Kere, J., Winblad, B., Graff, C. Genome scan on Swedish Alzheimer's disease families. Molec. Psychiat. 11: 182-186, 2006. [PubMed: 16288313] [Full Text: https://doi.org/10.1038/sj.mp.4001772]
van der Flier, W. M., Schoonenboom, S. N. M., Pijnenburg, Y. A. L., Fox, N. C., Scheltens, P. The effect of APOE genotype on clinical phenotype in Alzheimer disease. Neurology 67: 526-527, 2006. [PubMed: 16894123] [Full Text: https://doi.org/10.1212/01.wnl.0000228222.17111.2a]
Weeks, D. E., Lange, K. The affected-pedigree-member method of linkage analysis. Am. J. Hum. Genet. 42: 315-326, 1988. [PubMed: 3422543]
Wolk, D. A., Dickerson, B. C., Alzheimer's Disease Neuroimaging Initiative. Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer's disease. Proc. Nat. Acad. Sci. 107: 10256-10261, 2010. [PubMed: 20479234] [Full Text: https://doi.org/10.1073/pnas.1001412107]