apolipoprotein e4


Summary: A major and the second most common isoform of apolipoprotein E. In humans, Apo E4 differs from APOLIPOPROTEIN E3 at only one residue 112 (cysteine is replaced by arginine), and exhibits a lower resistance to denaturation and greater propensity to form folded intermediates. Apo E4 is a risk factor for ALZHEIMER DISEASE and CARDIOVASCULAR DISEASES.

Top Publications

  1. Louhija J, Miettinen H, Kontula K, Tikkanen M, Miettinen T, Tilvis R. Aging and genetic variation of plasma apolipoproteins. Relative loss of the apolipoprotein E4 phenotype in centenarians. Arterioscler Thromb. 1994;14:1084-9 pubmed
    ..8%; P < .05). Centenarians with the apolipoprotein B X2X2 genotype and apolipoprotein E4 phenotype had a higher mean plasma cholesterol level than those with the X1X1 genotype and E2 phenotype (5...
  2. Mahley R, Huang Y. Alzheimer disease: multiple causes, multiple effects of apolipoprotein E4, and multiple therapeutic approaches. Ann Neurol. 2009;65:623-5 pubmed publisher
  3. Kuusisto J, Koivisto K, Mykkanen L, Helkala E, Vanhanen M, Hanninen T, et al. Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study. BMJ. 1997;315:1045-9 pubmed
    ..7%) subjects were classified as having probable or possible Alzheimer's disease. In univariate analyses, apolipoprotein E4 phenotype (odds ratio; 95% confidence interval 3.24: 1.77 to 5.92), age (1.16; 1.05 to 1...
  4. Dong J, Pinto J, Guo X, Alonso A, TRANAH G, Cauley J, et al. The Prevalence of Anosmia and Associated Factors Among U.S. Black and White Older Adults. J Gerontol A Biol Sci Med Sci. 2017;72:1080-1086 pubmed publisher
    ..Anosmia is common in older adults, particularly among blacks. Further studies are needed to identify risk factors for anosmia and to investigate racial disparities in this sensory deficit. ..
  5. Deshpande S, Hasegawa R, Rabinowitz A, Whyte J, Roan C, Tabatabaei A, et al. Association of Playing High School Football With Cognition and Mental Health Later in Life. JAMA Neurol. 2017;74:909-918 pubmed publisher
    ..Little is known about the long-term cognitive and mental health consequences of exposure to football-related head trauma at the high school level...
  6. Itoh Y, Yamada M, Sodeyama N, Suematsu N, Matsushita M, Otomo E, et al. Atherosclerosis is not implicated in association of APOE epsilon4 with AD. Neurology. 1999;53:236-7 pubmed
  7. Overmyer M, Helisalmi S, Soininen H, Laakso M, Riekkinen P, Alafuzoff I. Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue. Acta Neuropathol. 1999;97:383-92 pubmed
  8. Artiga M, Bullido M, Frank A, Sastre I, Recuero M, Garcia M, et al. Risk for Alzheimer's disease correlates with transcriptional activity of the APOE gene. Hum Mol Genet. 1998;7:1887-92 pubmed
  9. Strittmatter W, Weisgraber K, Huang D, Dong L, Salvesen G, Pericak Vance M, et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:8098-102 pubmed

More Information


  1. Schraml F, Chen K, Ayutyanont N, Auttawut R, Langbaum J, Lee W, et al. Association between an Alzheimer's Disease-Related Index and APOE ?4 Gene Dose. PLoS ONE. 2013;8:e67163 pubmed publisher
    ..001). The HCI is associated with three levels of genetic risk for late-onset AD. This supports the possibility of using a single FDG PET measurement to help in the preclinical detection and tracking of AD. ..
  2. Krishna M, Kumar G, Veena S, Krishnaveni G, Kumaran K, Karat S, et al. Birth size, risk factors across life and cognition in late life: protocol of prospective longitudinal follow-up of the MYNAH (MYsore studies of Natal effects on Ageing and Health) cohort. BMJ Open. 2017;7:e012552 pubmed publisher
    ..This study will specifically examine, if lower birth weight is associated with poorer cognitive functioning in late life in a south Indian population...
  3. Yang D, Smith J, Zhou Z, Gandy S, Martins R. Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma. J Neurochem. 1997;68:721-5 pubmed
    ..The different A beta-binding properties of native apoE4 versus native apoE3 provide insight into the molecular mechanisms by which the APOE epsilon 4 allele exerts its risk factor effects in AD. ..
  4. Halliday M, Rege S, Ma Q, Zhao Z, Miller C, Winkler E, et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab. 2016;36:216-27 pubmed
    ..The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 (APOE4) gene, which is a major genetic risk factor for late-onset AD...
  5. Ye Q, Su F, Shu H, Gong L, Xie C, Zhou H, et al. Shared effects of the clusterin gene on the default mode network among individuals at risk for Alzheimer's disease. CNS Neurosci Ther. 2017;23:395-404 pubmed publisher
    ..The CLU gene could consistently affect the DMN FC with frontal regions among individuals at risk for Alzheimer's disease, and the CLU-T allele was associated with more compensatory neural processes in DMN changes. ..
  6. Payami H, Zareparsi S, Montee K, Sexton G, Kaye J, Bird T, et al. Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. Am J Hum Genet. 1996;58:803-11 pubmed
    ..These observations are consistent with the increased incidence of familial AD in women and may be a critical clue to the role of gender in the pathogenesis of AD. ..
  7. Arpawong T, Pendleton N, Mekli K, McArdle J, Gatz M, Armoskus C, et al. Genetic variants specific to aging-related verbal memory: Insights from GWASs in a population-based cohort. PLoS ONE. 2017;12:e0182448 pubmed publisher
    ..Findings from this first U.S. population-based GWAS study conducted on both age-related immediate and delayed verbal memory merit continued examination in other samples and additional measures of verbal memory. ..
  8. Yu L, Lutz M, Wilson R, Burns D, Roses A, Saunders A, et al. APOE ?4-TOMM40 '523 haplotypes and the risk of Alzheimer's disease in older Caucasian and African Americans. PLoS ONE. 2017;12:e0180356 pubmed publisher
    ..Further, both genotypic and allelic data support that among African Americans the ?4-'523-L haplotype had stronger effect on risk of AD dementia than other ?4-'523 haplotypes. ..
  9. Abdullah L, Evans J, Emmerich T, Crynen G, Shackleton B, Keegan A, et al. APOE ?4 specific imbalance of arachidonic acid and docosahexaenoic acid in serum phospholipids identifies individuals with preclinical Mild Cognitive Impairment/Alzheimer's Disease. Aging (Albany NY). 2017;9:964-985 pubmed publisher
    ..Despite the small sample size and a short follow-up, these results suggest that blood PL could potentially serve as biomarkers of preclinical MCI/AD...
  10. Luo X, Qiu T, Xu X, Huang P, Gu Q, Shen Z, et al. Decreased Inter-Hemispheric Functional Connectivity in Cognitively Intact Elderly APOE ɛ4 Carriers: A Preliminary Study. J Alzheimers Dis. 2016;50:1137-48 pubmed publisher
    ..71, p <  0.05). In our study, the presence of the APOE ɛ4 allele was linked with decreased inter-hemispheric RSFC, which was attributed to memory performance in carriers. ..
  11. Hooper C, de Souto Barreto P, Payoux P, Salabert A, Guyonnet S, Andrieu S, et al. Cross-sectional associations of cortical ?-amyloid with erythrocyte membrane long-chain polyunsaturated fatty acids in older adults with subjective memory complaints. J Neurochem. 2017;142:589-596 pubmed publisher
    ..Investigating the relationships between A? and PUFAs longitudinally would provide further evidence as to whether fatty acids, particularly arachidonic acid and linoleic acid, might modulate cognition through A?-dependent mechanisms. ..
  12. Quevenco F, Preti M, Van Bergen J, Hua J, Wyss M, Li X, et al. Memory performance-related dynamic brain connectivity indicates pathological burden and genetic risk for Alzheimer's disease. Alzheimers Res Ther. 2017;9:24 pubmed publisher
    ..As the observed altered brain network properties are associated with increased local iron, our findings may reflect secondary neuronal changes due to pathologic processes including oxidative stress. ..
  13. Kaufer D, Gandy S. APOE {epsilon}4 and bapineuzumab: Infusing pharmacogenomics into Alzheimer disease therapeutics. Neurology. 2009;73:2052-3 pubmed publisher
  14. Malkki H. Alzheimer disease: Sleep alleviates AD-related neuropathological processes. Nat Rev Neurol. 2013;9:657 pubmed publisher
  15. van Exel E, Koopman J, Bodegom D, Meij J, Knijff P, Ziem J, et al. Effect of APOE ?4 allele on survival and fertility in an adverse environment. PLoS ONE. 2017;12:e0179497 pubmed publisher
    ..Its adverse associations in affluent modern populations with later onset diseases of aging further characterize APOE-?4 as an example of antagonistic pleiotropy. ..
  16. Greenberg S, Rebeck G, Vonsattel J, Gomez Isla T, Hyman B. Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol. 1995;38:254-9 pubmed
    ..14. The increase in CAA remained even after controlling for the presence of Alzheimer's disease, suggesting that apoE epsilon 4 is a risk factor for CAA and CAA-related hemorrhage, independent of its association with Alzheimer's disease. ..
  17. Kivipelto M, Solomon A. Preventive neurology: on the way from knowledge to action. Neurology. 2009;73:168-9 pubmed publisher
  18. Lim Y, Mormino E. APOE genotype and early ?-amyloid accumulation in older adults without dementia. Neurology. 2017;89:1028-1034 pubmed publisher
    ..i>APOE genotype in conjunction with chronologic age may aid in participant selection for primary prevention trials aimed at halting A? accumulation before abnormal levels are reached. ..
  19. Lafaille Magnan M, Poirier J, Etienne P, Tremblay Mercier J, Frenette J, Rosa Neto P, et al. Odor identification as a biomarker of preclinical AD in older adults at risk. Neurology. 2017;89:327-335 pubmed publisher
    ..Diminished OI may be a practical and affordable biomarker of AD pathology. ..
  20. Miyata M, Smith J. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat Genet. 1996;14:55-61 pubmed
    ..E2 > E3 > E4 possessed antioxidant activity, and apoE bound certain metal ions. The decreased antioxidant activity of E4 could contribute to its association with Alzheimer's disease, cardiovascular disease and decreased longevity. ..
  21. Nathan B, Bellosta S, Sanan D, Weisgraber K, Mahley R, Pitas R. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science. 1994;264:850-2 pubmed
    b>Apolipoprotein E4 (apoE4), one of the three common isoforms of apoE, has been implicated in Alzheimer's disease. The effects of apoE on neuronal growth were determined in cultures of dorsal root ganglion neurons...
  22. Ma J, Zhou Y, Xu J, Liu X, Wang Y, Deng Y, et al. Association study of TREM2 polymorphism rs75932628 with late-onset Alzheimer's disease in Chinese Han population. Neurol Res. 2014;36:894-6 pubmed publisher
    ..Our study suggested that TREM2 (rs75932628-T) was rare in Chinese Han population. Further association studies with large samples are needed to further study the association of TREM2 with late-onset Alzheimer's disease. ..
  23. Tan C, Hyman B, Tan J, Hess C, Dillon W, Schellenberg G, et al. Polygenic hazard scores in preclinical Alzheimer disease. Ann Neurol. 2017;82:484-488 pubmed publisher
    ..Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimer neurodegeneration. Ann Neurol 2017;82:484-488...
  24. Bachmeier C, Shackleton B, Ojo J, Paris D, Mullan M, Crawford F. Apolipoprotein E isoform-specific effects on lipoprotein receptor processing. Neuromolecular Med. 2014;16:686-96 pubmed
    ..Based on these results, apoE4 appears less efficient than other apoE isoforms in regulating lipoprotein receptor shedding, which may explain the differential effects of these isoforms in removing A? from the brain. ..
  25. Nguyen D, Dhanasekaran P, Nickel M, Mizuguchi C, Watanabe M, Saito H, et al. Influence of domain stability on the properties of human apolipoprotein E3 and E4 and mouse apolipoprotein E. Biochemistry. 2014;53:4025-33 pubmed
    ..Together, the results show that the overall stability of the entire apoE molecule exerts a major influence on its lipid- and lipoprotein-binding properties. ..
  26. Bellosta S, Nathan B, Orth M, Dong L, Mahley R, Pitas R. Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth. J Biol Chem. 1995;270:27063-71 pubmed
    ..However, the data suggest that apoE4, which has been shown to be associated with late onset familial and sporadic Alzheimer's disease, may inhibit neuronal remodeling and contribute to the progression of the disease. ..
  27. Greenberg S, Briggs M, Hyman B, Kokoris G, Takis C, Kanter D, et al. Apolipoprotein E epsilon 4 is associated with the presence and earlier onset of hemorrhage in cerebral amyloid angiopathy. Stroke. 1996;27:1333-7 pubmed
    ..033). These effects were independent of the accompanying presence of Alzheimer's disease. The data support a specific role for apolipoprotein E epsilon 4 in accelerating the process that leads to amyloid angiopathy-related hemorrhage. ..
  28. Ly H, Verma N, Wu F, Liu M, Saatman K, Nelson P, et al. Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia. Ann Neurol. 2017;82:208-222 pubmed publisher
    ..Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins...
  29. Liu D, Pan X, Zhang J, Shen H, Collins N, Cole A, et al. APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice. Mol Neurodegener. 2015;10:7 pubmed publisher
    ..Thus, caution remains critical in determining whether APOE gene inactivation or therapies that correct the loss of positive function related to apoE4, are the appropriate therapeutic response. ..
  30. Nussbaum R. Genome-wide association studies, Alzheimer disease, and understudied populations. JAMA. 2013;309:1527-8 pubmed publisher
  31. Jun G, Chung J, Mez J, Barber R, Beecham G, Bennett D, et al. Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement. 2017;13:727-738 pubmed publisher
    ..7 × 10-6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10-6). Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci. ..
  32. Lineweaver T, Bondi M, Galasko D, Salmon D. Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults. Am J Psychiatry. 2014;171:201-8 pubmed publisher
    ..The patient's knowledge of his or her genotype and risk of Alzheimer's disease should be considered when evaluating cognition in the elderly. ..
  33. Blennow K, Bogdanovic N, Alafuzoff I, Ekman R, Davidsson P. Synaptic pathology in Alzheimer's disease: relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele. J Neural Transm (Vienna). 1996;103:603-18 pubmed
    ..One of the main risk-factors for the disorder is inheritance of the apolipoprotein E4 (ApoE4) allele...
  34. Westwood S, Liu B, Baird A, Anand S, Nevado Holgado A, Newby D, et al. The influence of insulin resistance on cerebrospinal fluid and plasma biomarkers of Alzheimer's pathology. Alzheimers Res Ther. 2017;9:31 pubmed publisher
    ..These data indicate that IR is not directly related to the level of CSF AD pathology in cognitively healthy men. Proteins that associated with both AD and IR are potential markers indicative of shared pathology. ..
  35. Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M, Tsenter J, et al. Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology. 1999;52:244-8 pubmed
    ..Additional studies of TBI patients are warranted to confirm their findings. ..
  36. Seshadri S, Drachman D, Lippa C. Apolipoprotein E epsilon 4 allele and the lifetime risk of Alzheimer's disease. What physicians know, and what they should know. Arch Neurol. 1995;52:1074-9 pubmed
    ..Most physicians managing patients with AD do not know the lifetime risk of AD, and very few know how APOE* epsilon 4 status modifies the risk. These clinically relevant risk figures should be more widely disseminated among physicians. ..
  37. Nedelska Z, Przybelski S, Lesnick T, Schwarz C, Lowe V, Machulda M, et al. 1H-MRS metabolites and rate of ?-amyloid accumulation on serial PET in clinically normal adults. Neurology. 2017;89:1391-1399 pubmed publisher
  38. Ryu H, Kwon O. Apolipoprotein E epsilon 4 allele is not associated with age at onset or MMSE of Parkinson's disease in a Korean study. Parkinsonism Relat Disord. 2010;16:615-7 pubmed publisher
  39. Andreasson U, Lautner R, Schott J, Mattsson N, Hansson O, Herukka S, et al. CSF biomarkers for Alzheimer's pathology and the effect size of APOE ?4. Mol Psychiatry. 2014;19:148-9 pubmed publisher
  40. Yamauchi K, Ebihara Y, Kawakami Y. Redox status of serum apolipoprotein E and its impact on HDL cholesterol levels. Clin Biochem. 2017;50:777-783 pubmed publisher
    ..001). The redox status of serum apoE might be related to the synthesis of HDL. The information concerning the redox status of serum apoE provided by the present method may be a potent indicator to evaluate various apoE-related diseases. ..
  41. Karimi M, Vedin I, Freund Levi Y, Basun H, Faxén Irving G, Eriksdotter M, et al. DHA-rich n-3 fatty acid supplementation decreases DNA methylation in blood leukocytes: the OmegAD study. Am J Clin Nutr. 2017;106:1157-1165 pubmed publisher
    ..Our data may be of importance in measuring various effects of marine oils, including gene expression, in patients with AD and in other patients taking n-3 FA supplements. This trial was registered at clinicaltrials.gov as NCT00211159. ..
  42. Kim H, Yoo J, Shin J, Chang Y, Jung J, Jo D, et al. Modelling APOE ?3/4 allele-associated sporadic Alzheimer's disease in an induced neuron. Brain. 2017;140:2193-2209 pubmed publisher
  43. Narayan P, Dragunow M. Alzheimer's Disease and Histone Code Alterations. Adv Exp Med Biol. 2017;978:321-336 pubmed publisher
    ..Monozygotic twin studies have revealed a discordance for AD, implicating that a combination of epigenetic and genetic factors are likely involved in the development of AD [5]. ..
  44. Zhao N, Liu C, Van Ingelgom A, Martens Y, Linares C, Knight J, et al. Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes. Neuron. 2017;96:115-129.e5 pubmed publisher
    ..Together, our study provides novel mechanistic insights into the pathogenic mechanisms of apoE4 and insulin resistance in AD. ..
  45. Naruse H, Goto J, Tsuji S. [Familial Alzheimer disease]. Nihon Rinsho. 2011;69 Suppl 10 Pt 2:246-51 pubmed
  46. Yaffe K, Haan M, Byers A, Tangen C, Kuller L. Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction. Neurology. 2000;54:1949-54 pubmed
    ..Potential mechanisms, including carotid atherosclerosis, by which epsilon4 may interact with estrogen and cognition warrant further investigation. ..
  47. van de Pol L, Scheltens P. Medial temporal lobe atrophy scores translated to clinical practice: editorial comment on 'influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut-offs'. J Intern Med. 2014;275:331-3 pubmed publisher
  48. Feng J, Xiang L, Wan G, Qi K, Sun L, Huang Z, et al. Is APOE ?3 a favourable factor for the longevity: an association study in Chinese population. J Genet. 2011;90:343-7 pubmed
  49. Vagelatos N, Eslick G. Type 2 diabetes as a risk factor for Alzheimer's disease: the confounders, interactions, and neuropathology associated with this relationship. Epidemiol Rev. 2013;35:152-60 pubmed publisher
    ..Therefore, the increased risk of clinically diagnosed AD seems to be mediated through cerebrovascular pathology. ..
  50. Bullido M, Artiga M, Recuero M, Sastre I, Garcia M, Aldudo J, et al. A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia. Nat Genet. 1998;18:69-71 pubmed
    ..In vitro studies suggest that the -491A/T polymorphism may increase risk for AD by altering the level of ApoE protein expression. ..
  51. Yahya R, Awad S, El Baz H, Saudy N, Abdelsalam O, Al Din M. Impact of ApoE genotypes variations on Toxoplasma patients with dementia. J Clin Neurosci. 2017;39:184-188 pubmed publisher
    ..001) between dementia and non-dementia patients in Toxoplasma infected patients in comparison to non-infected ones. Toxoplasma positive patients have more risk to develop dementia regardless ApoE4 carriage. ..
  52. Postupna N, Latimer C, Larson E, Sherfield E, Paladin J, Shively C, et al. Human Striatal Dopaminergic and Regional Serotonergic Synaptic Degeneration with Lewy Body Disease and Inheritance of APOE ε4. Am J Pathol. 2017;187:884-895 pubmed publisher
  53. Cardoso B, Hare D, Bush A, Li Q, Fowler C, Masters C, et al. Selenium Levels in Serum, Red Blood Cells, and Cerebrospinal Fluid of Alzheimer's Disease Patients: A Report from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL). J Alzheimers Dis. 2017;57:183-193 pubmed publisher
    ..The lack of change in the Se level is at odds with our previous observations in a Brazilian population deficient in Se, and we attribute this to the Australian cohort being Se-replete. ..
  54. Pankiewicz J, Guridi M, Kim J, Asuni A, Sanchez S, Sullivan P, et al. Blocking the apoE/A? interaction ameliorates A?-related pathology in APOE ?2 and ?4 targeted replacement Alzheimer model mice. Acta Neuropathol Commun. 2014;2:75 pubmed publisher
    ..These results indicate that both apoE2 and apoE4 isoforms contribute to A? deposition and future therapies targeting the apoE/A? interaction could produce favorable outcome in APOE ?2 and ?4 allele carriers. ..
  55. Yassine H, Croteau E, Rawat V, Hibbeln J, Rapoport S, Cunnane S, et al. DHA brain uptake and APOE4 status: a PET study with [1-11C]-DHA. Alzheimers Res Ther. 2017;9:23 pubmed publisher
    ..Our findings suggest an increase in the DHA incorporation coefficient in several brain regions in APOE4 carriers. These findings may contribute to understanding how APOE4 genotypes affect AD risk. ..
  56. Eisenstein M. Centenarians: Great expectations. Nature. 2012;492:S6-8 pubmed publisher
  57. Tautvydaitė D, Kukreja D, Antonietti J, Henry H, von Gunten A, Popp J. Interaction between personality traits and cerebrospinal fluid biomarkers of Alzheimer's disease pathology modulates cognitive performance. Alzheimers Res Ther. 2017;9:6 pubmed publisher
    ..Considering personality characteristics may help to appraise a person's cognitive reserve and the risk of cognitive decline in later life. ..
  58. Mizuguchi C, Hata M, Dhanasekaran P, Nickel M, Okuhira K, Phillips M, et al. Fluorescence study of domain structure and lipid interaction of human apolipoproteins E3 and E4. Biochim Biophys Acta. 2014;1841:1716-24 pubmed
  59. Arendt T, Schindler C, Brückner M, Eschrich K, Bigl V, Zedlick D, et al. Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein epsilon 4 allele. J Neurosci. 1997;17:516-29 pubmed
    ..This impairment of neuronal repair might lead to a more rapid functional decompensation, thereby contributing to an earlier onset and more rapid progression of the disease. ..
  60. Premkumar D, Cohen D, Hedera P, Friedland R, Kalaria R. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease. Am J Pathol. 1996;148:2083-95 pubmed
    ..Our results suggest that the APOE-epsilon4 allele is a significant factor in the development of CAA in AD and reveal the possibility that APOE is an independent factor in CAA and other vascular abnormalities associated with AD. ..
  61. Waring J, Tang Q, Robieson W, King D, Das U, Dubow J, et al. APOE-ɛ4 Carrier Status and Donepezil Response in Patients with Alzheimer's Disease. J Alzheimers Dis. 2015;47:137-48 pubmed publisher
  62. Tiraboschi P, Hansen L, Alford M, Sabbagh M, Schoos B, Masliah E, et al. Cholinergic dysfunction in diseases with Lewy bodies. Neurology. 2000;54:407-11 pubmed
    ..The lack of a relationship between epsilon4 allele dosage and midfrontal ChAT activity suggests that other factors may play a role in its decline in LBV. ..
  63. Messier C, Gagnon M. Cognitive decline associated with dementia and type 2 diabetes: the interplay of risk factors. Diabetologia. 2009;52:2471-4 pubmed publisher
  64. Evans S, Dowell N, Tabet N, King S, Hutton S, Rusted J. Disrupted neural activity patterns to novelty and effort in young adult APOE-e4 carriers performing a subsequent memory task. Brain Behav. 2017;7:e00612 pubmed publisher
    ..This provides further evidence of abnormal hippocampal recruitment in young adult e4 carriers, manifesting as both up and downregulation of neural activity, in the absence of behavioral performance differences. ..
  65. Williams J, Plassman B, Burke J, Benjamin S. Preventing Alzheimer's disease and cognitive decline. Evid Rep Technol Assess (Full Rep). 2010;:1-727 pubmed
    ..Further research that addresses the limitations of existing studies is needed prior to be able to make recommendations on interventions. ..
  66. Laskowitz D, Kolls B. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2010;74:2026; author reply 2026-7 pubmed publisher
  67. Vidal R, Calero M, Piccardo P, Farlow M, Unverzagt F, Mendez E, et al. Senile dementia associated with amyloid beta protein angiopathy and tau perivascular pathology but not neuritic plaques in patients homozygous for the APOE-epsilon4 allele. Acta Neuropathol. 2000;100:1-12 pubmed
    ..These cases emphasize the concept that tau deposits may be pathogenetically related to amyloid beta protein deposition. ..
  68. Itzhaki R. Herpes simplex virus type 1 and Alzheimer's disease: possible mechanisms and signposts. FASEB J. 2017;31:3216-3226 pubmed publisher
    ..Itzhaki, R. F. Herpes simplex virus type 1 and Alzheimer's disease: possible mechanisms and signposts. ..
  69. Vannini P, Hanseeuw B, Munro C, Amariglio R, Marshall G, Rentz D, et al. Hippocampal hypometabolism in older adults with memory complaints and increased amyloid burden. Neurology. 2017;88:1759-1767 pubmed publisher
    ..Decreased hippocampal metabolism may be a specific marker of subclinical changes in cognition due to amyloid pathology. However, longitudinal studies are needed to determine whether our findings foreshadow clinical decline. ..
  70. Higuchi M, Tashiro M, Arai H, Okamura N, Hara S, Higuchi S, et al. Glucose hypometabolism and neuropathological correlates in brains of dementia with Lewy bodies. Exp Neurol. 2000;162:247-56 pubmed
    ..In contrast, apolipoprotein E4 allele frequency and cerebrospinal fluid tau levels did not differ significantly between the two groups...
  71. SCHWARTZ A. What's next for Alzheimer treatment?: while A? isn't out of the picture yet, several other therapeutic routes are being explored. Ann Neurol. 2013;73:A7-9 pubmed publisher
  72. Steel A, Eslick G. Herpes Viruses Increase the Risk of Alzheimer's Disease: A Meta-Analysis. J Alzheimers Dis. 2015;47:351-64 pubmed publisher
    ..38; 95% CI 1.14-1.66]. Sub-analysis showed that APOE ?4 and HSV1 together increased the risk of AD development [OR 2.71; 95% CI 1.08-6.80]. HSV1 together with the presence of the APOE ?4 allele increases the risk of developing AD. ..
  73. Seeley W. Divergent network connectivity changes in healthy APOE ?4 carriers: disinhibition or compensation?. Arch Neurol. 2011;68:1107-8 pubmed publisher
  74. Daniele A, Matera M, Seripa D, Acciarri A, Bizzarro A, Pilotto A, et al. APOE epsilon 2/epsilon 4 genotype a risk factor for primary progressive aphasia in women. Arch Neurol. 2009;66:910-2 pubmed publisher
  75. Morishima Kawashima M, Oshima N, Ogata H, Yamaguchi H, Yoshimura M, Sugihara S, et al. Effect of apolipoprotein E allele epsilon4 on the initial phase of amyloid beta-protein accumulation in the human brain. Am J Pathol. 2000;157:2093-9 pubmed
    ..These findings strongly suggest that the presence of epsilon4 allele results in an earlier onset of Ass42 accumulation in the brain. ..
  76. Fujioka H, Phelix C, Friedland R, Zhu X, Perry E, Castellani R, et al. Apolipoprotein E4 prevents growth of malaria at the intraerythrocyte stage: implications for differences in racial susceptibility to Alzheimer's disease. J Health Care Poor Underserved. 2013;24:70-8 pubmed publisher
    ..These selective advantages may be relevant in the exploration of possible disparities between Black and Whites in the incidence of Alzheimer's Disease. ..
  77. Mayeux R, Ottman R, Maestre G, Ngai C, Tang M, Ginsberg H, et al. Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer's disease. Neurology. 1995;45:555-7 pubmed
    ..These data imply that the biological effects of head injury may increase the risk of AD, but only through a synergistic relationship with apolipoprotein-epsilon 4. ..