Is ApoE ɛ 4 a good biomarker for amyloid pathology in late onset Alzheimer’s disease?
- Maowen Ba†1, 2,
- Min Kong†3,
- Xiaofeng Li2, 4,
- Kok Pin Ng2, 5,
- Pedro Rosa-Neto2 and
- Serge Gauthier2Email author
© The Author(s). 2016
Received: 28 October 2016
Accepted: 11 November 2016
Published: 16 November 2016
Amyloid plaques are pathological hallmarks of Alzheimer’s Disease (AD) and biomarkers such as cerebrospinal fluid (CSF) β-amyloid 1–42 (Aβ1-42) and amyloid positron emission tomographic (PET) imaging are important in diagnosing amyloid pathology in vivo. ɛ4 allele of the Apolipoprotein E gene (ApoE ɛ 4), which is a major genetic risk factor for late onset AD, is an important genetic biomarker for AD pathophysiology. It has been shown that ApoE ɛ 4 is involved in Aβ deposition and formation of amyloid plaques. Studies have suggested the utility of peripheral blood ApoE ɛ 4 in AD diagnosis and risk assessment. However it is still a matter of debate whether ApoE ɛ 4 status would improve prediction of amyloid pathology and represent a cost-effective alternative to amyloid PET or CSF Aβ in resource-limited settings in late onset AD. Recent research suggest that the mean prevalence of PET amyloid-positivity is 95% in ApoE ɛ 4-positive AD patients. This short review aims to provide an updated information on the relationship between ApoE ɛ 4 and amyloid biomarkers.
KeywordsApolipoprotein E ɛ4 Alzheimer’s disease Amyloid
Alzheimer’s disease (AD) is the most common neurodegenerative dementia, which severely impacts daily living. The medical cost for AD patients is also significantly high . Advance in medical research have led to the discovery of biomarkers for the diagnosis of AD pathologies, such as decreased cerebrospinal fluid (CSF) β-amyloid 1–42 (Aβ1-42), positive amyloid positron emission tomographic (PET) imaging and presence of the Apolipoprotein E ɛ4 allele (ApoE ɛ 4) for amyloid pathology [2–6]. Aβ plaque is one of the main hallmarks of AD which is related to neuronal death [1, 7, 8]. CSF-Aβ1-42 and amyloid PET imaging are able to quantify the level of Aβ pathology while amyloid PET is able to show the distribution of Aβ deposits in the brain. However, the invasive examination of lumbar puncture and expensive tests of amyloid PET have restricted their use in clinical practice for AD diagnosis and risk assessment. The search for a cost effective biomarker with good prediction for AD pathology is the goal. ApoE ɛ 4 is one of the major and best-established genetic risk factor for late onset AD [9–11]. It has been shown that ApoE ɛ 4 is involved in Aβ deposition and the formation of amyloid plaques, which accounts for its role on the pathophysiology of AD and hence a potential biomarker for diagnosing amyloid pathology. Indeed, the development in neuroimaging technology has allowed us to assess the relationship between the ApoE ɛ 4 and amyloid PET imaging. This review aims to summarize the current evidences regarding the relationship between the ApoE ɛ 4 and amyloid biomarkers.
Back to basic: the effect of ApoE ɛ 4 on Aβ
ApoE ɛ 4, which is positive in > 40% AD cases, is one of the strongest genetic risk factor for AD among the three human ApoE isoforms (ε2, ε3 and ε4 allele) [12, 13]. Histopathological studies of AD brains show that ApoE ɛ 4 coexist with Aβ in amyloid plaques , demonstrating an association between ApoE ɛ 4 and Aβ in the pathological structure of AD. Epitope analysis shows that the 144–148 residues in the N-terminal region of ApoE ɛ 4 and the 13–17 residues in Aβ as the receptor-binding domain , are common sites that interact with each other. ApoE ɛ 4 plays a key role in AD pathophysiology because it is less effective in breaking down Aβ peptide compared to other ApoE isoforms, which results in an increased risk of formation of amyloid plaques. Meanwhile, ApoE ɛ 4-containing lipoprotein is seldom lipidated, which reduces its stability and this leads to a lower level of ApoE ɛ 4/Aβ complex. The decreased level of ApoE ɛ 4/Aβ complex further leads to the increased Aβ aggregation. Several in vivo studies have also clearly shown that when ApoE ɛ 4 deficient mice crosses with APP transgenic mice, there is decreased Aβ deposition compared to human ApoE ɛ 2 and ApoE ɛ 3 [13, 16]. On the other hand, human ApoE ɛ 4 overexpression increases Aβ deposition [16–19]. A further detailed quantitative research of Aβ homeostasis using in vivo microdialysis in human ApoE deficient and human amyloid precursor protein crossed mice showed that Aβ clearance reduced the most in mice with by ɛ 4 allele, followed by ɛ 3 and then ɛ 2 alleles. . These findings clearly show the significant role of ApoE ɛ 4 in the formation of fibrillar Aβ [16, 19] which results in cognitive impairment.
Current in clinic: the association between ApoE ɛ 4 and Aβ
Low CSF Aβ1-42 and high amyloid PET imaging in the brain are biomarkers which may support the diagnosis of AD. With the advancement of amyloid PET imaging and amyloid ligands development, it is now possible to visualize amyloid plaques in vivo in the brain. As mentioned above, ApoE ɛ 4 is a major genetic risk factor for amyloid pathology in late onset AD [9–11]. The presence of one copy of the ApoE ɛ 4 allele increases the risk of late onset AD by about 3.7 times while the presence of two copies increases this risk by about 12 times as compared to the ApoE ɛ 3 isoform . More importantly when compared with non-carriers, Aβ deposition and amyloid plaque formation is greater in ApoE ɛ 4 carriers. In the brain of ApoE ε4/ε4 AD patient, the level of Aβ oligomers is 2.7 times higher than ApoE ε3/ε3 AD patient and this corresponds to greater total amyloid plaque burden. This suggests that ApoE ɛ 4 influences Aβ oligomers metabolism. ApoE increases Aβ oligomers levels in an isoform dependent manner (ɛ 2 < ɛ 3 < ɛ 4) . A report from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database shows the influence of ApoE ɛ 4 dose on clinical and neuroimaging biomarkers across the AD spectrum (from cognitive normal to AD patients with severe cognitive impairment. ApoE ɛ 4 is associated with decreased CSF beta-amyloid (Aβ1–42) and increased cerebral Aβ deposition across the AD spectrum. ApoE ɛ 4 increases cerebral amyloid-β (Aβ) deposition in all the stages of AD development, and also influences Aβ-initiated cascade of downstream neurodegenerative effects, thereby increasing the risk of AD . A recent meta-analysis also shows that ApoE ɛ 4 carriers (either 1 or both alleles) were significantly associated with increased amyloid PET deposition, suggesting its potential effects on cortical amyloid burden . The difference of amyloid plaque burden between ApoE ɛ 4 carriers and ApoE ɛ 4 non carriers patients, may be explained that Aβ deposition starts earlier and continues for a longer time in ApoE ɛ 4 carriers. This theory is supported by the research in neuropathology and epidemiology, which showed earlier onset of disease and higher amyloid plaque burden in younger ApoE ɛ 4 carriers with AD. Another possible explaination for greater plaque burden in ApoE ɛ 4 carrier is that there may be a higher speed of amyloid deposition in ApoE ɛ 4 carriers over time in the process of disease [24–27]. Further studies are needed to investigate this relationship, including subgroups analyses according to diagnosis from a more homogeneous population. In contrary, one study showed the increased amyloid deposition in the frontal cortex in ApoE ɛ 4 noncarriers . It appears contradictory that lack of the important genetic risk factor for AD is related to increased amyloid burden. It was explained that the inconsistent outcome could be associated with confounding factors interfering with demographic characteristics, different assay protocols and even the accuracy of clinical diagnosis.
Three hundred seventy Subjects with clinical diagnosis of mild to moderate AD and known ApoE ɛ 4 genotype (adapted from the Degenhardt publication in Psychosomatics in 2016)
Amyloid FBP PET positive*
Amyloid FBP PET negative*
Accuracy of clinical diagnosis
ApoE ɛ 4(−)
ApoE ɛ 4(+/−)
ApoE ɛ 4(+)
Although, ApoE ɛ 4 genotype is associated with decreased CSF Aβ1–42 in AD patients [2, 32–34]. There were no enough available reports to assess the prevalence of concordance of ApoE ɛ 4 and CSF Aβ1–42-positivity in AD patients. Future research is still required to clarify the concordance of ApoE ɛ 4, CSF Aβ1–42 and amyloid PET positivity in AD patients. When the concordance is clarified, thus blood ApoE ɛ 4 genotype biomarker as one economic testing can be helpful in AD patients when considering amyloid evaluation in clinical practice, especially when an anti-amyloid drug would be available.
In summary, these basic and clinic researches support that ApoE ɛ 4 is highly associated with amyloid pathology in the brain. Especially, in confirmed AD patients with ApoE ɛ 4+, ApoE ɛ 4 genotype positivity almost equals brain amyloid positivity from a qualitative point of view. Future research exploring the dose-effect association between ApoE ɛ 4 genotypes and amyloid neuropathology of AD, or in conjunction with other markers can help to better understand the pathophysiological role of ApoE ɛ 4 and improve the diagnostic accuracy in AD. Considering the above relationship, blood ApoE ɛ 4 genotype positivity is an important referred biomarker for amyloid pathology and should be considered for use in AD diagnosis and future pre-treatment biological testing when an anti-amyloid drug will be available.
MWB is supported by Yantai Yuhuangding Hospital, China.
MK is supported by Yantai Yuhuangding Hospital, China.
XFL is supported by a Fellowship Program from Chongqing Medical University
KP Ng is supported by the National Medical Research Council (NMRC) Research Training Research
SG is supported by the Canadian Institutes for Health Research
Availability of data and materials
The datasets used during the current study available from the corresponding author on reasonable request.
MWB and MK made equal contributions to conception and design, acquisition of data, and in drafting the manuscript. XFL and KP Ng were involved in revising it critically for important intellectual content. SG and PRN was the general supervision of the research group. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Selkoe DJ. Preventing Alzheimer’s disease. Science. 2012;337(6101):1488–92.View ArticlePubMedGoogle Scholar
- Liu Y et al. Multiple Effect of APOE Genotype on Clinical and Neuroimaging Biomarkers Across Alzheimer’s Disease Spectrum. Mol Neurobiol. 2015;53(7):4539–47. [Epub ahead of print].Google Scholar
- Wilson RS, et al. The apolipoprotein E epsilon 4 allele and decline in different cognitive systems during a 6-year period. Arch Neurol. 2002;59(7):1154–60.View ArticlePubMedGoogle Scholar
- Shaw LM, et al. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol. 2009;65(4):403–13.View ArticlePubMedPubMed CentralGoogle Scholar
- Elias-Sonnenschein LS, Bertram L, Visser PJ. Relationship between genetic risk factors and markers for Alzheimer’s disease pathology. Biomark Med. 2012;6(4):477–95.View ArticlePubMedGoogle Scholar
- Klunk WE, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306–19.View ArticlePubMedGoogle Scholar
- Finder VH. Alzheimer’s disease: a general introduction and pathomechanism. J Alzheimers Dis. 2010;22 Suppl 3:5–19.PubMedGoogle Scholar
- Holtzman DM, Morris JC, Goate AM. Alzheimer’s disease: the challenge of the second century. Sci Transl Med. 2011;3(77):77sr1.View ArticlePubMedPubMed CentralGoogle Scholar
- Bu G. Apolipoprotein E, and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009;10(5):333–44.View ArticlePubMedPubMed CentralGoogle Scholar
- Yu JT, Tan L, Hardy J. Apolipoprotein E in Alzheimer’s disease: an update. Annu Rev Neurosci. 2014;37:79–100.View ArticlePubMedGoogle Scholar
- Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63(3):287–303.View ArticlePubMedPubMed CentralGoogle Scholar
- Farrer LA, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278(16):1349–56.View ArticlePubMedGoogle Scholar
- Kanekiyo T, Xu H, Bu G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron. 2014;81(4):740–54.View ArticlePubMedPubMed CentralGoogle Scholar
- Namba Y, et al. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 1991;541(1):163–6.View ArticlePubMedGoogle Scholar
- Winkler K, et al. Competition of Abeta amyloid peptide and apolipoprotein E for receptor-mediated endocytosis. J Lipid Res. 1999;40(3):447–55.PubMedGoogle Scholar
- Irizarry MC, et al. Modulation of A beta deposition in APP transgenic mice by an apolipoprotein E null background. Ann N Y Acad Sci. 2000;920:171–8.View ArticlePubMedGoogle Scholar
- Holtzman DM, et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A. 2000;97(6):2892–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Fagan AM, et al. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2002;9(3):305–18.View ArticlePubMedGoogle Scholar
- Bales KR, et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet. 1997;17(3):263–4.View ArticlePubMedGoogle Scholar
- Castellano JM, et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med. 2011;3(89):89ra57.View ArticlePubMedPubMed CentralGoogle Scholar
- Corder EH, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–3.View ArticlePubMedGoogle Scholar
- Hashimoto T, et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J Neurosci. 2012;32(43):15181–92.View ArticlePubMedPubMed CentralGoogle Scholar
- Liu Y, et al. APOE genotype and neuroimaging markers of Alzheimer’s disease: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2015;86(2):127–34.View ArticlePubMedGoogle Scholar
- Näslund J, et al. Characterization of stable complexes involving apolipoprotein E and the amyloid beta peptide in Alzheimer’s disease brain. Neuron. 1995;15(1):219–28.View ArticlePubMedGoogle Scholar
- Rebeck GW, et al. Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron. 1993;11(4):575–80.View ArticlePubMedGoogle Scholar
- Ashford JW. APOE genotype effects on Alzheimer’s disease onset and epidemiology. J Mol Neurosci. 2004;23(3):157–65.View ArticlePubMedGoogle Scholar
- Sando SB, et al. APOE epsilon 4 lowers age at onset and is a high risk factor for Alzheimer’s disease; a case control study from central Norway. BMC Neurol. 2008;8:9.View ArticlePubMedPubMed CentralGoogle Scholar
- Ossenkoppele R, et al. Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia. Neurology. 2013;80(4):359–65.View ArticlePubMedGoogle Scholar
- Leuzy A, et al. Pittsburgh compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European memory clinic study. Brain. 2016. doi:https://doi.org/10.1093/brain/aww160 [Epub ahead of print].PubMedPubMed CentralGoogle Scholar
- Ossenkoppele R, et al. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA. 2015;313(19):1939–49.View ArticlePubMedPubMed CentralGoogle Scholar
- Degenhardt EK, et al. Florbetapir F18 PET amyloid neuroimaging and characteristics in patients with mild and moderate Alzheimer dementia. Psychosomatics. 2016;57(2):208–16.View ArticlePubMedGoogle Scholar
- Tapiola T, et al. Relationship between apoE genotype and CSF beta-amyloid (1–42) and tau in patients with probable and definite Alzheimer’s disease. Neurobiol Aging. 2000;21(5):735–40.View ArticlePubMedGoogle Scholar
- Yassine HN, et al. The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease. Alzheimers Res Ther. 2016;8:25. doi:https://doi.org/10.1186/s13195-016-0194-x.View ArticlePubMedPubMed CentralGoogle Scholar
- Mehrabian S, et al. Cerebrospinal fluid biomarkers for Alzheimer’s disease: the role of apolipoprotein E genotype, age, and sex. Neuropsychiatr Dis Treat. 2015;11:3105–10.View ArticlePubMedPubMed CentralGoogle Scholar