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1.
Figure 3

Figure 3. The role of Apolipoprotein E4 in Alzheimer disease pathogenesis. From: Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy.

ApoE4 confers toxic gain of function, loss of neuroprotective function or both in the pathogenesis of Alzheimer disease. Key functional differences between ApoE4 and ApoE3 are illustrated. Abbreviations: Aβ, amyloid-β; ApoE, Apolipoprotein E.

Chia-Chen Liu, et al. Nat Rev Neurol. ;9(2):106-118.
2.
Figure 1

Figure 1. APOE ε4 is a major genetic risk factor for Alzheimer disease. From: Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy.

(a) The ApoE2, E3, and E4 isoforms, which are encoded by the ε2, ε3 and ε4 alleles of the APOE gene, respectively, differ from one another at amino acid residues 112 and/or 158 (red circles). ApoE has two structural domains: the N-terminal domain, which contains the receptor-binding region (residues 136–150), and the C-terminal domain, which contains the lipid-binding region (residues 244–272); the two domains are joined by a hinge region. A meta-analysis demonstrated a significant association between the ε4 allele of APOE and AD.10 (b) APOE ε4 increases the risk of AD and lowers the age of disease onset in a gene-dose-dependent manner.7, 20 Abbreviations: AD, Alzheimer disease; ApoE, Apolipoprotein E.

Chia-Chen Liu, et al. Nat Rev Neurol. ;9(2):106-118.
3.
Figure 2

Figure 2. Apolipoprotein E and amyloid-β metabolism in the brain. From: Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy.

The main Aβ clearance pathways include receptor-mediated uptake by neurons and glia, drainage into interstitial fluid or through the BBB, and proteolytic degradation by IDE and neprilysin. Impaired clearance of Aβ can cause Aβ accumulation in brain parenchyma, leading to formation of neurotoxic Aβ oligomers and amyloid plaques. Aβ accumulation in the perivascular region leads to CAA, which disrupts blood vessel function. ApoE is primarily synthesized by astrocytes and microglia, and is lipidated by the ABCA1 transporter to form lipoprotein particles. Lipidated ApoE binds to soluble Aβ and facilitates Aβ uptake through cell surface receptors, including LRP1, LDLR, and HSPG175, 177 in a manner that probably depends on ApoE isoform and its level of lipidation. ApoE facilitates binding and internalization of soluble Aβ by glial cells, disrupts Aβ clearance at the BBB in an isoform-dependent manner (ApoE4 > ApoE3 > ApoE2) and influences CAA pathogenesis. Abbreviations: Aβ, amyloid-β; ABCA1, ATP-binding cassette A1; BBB, blood–brain barrier; CAA, cerebral amyloid angiopathy; HSPG, heparan sulphate proteoglycan; IDE, insulin-degrading enzyme; LDLR, low-density lipoprotein receptor; LRP1, low-density lipoprotein receptor-related protein 1; LXR, liver X receptor.

Chia-Chen Liu, et al. Nat Rev Neurol. ;9(2):106-118.
4.
Figure 4

Figure 4. Abnormal brain function and enhanced neuropathology and memory decline in cognitively normal APOE ε4 carriers. From: Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy.

(a) 18F-fluorodeoxyglucose PET images show that cognitively normal APOE ε4 carriers have lower glucose metabolism than do noncarriers. (b) APOE ε4 carriers exhibit a greater increase in functional MRI signal in brain regions associated with task performance, and show increases in additional regions compared with APOE ε3 carriers. (c) Age-related memory decline occurs more rapidly in APOE ε4 carriers than noncarriers, starting from age 55–60 years. (d) APOE ε4 carriers show increased cerebral Aβ deposition which persists in greater frequencies with age compared with noncarriers. Increased PiB binding and reduced CSF Aβ42 levels reflect cerebral amyloid deposition. Abbreviations: Aβ, amyloid-β; APOE, apolipoprotein E; CSF, cerebrospinal fluid; PiB, Pittsburg compund B. Part a, is modified, with permission from the National Academy of Science, USA © Small, G. W. et al. Proc. Natl Acad. Sci. USA 97, 6037–6042 (2000). Part b, is modified, with permission from the Massachusetts Medical Society © Bookheimer, S. Y. et al. N. Engl. J. Med. 343, 450–456 (2000). Part c, is modified, with permission from the Massachusetts Medical Society © Caselli et al. N. Engl. J. Med. 361, 255–263 (2009). Part d is modified, with permission, from John Wiley and Sons © Morris, J. C. et al. Ann. Neurol. 67, 122–131 (2010).

Chia-Chen Liu, et al. Nat Rev Neurol. ;9(2):106-118.

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