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The role of APOE on lipid homeostasis and inflammation in normal brains

Thematic Review Series: ApoE and Lipid Homeostasis in Alzheimer's Disease
Open AccessPublished:March 02, 2017DOI:https://doi.org/10.1194/jlr.R075408
      The role of APOE in the risk of Alzheimer's disease (AD) has largely focused on its effects on AD pathological processes. However, there are increasing data that APOE genotype affects processes in normal brains. Studies of young cognitively normal humans show effects of APOE genotype on brain structure and activity. Studies of normal APOE knock-in mice show effects of APOE genotype on brain structure, neuronal markers, and behavior. APOE interactions with molecules important for lipid efflux and lipid endocytosis underlie effects of APOE genotype on neuroinflammation and lipoprotein composition. These effects provide important targets for new therapies for reduction of the risk of AD before any signs of pathogenesis.
      APOE genotype has the most profound genetic risk on late onset Alzheimer's disease (AD) (
      • Raber J.
      • Huang Y.
      • Ashford J.W.
      ApoE genotype accounts for the vast majority of AD risk and AD pathology.
      ). APOE4 promotes earlier amyloid deposition and clinical symptoms of AD by about 15 years per allele (
      • Jansen W.J.
      • Ossenkoppele R.
      • Knol D.L.
      • Tijms B.M.
      • Scheltens P.
      • Verhey F.R.
      • Visser P.J.
      • Amyloid Biomarker Study Group
      • Aalten P.
      • Aarsland D.
      • et al.
      Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.
      ). With an allele frequency of 0.14, APOE4 is present in approximately 25% of the US population (
      • Liu C.C.
      • Kanekiyo T.
      • Xu H.
      • Bu G.
      Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy.
      ). Thus, there are nearly 80 million people in the US who carry this risk, without any risk-altering treatments. APOE2, in contrast, lowers the AD risk in about 35 million US individuals. The main questions that these observations raise are: how does APOE genotype affect the risk of AD, and what can be done to decrease that risk in individuals? In this review, we will be examining whether the roles of APOE in neuroinflammation or lipid homeostasis before AD pathogenesis may predispose the brain to damage that occurs later in aging with the accumulation of the Aβ peptide.

      THE EFFECTS OF APOE GENOTYPE ON INFLAMMATION

      Inflammation is a potential early indicator of AD risk or AD onset in humans because genetic factors related to immune functions and inflammation have been identified in genome-wide association studies of AD (
      • Malik M.
      • Parikh I.
      • Vasquez J.B.
      • Smith C.
      • Tai L.
      • Bu G.
      • LaDu M.J.
      • Fardo D.W.
      • Rebeck G.W.
      • Estus S.
      Genetics ignite focus on microglial inflammation in Alzheimer's disease.
      ). APOE is one of these AD risk genes related to neuroinflammation, as evidenced by several in vitro and in vivo systems. In vivo studies rely largely on mice with the coding sequence of the human APOE alleles replacing the mouse APOE gene as the best animal model for normal APOE regulation and function (
      • Sullivan P.M.
      • Mezdour H.
      • Aratani Y.
      • Knouff C.
      • Najib J.
      • Reddick R.L.
      • Quarfordt S.H.
      • Maeda N.
      Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis.
      ). The APOE4 knock-in mice are more susceptible to inflammation induced by lipopolysaccharide (
      • Zhu Y.
      • Nwabuisi-Heath E.
      • Dumanis S.B.
      • Tai L.M.
      • Yu C.
      • Rebeck G.W.
      • LaDu M.J.
      APOE genotype alters glial activation and loss of synaptic markers in mice.
      ) or by Aβ deposition (
      • Rodriguez G.A.
      • Tai L.M.
      • LaDu M.J.
      • Rebeck G.W.
      Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition.
      ) compared with APOE2 and APOE3 mice. APOE4 mice are also more susceptible to brain damage that has strong inflammatory components, such as traumatic brain injury (
      • Mannix R.C.
      • Zhang J.
      • Park J.
      • Zhang X.
      • Bilal K.
      • Walker K.
      • Tanzi R.E.
      • Tesco G.
      • Whalen M.J.
      Age-dependent effect of apolipoprotein E4 on functional outcome after controlled cortical impact in mice.
      ) and experimental autoimmune encephalomyelitis (
      • Tu J.L.
      • Zhao C.B.
      • Vollmer T.
      • Coons S.
      • Lin H.J.
      • Marsh S.
      • Treiman D.M.
      • Shi J.
      APOE 4 polymorphism results in early cognitive deficits in an EAE model.
      ). In APOE mouse models, peptides based on the APOE receptor binding domain prevent or alleviate effects of inflammation-related insults, such as lipopolysaccharide-induced inflammation (
      • Lynch J.R.
      • Tang W.
      • Wang H.
      • Vitek M.P.
      • Bennett E.R.
      • Sullivan P.M.
      • Warner D.S.
      • Laskowitz D.T.
      APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response.
      ), traumatic brain injury (
      • Lynch J.R.
      • Wang H.
      • Mace B.
      • Leinenweber S.
      • Warner D.S.
      • Bennett E.R.
      • Vitek M.P.
      • McKenna S.
      • Laskowitz D.T.
      A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury.
      ), intracerebral hemorrhage (
      • James M.L.
      • Sullivan P.M.
      • Lascola C.D.
      • Vitek M.P.
      • Laskowitz D.T.
      Pharmacogenomic effects of apolipoprotein E on intracerebral hemorrhage.
      ), and focal ischemia (
      • Wang H.
      • Anderson L.G.
      • Lascola C.D.
      • James M.L.
      • Venkatraman T.N.
      • Bennett E.R.
      • Acheson S.K.
      • Vitek M.P.
      • Laskowitz D.T.
      Apolipoprotein E mimetic peptides improve outcome after focal ischemia.
      ). Similar effects are seen in vitro. APOE isoforms affect inflammatory processes in microglia and astrocytes, with APOE4 promoting the strongest inflammatory effects (
      • Lynch J.R.
      • Tang W.
      • Wang H.
      • Vitek M.P.
      • Bennett E.R.
      • Sullivan P.M.
      • Warner D.S.
      • Laskowitz D.T.
      APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response.
      ,
      • Guo L.
      • LaDu M.J.
      • Van Eldik L.J.
      A dual role for apolipoprotein E in neuroinflammation: anti- and pro-inflammatory activity.
      ,
      • Vitek M.P.
      • Brown C.M.
      • Colton C.A.
      APOE genotype-specific differences in the innate immune response.
      ). An APOE peptide inhibits inflammatory processes in isolated microglia (
      • Pocivavsek A.
      • Burns M.P.
      • Rebeck G.W.
      Low-density lipoprotein receptors regulate microglial inflammation through c-Jun N-terminal kinase.
      ) through the APOE receptor, LRP1 (
      • Pocivavsek A.
      • Mikhailenko I.
      • Strickland D.K.
      • Rebeck G.W.
      Microglial low-density lipoprotein receptor-related protein 1 modulates c-Jun N-terminal kinase activation.
      ). APOE similarly induces an anti-inflammatory phenotype in isolated macrophages through the APOE receptors, ApoER2 and VLDLR (
      • Baitsch D.
      • Bock H.H.
      • Engel T.
      • Telgmann R.
      • Muller-Tidow C.
      • Varga G.
      • Bot M.
      • Herz J.
      • Robenek H.
      • von Eckardstein A.
      • et al.
      Apolipoprotein E induces antiinflammatory phenotype in macrophages.
      ). Interestingly, blocking inflammatory signaling increases APOE expression in microglia (
      • Pocivavsek A.
      • Rebeck G.W.
      Inhibition of c-Jun N-terminal kinase increases apoE expression in vitro and in vivo.
      ), suggesting that APOE levels and inflammation are in a negative feedback loop, with APOE inhibiting inflammation and inflammation inhibiting APOE levels. These data indicate that APOE is associated with increased inflammatory responses before and after the onset of AD pathogenesis.

      THE EFFECTS OF APOE GENOTYPE ON LIPID HOMEOSTASIS

      APOE is one of the primary apolipoproteins in CNS lipid metabolism (
      • Pitas R.E.
      • Boyles J.K.
      • Lee S.H.
      • Hui D.
      • Weisgraber K.H.
      Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E(LDL) receptors in the brain.
      ). Thus, an effect of APOE genotype on brain lipid homeostasis may underlie the AD risk associated with APOE. As with inflammation, this possibility is supported by the identification of lipid-related genetic risk factors for AD (
      • Karch C.M.
      • Goate A.M.
      Alzheimer's disease risk genes and mechanisms of disease pathogenesis.
      ), particularly APOJ (or clusterin) (
      • Harold D.
      • Abraham R.
      • Hollingworth P.
      • Sims R.
      • Gerrish A.
      • Hamshere M.L.
      • Pahwa J.S.
      • Moskvina V.
      • Dowzell K.
      • Williams A.
      • et al.
      Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.
      ,
      • Lambert J.C.
      • Heath S.
      • Even G.
      • Campion D.
      • Sleegers K.
      • Hiltunen M.
      • Combarros O.
      • Zelenika D.
      • Bullido M.J.
      • Tavernier B.
      • et al.
      Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.
      ). Although APOJ is not as strong of a genetic risk factor as APOE [the polymorphic site in APOJ has an odds ratio of about 0.9 for the minor allele, compared with an odds ratio of about 5 for the APOE-ε4 allele (
      • Jun G.
      • Naj A.C.
      • Beecham G.W.
      • Wang L.S.
      • Buros J.
      • Gallins P.J.
      • Buxbaum J.D.
      • Ertekin-Taner N.
      • Fallin M.D.
      • Friedland R.
      • et al.
      Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes.
      )], both APOE and APOJ are components of CNS lipoproteins (
      • Borghini I.
      • Barja F.
      • Pometta D.
      • James R.W.
      Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal fluid.
      ) and are associated with the functions of CNS lipoproteins: lipid efflux and lipid delivery (
      • Rebeck G.W.
      • Alonzo N.C.
      • Berezovska O.
      • Harr S.D.
      • Knowles R.B.
      • Growdon J.H.
      • Hyman B.T.
      • Mendez A.J.
      Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different APOE genotypes.
      ).
      APOE and APOJ interact with lipid debris in the brain (
      • White F.
      • Nicoll J.A.
      • Horsburgh K.
      Alterations in ApoE and ApoJ in relation to degeneration and regeneration in a mouse model of entorhinal cortex lesion.
      ) and APOE is necessary for the removal of degenerating membrane after injury (
      • Fagan A.M.
      • Murphy B.A.
      • Patel S.N.
      • Kilbridge J.F.
      • Mobley W.C.
      • Bu G.
      • Holtzman D.M.
      Evidence for normal aging of the septo-hippocampal cholinergic system in apoE (−/−) mice but impaired clearance of axonal degeneration products following injury.
      ). APOE lipoproteins also accumulate lipid from a cellular efflux mechanism with the ABCA1 transporter (
      • Koldamova R.
      • Fitz N.F.
      • Lefterov I.
      ATP-binding cassette transporter A1: from metabolism to neurodegeneration.
      ). Deletion of the ABCA1 gene decreases levels of APOE (
      • Hirsch-Reinshagen V.
      • Zhou S.
      • Burgess B.L.
      • Bernier L.
      • McIsaac S.A.
      • Chan J.Y.
      • Tansley G.H.
      • Cohn J.S.
      • Hayden M.R.
      • Wellington C.L.
      Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain.
      ,
      • Wahrle S.E.
      • Jiang H.
      • Parsadanian M.
      • Hartman R.E.
      • Bales K.R.
      • Paul S.M.
      • Holtzman D.M.
      Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease.
      ) and increases the deposition of Aβ (
      • Wahrle S.E.
      • Jiang H.
      • Parsadanian M.
      • Hartman R.E.
      • Bales K.R.
      • Paul S.M.
      • Holtzman D.M.
      Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease.
      ) in the brain. APOE isoforms differ in their ability to promote cholesterol efflux from cells, with APOE2 having the greatest efficiency and APOE4 the least (
      • Michikawa M.
      • Fan Q.W.
      • Isobe I.
      • Yanagisawa K.
      Apolipoprotein E exhibits isoform-specific promotion of lipid efflux from astrocytes and neurons in culture.
      ,
      • Minagawa H.
      • Gong J.S.
      • Jung C.G.
      • Watanabe A.
      • Lund-Katz S.
      • Phillips M.C.
      • Saito H.
      • Michikawa M.
      Mechanism underlying apolipoprotein E (ApoE) isoform-dependent lipid efflux from neural cells in culture.
      ). This efflux is the first step in the generation of APOE-lipid complexes. APOE4 was found to be part of smaller complexes in normal mouse brains (
      • Boehm-Cagan A.
      • Michaelson D.M.
      Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene.
      ,
      • Boehm-Cagan A.
      • Bar R.
      • Liraz O.
      • Bielicki J.K.
      • Johansson J.O.
      • Michaelson D.M.
      ABCA1 agonist reverses the apoE4-driven cognitive and brain pathologies.
      ), and in mouse brain expressing different APOE isoforms from virus (
      • Hu J.
      • Liu C.C.
      • Chen X.F.
      • Zhang Y.W.
      • Xu H.
      • Bu G.
      Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice.
      ,
      • Dodart J.C.
      • Marr R.A.
      • Koistinaho M.
      • Gregersen B.M.
      • Malkani S.
      • Verma I.M.
      • Paul S.M.
      Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease.
      ). In contrast, APOE2 was associated with larger complexes (
      • Hu J.
      • Liu C.C.
      • Chen X.F.
      • Zhang Y.W.
      • Xu H.
      • Bu G.
      Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice.
      ). The relevance of these findings to humans was demonstrated through analysis of human cerebrospinal fluid (CSF), with APOE complexes largest in APOE2.3 individuals and smallest in APOE4.4 individuals (
      • Heinsinger N.M.
      • Gachechiladze M.A.
      • Rebeck G.W.
      Apolipoprotein E genotype affects size of apoE complexes in cerebrospinal fluid.
      ). Consistent with the hypothesis that APOE4 is associated with smaller lipoproteins, APOE4 lipoproteins promoted less cholesterol efflux than APOE3 lipoproteins (
      • Yassine H.N.
      • Feng Q.
      • Chiang J.
      • Petrosspour L.M.
      • Fonteh A.N.
      • Chui H.C.
      • Harrington M.G.
      ABCA1-mediated cholesterol efflux capacity to cerebrospinal fluid is reduced in patients with mild cognitive impairment and Alzheimer's disease.
      ), and APOE4-positive individuals had more lipid-depleted APOE in their CSF than APOE4-negative individuals (
      • Hanson A.J.
      • Bayer-Carter J.L.
      • Green P.S.
      • Montine T.J.
      • Wilkinson C.W.
      • Baker L.D.
      • Watson G.S.
      • Bonner L.M.
      • Callaghan M.
      • Leverenz J.B.
      • et al.
      Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides: randomized clinical trial.
      ).
      Lipid delivery to cells occurs as APOE and APOJ are endocytosed via members of the LDL receptor family (
      • Harris-White M.E.
      • Frautschy S.A.
      Low density lipoprotein receptor-related proteins (LRPs), Alzheimer's and cognition.
      ); endocytosis promotes neurite outgrowth (
      • Nathan B.P.
      • Bellosta S.
      • Sanan D.A.
      • Weisgraber K.H.
      • Mahley R.W.
      • Pitas R.E.
      Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro.
      ), neuronal sprouting (
      • Teter B.
      • Xu P.T.
      • Gilbert J.R.
      • Roses A.D.
      • Galasko D.
      • Cole G.M.
      Human apolipoprotein E isoform-specific differences in neuronal sprouting in organotypic hippocampal culture.
      ), and synapse formation (
      • Mauch D.H.
      • Nagler K.
      • Schumacher S.
      • Goritz C.
      • Muller E.C.
      • Otto A.
      • Pfrieger F.W.
      CNS synaptogenesis promoted by glia-derived cholesterol.
      ). APOE and APOJ also promote endocytosis through TREM2 (
      • Yeh F.L.
      • Wang Y.
      • Tom I.
      • Gonzalez L.C.
      • Sheng M.
      TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia.
      ,
      • Atagi Y.
      • Liu C.C.
      • Painter M.M.
      • Chen X.F.
      • Verbeeck C.
      • Zheng H.
      • Li X.
      • Rademakers R.
      • Kang S.S.
      • Xu H.
      • et al.
      Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2).
      ), another prominent genetic risk factor for AD (
      • Jonsson T.
      • Stefansson H.
      • Steinberg S.
      • Jonsdottir I.
      • Jonsson P.V.
      • Snaedal J.
      • Bjornsson S.
      • Huttenlocher J.
      • Levey A.I.
      • Lah J.J.
      • et al.
      Variant of TREM2 associated with the risk of Alzheimer's disease.
      ). These processes involve clearance into neurons as well as glia (
      • Mulder S.D.
      • Nielsen H.M.
      • Blankenstein M.A.
      • Eikelenboom P.
      • Veerhuis R.
      Apolipoproteins E and J interfere with amyloid-beta uptake by primary human astrocytes and microglia in vitro.
      ,
      • Cole G.M.
      • Beech W.
      • Frautschy S.A.
      • Sigel J.
      • Glasgow C.
      • Ard M.D.
      Lipoprotein effects on Abeta accumulation and degradation by microglia in vitro.
      ) or across the blood brain barrier (
      • Bell R.D.
      • Sagare A.P.
      • Friedman A.E.
      • Bedi G.S.
      • Holtzman D.M.
      • Deane R.
      • Zlokovic B.V.
      Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system.
      ). The need for clearance of lipids from the brain may increase with age as membrane damage accumulates and neuronal loss occurs.
      The effects of the reduced lipidation capacity of APOE4 may result in reduced neuronal protection or repair. Neuronal injury increases brain APOE levels (
      • Ignatius M.J.
      • Gebicke-Harter P.J.
      • Skene J.H.
      • Schilling J.W.
      • Weisgraber K.H.
      • Mahley R.W.
      • Shooter E.M.
      Expression of apolipoprotein E during nerve degeneration and regeneration.
      ), although the increase is not immediate (
      • Washington P.M.
      • Burns M.P.
      The effect of the APOE4 gene on accumulation of Aβ40 after brain injury cannot be reversed by increasing apoE4 protein.
      ). The presence of an APOE4 allele decreases the brain's neuronal reparative capacity in AD patients (
      • Arendt T.
      • Schindler C.
      • Bruckner M.K.
      • Eschrich K.
      • Bigl V.
      • Zedlick D.
      • Marcova L.
      Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein epsilon 4 allele.
      ). We hypothesize that reduced lipidation of CNS lipoproteins may be an important risk factor of AD; biomarker-based APOE lipidation may be useful in measuring levels of neuroprotection in the brain environment (
      • Heinsinger N.M.
      • Gachechiladze M.A.
      • Rebeck G.W.
      Apolipoprotein E genotype affects size of apoE complexes in cerebrospinal fluid.
      ). The effects of APOE genotype on lipidation may be causally related to some effects of inflammation, due to direct effects on high levels of cholesterol on inflammation (
      • Ringheim G.E.
      • Szczepanik A.M.
      Brain inflammation, cholesterol, and glutamate as interconnected participants in the pathology of Alzheimer's disease.
      ) or to the connections of regulatory systems controlling brain lipid homeostasis and inflammation (
      • Courtney R.
      • Landreth G.E.
      LXR regulation of brain cholesterol: from development to disease.
      ).

      THE EFFECTS OF APOE GENOTYPE ON APOE LEVELS AND POSTTRANSLATIONAL MODIFICATION

      Humans with the APOE4 allele have smaller APOE lipoproteins and lower APOE levels in the CSF and plasma, whereas those with the APOE2 allele have larger APOE lipoproteins and higher APOE levels (
      • Castellano J.M.
      • Kim J.
      • Stewart F.R.
      • Jiang H.
      • DeMattos R.B.
      • Patterson B.W.
      • Fagan A.M.
      • Morris J.C.
      • Mawuenyega K.G.
      • Cruchaga C.
      • et al.
      Human apoE isoforms differentially regulate brain amyloid-β peptide clearance.
      ,
      • Cruchaga C.
      • Kauwe J.S.
      • Nowotny P.
      • Bales K.
      • Pickering E.H.
      • Mayo K.
      • Bertelsen S.
      • Hinrichs A.
      • Alzheimer's Disease Neuroimaging Initiative
      • Fagan A.M.
      • et al.
      Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease.
      ). APOE4 knock-in mice also have lower levels of APOE in the brain, CSF, plasma, and interstitial fluid compared with APOE3 or APOE2 mice (
      • Vitek M.P.
      • Brown C.M.
      • Colton C.A.
      APOE genotype-specific differences in the innate immune response.
      ,
      • Sullivan P.M.
      • Han B.
      • Liu F.
      • Mace B.E.
      • Ervin J.F.
      • Wu S.
      • Koger D.
      • Paul S.
      • Bales K.R.
      Reduced levels of human apoE4 protein in an animal model of cognitive impairment.
      ,
      • Riddell D.R.
      • Zhou H.
      • Atchison K.
      • Warwick H.K.
      • Atkinson P.J.
      • Jefferson J.
      • Xu L.
      • Aschmies S.
      • Kirksey Y.
      • Hu Y.
      • et al.
      Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels.
      ). The lower levels of APOE may be due to increased degradation of APOE4 compared with the other isoforms (
      • Riddell D.R.
      • Zhou H.
      • Atchison K.
      • Warwick H.K.
      • Atkinson P.J.
      • Jefferson J.
      • Xu L.
      • Aschmies S.
      • Kirksey Y.
      • Hu Y.
      • et al.
      Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels.
      ). If APOE4 individuals have both smaller lipoproteins and less APOE, then there could be a twofold impact on lipid clearance and delivery processes that contributes to the increased risk for AD.
      There are also important posttranslational modifications to the APOE protein. Most notably, APOE4 lacks cysteine residues for the formation of APOE-APOE homodimers and APOE-APOAII heterodimers (
      • Rebeck G.W.
      • Alonzo N.C.
      • Berezovska O.
      • Harr S.D.
      • Knowles R.B.
      • Growdon J.H.
      • Hyman B.T.
      • Mendez A.J.
      Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different APOE genotypes.
      ), whereas APOE3 contains one cysteine and APOE2 contains two cysteines for dimer formation. APOE4 is associated with enhanced cleavage of the C terminus of APOE (
      • Harris F.M.
      • Brecht W.J.
      • Xu Q.
      • Tesseur I.
      • Kekonius L.
      • Wyss-Coray T.
      • Fish J.D.
      • Masliah E.
      • Hopkins P.C.
      • Scearce-Levie K.
      • et al.
      Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice.
      ), which exacerbates the effects of Aβ on inflammation and behavioral deficits in mice (
      • Bien-Ly N.
      • Andrews-Zwilling Y.
      • Xu Q.
      • Bernardo A.
      • Wang C.
      • Huang Y.
      C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-beta (Abeta) and acts in concert with Abeta to elicit neuronal and behavioral deficits in mice.
      ). This cleaved APOE4 is neuron specific and induced by neuronal stress (
      • Brecht W.J.
      • Harris F.M.
      • Chang S.
      • Tesseur I.
      • Yu G.Q.
      • Xu Q.
      • Dee Fish J.
      • Wyss-Coray T.
      • Buttini M.
      • Mucke L.
      • et al.
      Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice.
      ), with the APOE4 fragments inducing neuronal dysfunction (
      • Huang Y.
      • Liu X.Q.
      • Wyss-Coray T.
      • Brecht W.J.
      • Sanan D.A.
      • Mahley R.W.
      Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons.
      ). Finally, the APOE protein is modified by O-glycosylation (
      • Wernette-Hammond M.E.
      • Lauer S.J.
      • Corsini A.
      • Walker D.
      • Taylor J.M.
      • Rall Jr, S.C.
      Glycosylation of human apolipoprotein E. The carbohydrate attachment site is threonine 194.
      ), and to a greater extent in the CNS than in the periphery (
      • Rebeck G.W.
      • Alonzo N.C.
      • Berezovska O.
      • Harr S.D.
      • Knowles R.B.
      • Growdon J.H.
      • Hyman B.T.
      • Mendez A.J.
      Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different APOE genotypes.
      ). We have identified biochemical differences in modified versions of brain APOE: unmodified APOE is solubilized only in the presence of detergent and modified APOE is solubilized in saline (
      • DiBattista A.M.
      • Dumanis S.B.
      • Newman J.
      • Rebeck G.W.
      Identification and modification of amyloid-independent phenotypes of APOE4 mice.
      ). The ratio of these different forms is altered by APOE genotypes in mouse and human brains (
      • DiBattista A.M.
      • Dumanis S.B.
      • Newman J.
      • Rebeck G.W.
      Identification and modification of amyloid-independent phenotypes of APOE4 mice.
      ). The APOE isoform effects on APOE levels and on dimer formation support loss-of-function explanations for the effects of APOE4, with APOE4 less able to clear debris and deliver lipids than APOE2 or APOE3. In contrast, effects of APOE cleavage fragments on neurotoxicity (
      • Tolar M.
      • Keller J.N.
      • Chan S.
      • Mattson M.P.
      • Marques M.A.
      • Crutcher K.A.
      Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity.
      ) or the inhibitory effects of APOE4 toward neuronal sprouting (
      • Teter B.
      • Xu P.T.
      • Gilbert J.R.
      • Roses A.D.
      • Galasko D.
      • Cole G.M.
      Defective neuronal sprouting by human apolipoprotein E4 is a gain-of-negative function.
      ) support a gain-of-function explanation. Understanding of APOE functions requires a better understanding of the different forms of APOE present in the CNS, particularly because treatment approaches could involve the increase or the decrease of APOE4 levels.

      THE EFFECTS OF APOE GENOTYPE ON NORMAL CNS FUNCTIONS

      APOE genotype affects a number of CNS phenotypes in young individuals, as demonstrated both in mice and in humans (
      • DiBattista A.M.
      • Dumanis S.B.
      • Newman J.
      • Rebeck G.W.
      Identification and modification of amyloid-independent phenotypes of APOE4 mice.
      ). APOE4 knock-in mice have several differences compared with APOE3 mice. In measures of behavior, APOE4 is associated with deficits in spatial learning and memory (
      • Rodriguez G.A.
      • Burns M.P.
      • Weeber E.J.
      • Rebeck G.W.
      Young APOE4 targeted replacement mice exhibit poor spatial learning and memory, with reduced dendritic spine density in the medial entorhinal cortex.
      ,
      • Bour A.
      • Grootendorst J.
      • Vogel E.
      • Kelche C.
      • Dodart J.C.
      • Bales K.
      • Moreau P.H.
      • Sullivan P.M.
      • Mathis C.
      Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks.
      ,
      • Grootendorst J.
      • Bour A.
      • Vogel E.
      • Kelche C.
      • Sullivan P.M.
      • Dodart J.C.
      • Bales K.
      • Mathis C.
      Human apoE targeted replacement mouse lines: h-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior.
      ,
      • Knoferle J.
      • Yoon S.Y.
      • Walker D.
      • Leung L.
      • Gillespie A.K.
      • Tong L.M.
      • Bien-Ly N.
      • Huang Y.
      Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice.
      ). In measures of neuronal complexity, APOE4 is associated with reduced dendritic arborization (
      • Dumanis S.B.
      • Tesoriero J.A.
      • Babus L.W.
      • Nguyen M.T.
      • Trotter J.H.
      • Ladu M.J.
      • Weeber E.J.
      • Turner R.S.
      • Xu B.
      • Rebeck G.W.
      • et al.
      ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo.
      ,
      • Wang C.
      • Wilson W.A.
      • Moore S.D.
      • Mace B.E.
      • Maeda N.
      • Schmechel D.E.
      • Sullivan P.M.
      Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology.
      ), neuronal activity (
      • Gillespie A.K.
      • Jones E.A.
      • Lin Y.H.
      • Karlsson M.P.
      • Kay K.
      • Yoon S.Y.
      • Tong L.M.
      • Nova P.
      • Carr J.S.
      • Frank L.M.
      • et al.
      Apolipoprotein E4 causes age-dependent disruption of slow gamma oscillations during hippocampal sharp-wave ripples.
      ), the balance of excitatory and inhibitory neurons (
      • Leung L.
      • Andrews-Zwilling Y.
      • Yoon S.Y.
      • Jain S.
      • Ring K.
      • Dai J.
      • Wang M.M.
      • Tong L.
      • Walker D.
      • Huang Y.
      Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice.
      ), neurotransmitter release (
      • Klein R.C.
      • Acheson S.K.
      • Mace B.E.
      • Sullivan P.M.
      • Moore S.D.
      Altered neurotransmission in the lateral amygdala in aged human apoE4 targeted replacement mice.
      ,
      • Klein R.C.
      • Mace B.E.
      • Moore S.D.
      • Sullivan P.M.
      Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2.
      ,
      • Dolejší E.
      • Liraz O.
      • Rudajev V.
      • Zimcik P.
      • Dolezal V.
      • Michaelson D.M.
      Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice.
      ), and dendritic spine density (
      • Rodriguez G.A.
      • Burns M.P.
      • Weeber E.J.
      • Rebeck G.W.
      Young APOE4 targeted replacement mice exhibit poor spatial learning and memory, with reduced dendritic spine density in the medial entorhinal cortex.
      ,
      • Dumanis S.B.
      • Tesoriero J.A.
      • Babus L.W.
      • Nguyen M.T.
      • Trotter J.H.
      • Ladu M.J.
      • Weeber E.J.
      • Turner R.S.
      • Xu B.
      • Rebeck G.W.
      • et al.
      ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo.
      ,
      • Ji Y.
      • Gong Y.
      • Gan W.
      • Beach T.
      • Holtzman D.M.
      • Wisniewski T.
      Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients.
      ). In measures of immunohistochemistry, APOE4 is associated with alterations in levels of VGlut1 (
      • Boehm-Cagan A.
      • Michaelson D.M.
      Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene.
      ,
      • Dumanis S.B.
      • DiBattista A.M.
      • Miessau M.
      • Moussa C.E.
      • Rebeck G.W.
      APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals.
      ) and in levels of specific APOE receptors (
      • Gilat-Frenkel M.
      • Boehm-Cagan A.
      • Liraz O.
      • Xian X.
      • Herz J.
      • Michaelson D.M.
      Involvement of the Apoer2 and Lrp1 receptors in mediating the pathological effects of ApoE4 in vivo.
      ). Finally, in biochemical measures, APOE4 is associated with alterations in APOE solubilization (
      • DiBattista A.M.
      • Dumanis S.B.
      • Newman J.
      • Rebeck G.W.
      Identification and modification of amyloid-independent phenotypes of APOE4 mice.
      ) and presynaptic metabolic abnormalities (
      • Dumanis S.B.
      • DiBattista A.M.
      • Miessau M.
      • Moussa C.E.
      • Rebeck G.W.
      APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals.
      ). Thus, in normal mice, APOE4 is associated with many different aspects of brain function, effects important for later brain impairments.
      In measures of normal human behavior, APOE4 is associated with reduced verbal memory (
      • Caselli R.J.
      • Reiman E.M.
      • Osborne D.
      • Hentz J.G.
      • Baxter L.C.
      • Hernandez J.L.
      • Alexander G.G.
      Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele.
      ), as well as visual recall and memory retention (
      • Acevedo S.F.
      • Piper B.J.
      • Craytor M.J.
      • Benice T.S.
      • Raber J.
      Apolipoprotein E4 and sex affect neurobehavioral performance in primary school children.
      ). In measures of human brain activity using functional magnetic resonance imaging, APOE4 is associated with increased brain activity in the default mode network, and the hippocampus during an encoding task (
      • Filippini N.
      • Rao A.
      • Wetten S.
      • Gibson R.A.
      • Borrie M.
      • Guzman D.
      • Kertesz A.
      • Loy-English I.
      • Williams J.
      • Nichols T.
      • et al.
      Anatomically-distinct genetic associations of APOE epsilon4 allele load with regional cortical atrophy in Alzheimer's disease.
      ). Indeed, medial temporal lobe (MTL) activation is altered by APOE genotype during diverse behavioral tasks (
      • Rusted J.M.
      • Evans S.L.
      • King S.L.
      • Dowell N.
      • Tabet N.
      • Tofts P.S.
      APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures.
      ,
      • Green A.E.
      • Gray J.R.
      • Deyoung C.G.
      • Mhyre T.R.
      • Padilla R.
      • Dibattista A.M.
      • William Rebeck G.
      A combined effect of two Alzheimer's risk genes on medial temporal activity during executive attention in young adults.
      ,
      • Borghesani P.R.
      • Johnson L.C.
      • Shelton A.L.
      • Peskind E.R.
      • Aylward E.H.
      • Schellenberg G.D.
      • Cherrier M.M.
      Altered medial temporal lobe responses during visuospatial encoding in healthy APOE*4 carriers.
      ) and APOE4 carriers have reduced grid-cell-like representations in the entorhinal cortex and increased hippocampal activation (
      • Kunz L.
      • Schroder T.N.
      • Lee H.
      • Montag C.
      • Lachmann B.
      • Sariyska R.
      • Reuter M.
      • Stirnberg R.
      • Stocker T.
      • Messing-Floeter P.C.
      • et al.
      Reduced grid-cell-like representations in adults at genetic risk for Alzheimer's disease.
      ). APOE genotype in the absence of AD is also associated with differences in brain structure. APOE4 is associated with differences in the MTL at birth (
      • Dean III, D.C.
      • Jerskey B.A.
      • Chen K.
      • Protas H.
      • Thiyyagura P.
      • Roontiva A.
      • O'Muircheartaigh J.
      • Dirks H.
      • Waskiewicz N.
      • Lehman K.
      • et al.
      Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study.
      ,
      • Knickmeyer R.C.
      • Wang J.
      • Zhu H.
      • Geng X.
      • Woolson S.
      • Hamer R.M.
      • Konneker T.
      • Lin W.
      • Styner M.
      • Gilmore J.H.
      Common variants in psychiatric risk genes predict brain structure at birth.
      ) [the effects of APOE4 on MTL structure in older individuals is mixed (
      • Filippini N.
      • Rao A.
      • Wetten S.
      • Gibson R.A.
      • Borrie M.
      • Guzman D.
      • Kertesz A.
      • Loy-English I.
      • Williams J.
      • Nichols T.
      • et al.
      Anatomically-distinct genetic associations of APOE epsilon4 allele load with regional cortical atrophy in Alzheimer's disease.
      ,
      • Di Battista A.M.
      • Heinsinger N.M.
      • Rebeck G.W.
      Alzheimer's disease genetic risk factor APOE-ε4 also affects normal brain function.
      ,
      • Matura S.
      • Prvulovic D.
      • Jurcoane A.
      • Hartmann D.
      • Miller J.
      • Scheibe M.
      • O'Dwyer L.
      • Oertel-Knochel V.
      • Knochel C.
      • Reinke B.
      • et al.
      Differential effects of the ApoE4 genotype on brain structure and function.
      ,
      • O'Dwyer L.
      • Lamberton F.
      • Matura S.
      • Tanner C.
      • Scheibe M.
      • Miller J.
      • Rujescu D.
      • Prvulovic D.
      • Hampel H.
      Reduced hippocampal volume in healthy young ApoE4 carriers: an MRI study.
      )]. There are differences in brain connectivity based on APOE and APOJ genotypes determined by diffusion tensor imaging (
      • Stevens B.W.
      • DiBattista A.M.
      • William Rebeck G.
      • Green A.E.
      A gene-brain-cognition pathway for the effect of an Alzheimers risk gene on working memory in young adults.
      ). Differences in brain structure in APOE4 individuals are also supported by the observation that dendritic spine density in the hippocampus is lower in aged APOE4 individuals with no evidence of Aβ deposition (
      • Ji Y.
      • Gong Y.
      • Gan W.
      • Beach T.
      • Holtzman D.M.
      • Wisniewski T.
      Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients.
      ). Some of these differences are consistent with increased brain activity or connectivity in young individuals with APOE4. The antagonistic pleiotropy hypothesis posits that APOE4 has a positive effect on brain activity and behavior at young ages, but is detrimental at older ages (
      • Han S.D.
      • Bondi M.W.
      Revision of the apolipoprotein E compensatory mechanism recruitment hypothesis.
      ). In general, the human studies and mouse studies together have supported the hypothesis that APOE genotype impacts normal brain structure and function independent of AD pathology.

      APOE-DIRECTED PREVENTATIVE TREATMENTS

      Understanding of the basic biology of APOE helps to identify mechanism-based therapies that could rescue APOE4 phenotypes. In normal brains, these phenotypes could predispose to Aβ deposition with aging, which could be prevented by early prophylactic approaches. For example, as mentioned above, APOE mimetic peptides could serve as a therapeutic approach for APOE4 individuals for AD, as well as other diseases with neuro-inflammatory components (
      • Laskowitz D.T.
      • Vitek M.P.
      Apolipoprotein E and neurological disease: therapeutic potential and pharmacogenomic interactions.
      ). The introduction of active APOE peptides could alleviate conditions caused by lower APOE levels in APOE4 individuals (
      • Riddell D.R.
      • Zhou H.
      • Atchison K.
      • Warwick H.K.
      • Atkinson P.J.
      • Jefferson J.
      • Xu L.
      • Aschmies S.
      • Kirksey Y.
      • Hu Y.
      • et al.
      Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels.
      ).
      Another potential AD preventative treatment is the class of nonsteroidal anti-inflammatory drugs (NSAIDs). Epidemiological studies have repeatedly shown that early NSAID use is associated with reduced AD risk in humans (
      • Cornelius C.
      • Fastbom J.
      • Winblad B.
      • Viitanen M.
      Aspirin, NSAIDs, risk of dementia, and influence of the apolipoprotein E epsilon 4 allele in an elderly population.
      ,
      • Lindsay J.
      • Laurin D.
      • Verreault R.
      • Hebert R.
      • Helliwell B.
      • Hill G.B.
      • McDowell I.
      Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging.
      ,
      • Stewart W.F.
      • Kawas C.
      • Corrada M.
      • Metter E.J.
      Risk of Alzheimer's disease and duration of NSAID use.
      ,
      • Zandi P.P.
      • Anthony J.C.
      • Hayden K.M.
      • Mehta K.
      • Mayer L.
      • Breitner J.C.
      • Cache County Study Investigators
      Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study.
      ,
      • in't Veld B.A.
      • Ruitenberg A.
      • Hofman A.
      • Stricker B.H.
      • Breteler M.M.
      Antihypertensive drugs and incidence of dementia: the Rotterdam Study.
      ), but NSAIDs have been unsuccessful at treating AD in clinical trials (
      • Pasqualetti P.
      • Bonomini C.
      • Dal Forno G.
      • Paulon L.
      • Sinforiani E.
      • Marra C.
      • Zanetti O.
      • Rossini P.M.
      A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer's disease.
      ), or preventing AD in short-term prevention trials of the elderly (
      • Breitner J.C.
      • Baker L.D.
      • Montine T.J.
      • Meinert C.L.
      • Lyketsos C.G.
      • Ashe K.H.
      • Brandt J.
      • Craft S.
      • Evans D.E.
      • Green R.C.
      • et al.
      Extended results of the Alzheimer's disease anti-inflammatory prevention trial.
      ). Interestingly, the preventative effect of NSAIDs may be most powerful in those with the APOE4 risk genotype (
      • Cornelius C.
      • Fastbom J.
      • Winblad B.
      • Viitanen M.
      Aspirin, NSAIDs, risk of dementia, and influence of the apolipoprotein E epsilon 4 allele in an elderly population.
      ,
      • Hayden K.M.
      • Zandi P.P.
      • Khachaturian A.S.
      • Szekely C.A.
      • Fotuhi M.
      • Norton M.C.
      • Tschanz J.T.
      • Pieper C.F.
      • Corcoran C.
      • Lyketsos C.G.
      • et al.
      Does NSAID use modify cognitive trajectories in the elderly? The Cache County Study.
      ,
      • Szekely C.A.
      • Breitner J.C.
      • Fitzpatrick A.L.
      • Rea T.D.
      • Psaty B.M.
      • Kuller L.H.
      • Zandi P.P.
      NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type.
      ,
      • Yip A.G.
      • Green R.C.
      • Huyck M.
      • Cupples L.A.
      • Farrer L.A.
      • Group M.S.
      Nonsteroidal anti-inflammatory drug use and Alzheimer's disease risk: the MIRAGE study.
      ). These findings suggest that NSAIDs are protective against AD, but only before accumulation of the neuropathological changes associated with AD (
      • Breitner J.C.
      • Baker L.D.
      • Montine T.J.
      • Meinert C.L.
      • Lyketsos C.G.
      • Ashe K.H.
      • Brandt J.
      • Craft S.
      • Evans D.E.
      • Green R.C.
      • et al.
      Extended results of the Alzheimer's disease anti-inflammatory prevention trial.
      ). We have tested this hypothesis by treating APOE4 mice with the NSAID, ibuprofen. Ibuprofen rescues the effects of APOE4 genotype on reduced dendritic spine density and on the altered distribution of APOE in brain fractions (
      • DiBattista A.M.
      • Dumanis S.B.
      • Newman J.
      • Rebeck G.W.
      Identification and modification of amyloid-independent phenotypes of APOE4 mice.
      ). These effects of ibuprofen support the epidemiological data that NSAIDs may reduce AD risk factors in normal individuals.
      Yet another approach is to counteract the effects of APOE4 genotypes on the deficient APOE levels and reduced APOE4 lipidation. APOE and related molecules are regulated as part of the LXR/RXR transcriptional system, making that an attractive target for drug discovery (
      • Hong C.
      • Tontonoz P.
      Liver X receptors in lipid metabolism: opportunities for drug discovery.
      ). LXR activation promotes brain lipid efflux through induction of genes, such as APOE and ABCA1, and, in mouse models, leads to a decrease in lipids in synaptosomes (
      • Eckert G.P.
      • Vardanian L.
      • Rebeck G.W.
      • Burns M.P.
      Regulation of central nervous system cholesterol homeostasis by the liver X receptor agonist TO-901317.
      ). As mentioned above, reducing ABCA1 in genetic knock-out models decreases APOE and increases Aβ in mouse brain (
      • Hirsch-Reinshagen V.
      • Zhou S.
      • Burgess B.L.
      • Bernier L.
      • McIsaac S.A.
      • Chan J.Y.
      • Tansley G.H.
      • Cohn J.S.
      • Hayden M.R.
      • Wellington C.L.
      Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain.
      ,
      • Wahrle S.E.
      • Jiang H.
      • Parsadanian M.
      • Hartman R.E.
      • Bales K.R.
      • Paul S.M.
      • Holtzman D.M.
      Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease.
      ). LXR agonists increase APOE and ABCA1, reducing Aβ levels (
      • Riddell D.R.
      • Zhou H.
      • Atchison K.
      • Warwick H.K.
      • Atkinson P.J.
      • Jefferson J.
      • Xu L.
      • Aschmies S.
      • Kirksey Y.
      • Hu Y.
      • et al.
      Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels.
      ,
      • Donkin J.J.
      • Stukas S.
      • Hirsch-Reinshagen V.
      • Namjoshi D.
      • Wilkinson A.
      • May S.
      • Chan J.
      • Fan J.
      • Collins J.
      • Wellington C.L.
      ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice.
      ), improving behavior (
      • Donkin J.J.
      • Stukas S.
      • Hirsch-Reinshagen V.
      • Namjoshi D.
      • Wilkinson A.
      • May S.
      • Chan J.
      • Fan J.
      • Collins J.
      • Wellington C.L.
      ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice.
      ,
      • Fitz N.F.
      • Castranio E.L.
      • Carter A.Y.
      • Kodali R.
      • Lefterov I.
      • Koldamova R.
      Improvement of memory deficits and amyloid-β clearance in aged APP23 mice treated with a combination of anti-amyloid-β antibody and LXR agonist.
      ), and increasing synaptic plasticity (
      • Sandoval-Hernández A.G.
      • Buitrago L.
      • Moreno H.
      • Cardona-Gomez G.P.
      • Arboleda G.
      Role of liver X receptor in AD pathophysiology.
      ). An RXR agonist, bexarotene, reduces Aβ accumulation in a mouse model (
      • Cramer P.E.
      • Cirrito J.R.
      • Wesson D.W.
      • Lee C.Y.
      • Karlo J.C.
      • Zinn A.E.
      • Casali B.T.
      • Restivo J.L.
      • Goebel W.D.
      • James M.J.
      • et al.
      ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.
      ), dependent on the presence of both APOE and ABCA1 (
      • Corona A.W.
      • Kodoma N.
      • Casali B.T.
      • Landreth G.E.
      ABCA1 is necessary for bexarotene-mediated clearance of soluble amyloid beta from the hippocampus of APP/PS1 mice.
      ). Bexarotene also rescues the impaired APOE lipidation and reversed behavioral deficits in APOE4 mice (
      • Boehm-Cagan A.
      • Michaelson D.M.
      Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene.
      ). Finally, induction of ABCA1 activity could be a useful AD therapeutic approach: an agonist for ABCA1 reversed the effects of APOE4 on reduced lipoprotein lipidation, synaptic markers, and behavioral deficits (
      • Boehm-Cagan A.
      • Bar R.
      • Liraz O.
      • Bielicki J.K.
      • Johansson J.O.
      • Michaelson D.M.
      ABCA1 agonist reverses the apoE4-driven cognitive and brain pathologies.
      ). Specifically increasing the function of ABCA1 is a particularly interesting approach to altering APOE lipid metabolism, because it relies only on promoting lipid efflux through ABCA1, and not induction of the other genes of the LXR transcription system (
      • Hong C.
      • Tontonoz P.
      Liver X receptors in lipid metabolism: opportunities for drug discovery.
      ).

      CONCLUSIONS

      The unparalleled effect of APOE on AD risk in older individuals and its varied effects on the function of younger brains emphasize the need to study AD prevention strategies related to APOE. Studies on APOE in inflammation and lipid homeostasis are providing mechanisms for how brain alterations associated with APOE4 might be rescued (Fig. 1). The many people who have inherited this strong predisposition to AD have no treatments to help them avoid AD and, with increased access to genome sequencing, more of them are recognizing that they are at frighteningly high risk. This population of APOE4-positive individuals provides a logical target for in-depth studies of promising AD prevention approaches that are not necessarily related to the neuropathological accumulation of Aβ (
      • Sperling R.
      • Mormino E.
      • Johnson K.
      The evolution of preclinical Alzheimer's disease: implications for prevention trials.
      ). While prevention approaches to AD are difficult to evaluate, given the need to measure long-term effects, they provide hope if the approaches of treating individuals after the onset of AD pathogenesis are unsuccessful.
      Figure thumbnail gr1
      Fig. 1CNS APOE functions. CNS APOE (in blue) is secreted from glia. It is lipidated through interactions with ABCA1 on neurons and glia, forming high-density CNS lipoproteins (in yellow). These lipoproteins can deliver lipids to neurons to promote neuronal complexity. Compared with APOE3, APOE4 is less able to promote cholesterol efflux, forming smaller CNS lipoproteins, and less able to deliver lipids to neurons for neuroprotective functions. APOE lipoproteins also inhibit glial inflammation, with the smaller and fewer APOE4 lipoproteins less capable of this function. Chronic glial inflammation in the APOE4 brain contributes to neuronal dysfunction and impaired APOE regulation, but these APOE4 phenotypes can be mitigated through treatments with anti-inflammatory agents (NSAID).

      REFERENCES

        • Raber J.
        • Huang Y.
        • Ashford J.W.
        ApoE genotype accounts for the vast majority of AD risk and AD pathology.
        Neurobiol. Aging. 2004; 25: 641-650
        • Jansen W.J.
        • Ossenkoppele R.
        • Knol D.L.
        • Tijms B.M.
        • Scheltens P.
        • Verhey F.R.
        • Visser P.J.
        • Amyloid Biomarker Study Group
        • Aalten P.
        • Aarsland D.
        • et al.
        Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.
        JAMA. 2015; 313: 1924-1938
        • Liu C.C.
        • Kanekiyo T.
        • Xu H.
        • Bu G.
        Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy.
        Nat. Rev. Neurol. 2013; 9 ([Erratum. 2013. Nat. Rev. Neurol. 9: 184.]): 106-118
        • Malik M.
        • Parikh I.
        • Vasquez J.B.
        • Smith C.
        • Tai L.
        • Bu G.
        • LaDu M.J.
        • Fardo D.W.
        • Rebeck G.W.
        • Estus S.
        Genetics ignite focus on microglial inflammation in Alzheimer's disease.
        Mol. Neurodegener. 2015; 10: 52
        • Sullivan P.M.
        • Mezdour H.
        • Aratani Y.
        • Knouff C.
        • Najib J.
        • Reddick R.L.
        • Quarfordt S.H.
        • Maeda N.
        Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis.
        J. Biol. Chem. 1997; 272: 17972-17980
        • Zhu Y.
        • Nwabuisi-Heath E.
        • Dumanis S.B.
        • Tai L.M.
        • Yu C.
        • Rebeck G.W.
        • LaDu M.J.
        APOE genotype alters glial activation and loss of synaptic markers in mice.
        Glia. 2012; 60: 559-569
        • Rodriguez G.A.
        • Tai L.M.
        • LaDu M.J.
        • Rebeck G.W.
        Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition.
        J. Neuroinflammation. 2014; 11: 111
        • Mannix R.C.
        • Zhang J.
        • Park J.
        • Zhang X.
        • Bilal K.
        • Walker K.
        • Tanzi R.E.
        • Tesco G.
        • Whalen M.J.
        Age-dependent effect of apolipoprotein E4 on functional outcome after controlled cortical impact in mice.
        J. Cereb. Blood Flow Metab. 2011; 31: 351-361
        • Tu J.L.
        • Zhao C.B.
        • Vollmer T.
        • Coons S.
        • Lin H.J.
        • Marsh S.
        • Treiman D.M.
        • Shi J.
        APOE 4 polymorphism results in early cognitive deficits in an EAE model.
        Biochem. Biophys. Res. Commun. 2009; 384: 466-470
        • Lynch J.R.
        • Tang W.
        • Wang H.
        • Vitek M.P.
        • Bennett E.R.
        • Sullivan P.M.
        • Warner D.S.
        • Laskowitz D.T.
        APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response.
        J. Biol. Chem. 2003; 278: 48529-48533
        • Lynch J.R.
        • Wang H.
        • Mace B.
        • Leinenweber S.
        • Warner D.S.
        • Bennett E.R.
        • Vitek M.P.
        • McKenna S.
        • Laskowitz D.T.
        A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury.
        Exp. Neurol. 2005; 192: 109-116
        • James M.L.
        • Sullivan P.M.
        • Lascola C.D.
        • Vitek M.P.
        • Laskowitz D.T.
        Pharmacogenomic effects of apolipoprotein E on intracerebral hemorrhage.
        Stroke. 2009; 40: 632-639
        • Wang H.
        • Anderson L.G.
        • Lascola C.D.
        • James M.L.
        • Venkatraman T.N.
        • Bennett E.R.
        • Acheson S.K.
        • Vitek M.P.
        • Laskowitz D.T.
        Apolipoprotein E mimetic peptides improve outcome after focal ischemia.
        Exp. Neurol. 2013; 241: 67-74
        • Guo L.
        • LaDu M.J.
        • Van Eldik L.J.
        A dual role for apolipoprotein E in neuroinflammation: anti- and pro-inflammatory activity.
        J. Mol. Neurosci. 2004; 23: 205-212
        • Vitek M.P.
        • Brown C.M.
        • Colton C.A.
        APOE genotype-specific differences in the innate immune response.
        Neurobiol. Aging. 2009; 30: 1350-1360
        • Pocivavsek A.
        • Burns M.P.
        • Rebeck G.W.
        Low-density lipoprotein receptors regulate microglial inflammation through c-Jun N-terminal kinase.
        Glia. 2009; 57: 444-453
        • Pocivavsek A.
        • Mikhailenko I.
        • Strickland D.K.
        • Rebeck G.W.
        Microglial low-density lipoprotein receptor-related protein 1 modulates c-Jun N-terminal kinase activation.
        J. Neuroimmunol. 2009; 214: 25-32
        • Baitsch D.
        • Bock H.H.
        • Engel T.
        • Telgmann R.
        • Muller-Tidow C.
        • Varga G.
        • Bot M.
        • Herz J.
        • Robenek H.
        • von Eckardstein A.
        • et al.
        Apolipoprotein E induces antiinflammatory phenotype in macrophages.
        Arterioscler. Thromb. Vasc. Biol. 2011; 31: 1160-1168
        • Pocivavsek A.
        • Rebeck G.W.
        Inhibition of c-Jun N-terminal kinase increases apoE expression in vitro and in vivo.
        Biochem. Biophys. Res. Commun. 2009; 387: 516-520
        • Pitas R.E.
        • Boyles J.K.
        • Lee S.H.
        • Hui D.
        • Weisgraber K.H.
        Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E(LDL) receptors in the brain.
        J. Biol. Chem. 1987; 262: 14352-14360
        • Karch C.M.
        • Goate A.M.
        Alzheimer's disease risk genes and mechanisms of disease pathogenesis.
        Biol. Psychiatry. 2015; 77: 43-51
        • Harold D.
        • Abraham R.
        • Hollingworth P.
        • Sims R.
        • Gerrish A.
        • Hamshere M.L.
        • Pahwa J.S.
        • Moskvina V.
        • Dowzell K.
        • Williams A.
        • et al.
        Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.
        Nat. Genet. 2009; 41 ([Erratum. 2009. Nat. Genet. 41: 1156. Erratum. 2013. Nat. Genet. 45: 712.]): 1088-1093
        • Lambert J.C.
        • Heath S.
        • Even G.
        • Campion D.
        • Sleegers K.
        • Hiltunen M.
        • Combarros O.
        • Zelenika D.
        • Bullido M.J.
        • Tavernier B.
        • et al.
        Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.
        Nat. Genet. 2009; 41: 1094-1099
        • Jun G.
        • Naj A.C.
        • Beecham G.W.
        • Wang L.S.
        • Buros J.
        • Gallins P.J.
        • Buxbaum J.D.
        • Ertekin-Taner N.
        • Fallin M.D.
        • Friedland R.
        • et al.
        Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes.
        Arch. Neurol. 2010; 67: 1473-1484
        • Borghini I.
        • Barja F.
        • Pometta D.
        • James R.W.
        Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal fluid.
        Biochim. Biophys. Acta. 1995; 1255: 192-200
        • Rebeck G.W.
        • Alonzo N.C.
        • Berezovska O.
        • Harr S.D.
        • Knowles R.B.
        • Growdon J.H.
        • Hyman B.T.
        • Mendez A.J.
        Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different APOE genotypes.
        Exp. Neurol. 1998; 149: 175-182
        • White F.
        • Nicoll J.A.
        • Horsburgh K.
        Alterations in ApoE and ApoJ in relation to degeneration and regeneration in a mouse model of entorhinal cortex lesion.
        Exp. Neurol. 2001; 169: 307-318
        • Fagan A.M.
        • Murphy B.A.
        • Patel S.N.
        • Kilbridge J.F.
        • Mobley W.C.
        • Bu G.
        • Holtzman D.M.
        Evidence for normal aging of the septo-hippocampal cholinergic system in apoE (−/−) mice but impaired clearance of axonal degeneration products following injury.
        Exp. Neurol. 1998; 151: 314-325
        • Koldamova R.
        • Fitz N.F.
        • Lefterov I.
        ATP-binding cassette transporter A1: from metabolism to neurodegeneration.
        Neurobiol. Dis. 2014; 72 Pt. A: 13-21
        • Hirsch-Reinshagen V.
        • Zhou S.
        • Burgess B.L.
        • Bernier L.
        • McIsaac S.A.
        • Chan J.Y.
        • Tansley G.H.
        • Cohn J.S.
        • Hayden M.R.
        • Wellington C.L.
        Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain.
        J. Biol. Chem. 2004; 279: 41197-41207
        • Wahrle S.E.
        • Jiang H.
        • Parsadanian M.
        • Hartman R.E.
        • Bales K.R.
        • Paul S.M.
        • Holtzman D.M.
        Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease.
        J. Biol. Chem. 2005; 280: 43236-43242
        • Michikawa M.
        • Fan Q.W.
        • Isobe I.
        • Yanagisawa K.
        Apolipoprotein E exhibits isoform-specific promotion of lipid efflux from astrocytes and neurons in culture.
        J. Neurochem. 2000; 74: 1008-1016
        • Minagawa H.
        • Gong J.S.
        • Jung C.G.
        • Watanabe A.
        • Lund-Katz S.
        • Phillips M.C.
        • Saito H.
        • Michikawa M.
        Mechanism underlying apolipoprotein E (ApoE) isoform-dependent lipid efflux from neural cells in culture.
        J. Neurosci. Res. 2009; 87: 2498-2508
        • Boehm-Cagan A.
        • Michaelson D.M.
        Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene.
        J. Neurosci. 2014; 34: 7293-7301
        • Boehm-Cagan A.
        • Bar R.
        • Liraz O.
        • Bielicki J.K.
        • Johansson J.O.
        • Michaelson D.M.
        ABCA1 agonist reverses the apoE4-driven cognitive and brain pathologies.
        J. Alzheimers Dis. 2016; 54: 1219-1233
        • Hu J.
        • Liu C.C.
        • Chen X.F.
        • Zhang Y.W.
        • Xu H.
        • Bu G.
        Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice.
        Mol. Neurodegener. 2015; 10: 6
        • Dodart J.C.
        • Marr R.A.
        • Koistinaho M.
        • Gregersen B.M.
        • Malkani S.
        • Verma I.M.
        • Paul S.M.
        Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease.
        Proc. Natl. Acad. Sci. USA. 2005; 102: 1211-1216
        • Heinsinger N.M.
        • Gachechiladze M.A.
        • Rebeck G.W.
        Apolipoprotein E genotype affects size of apoE complexes in cerebrospinal fluid.
        J. Neuropathol. Exp. Neurol. 2016; 75: 918-924
        • Yassine H.N.
        • Feng Q.
        • Chiang J.
        • Petrosspour L.M.
        • Fonteh A.N.
        • Chui H.C.
        • Harrington M.G.
        ABCA1-mediated cholesterol efflux capacity to cerebrospinal fluid is reduced in patients with mild cognitive impairment and Alzheimer's disease.
        J. Am. Heart Assoc. 2016; 5: e002886
        • Hanson A.J.
        • Bayer-Carter J.L.
        • Green P.S.
        • Montine T.J.
        • Wilkinson C.W.
        • Baker L.D.
        • Watson G.S.
        • Bonner L.M.
        • Callaghan M.
        • Leverenz J.B.
        • et al.
        Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides: randomized clinical trial.
        JAMA Neurol. 2013; 70: 972-980
        • Harris-White M.E.
        • Frautschy S.A.
        Low density lipoprotein receptor-related proteins (LRPs), Alzheimer's and cognition.
        Curr. Drug Targets CNS Neurol. Disord. 2005; 4: 469-480
        • Nathan B.P.
        • Bellosta S.
        • Sanan D.A.
        • Weisgraber K.H.
        • Mahley R.W.
        • Pitas R.E.
        Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro.
        Science. 1994; 264: 850-852
        • Teter B.
        • Xu P.T.
        • Gilbert J.R.
        • Roses A.D.
        • Galasko D.
        • Cole G.M.
        Human apolipoprotein E isoform-specific differences in neuronal sprouting in organotypic hippocampal culture.
        J. Neurochem. 1999; 73: 2613-2616
        • Mauch D.H.
        • Nagler K.
        • Schumacher S.
        • Goritz C.
        • Muller E.C.
        • Otto A.
        • Pfrieger F.W.
        CNS synaptogenesis promoted by glia-derived cholesterol.
        Science. 2001; 294: 1354-1357
        • Yeh F.L.
        • Wang Y.
        • Tom I.
        • Gonzalez L.C.
        • Sheng M.
        TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia.
        Neuron. 2016; 91: 328-340
        • Atagi Y.
        • Liu C.C.
        • Painter M.M.
        • Chen X.F.
        • Verbeeck C.
        • Zheng H.
        • Li X.
        • Rademakers R.
        • Kang S.S.
        • Xu H.
        • et al.
        Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2).
        J. Biol. Chem. 2015; 290: 26043-26050
        • Jonsson T.
        • Stefansson H.
        • Steinberg S.
        • Jonsdottir I.
        • Jonsson P.V.
        • Snaedal J.
        • Bjornsson S.
        • Huttenlocher J.
        • Levey A.I.
        • Lah J.J.
        • et al.
        Variant of TREM2 associated with the risk of Alzheimer's disease.
        N. Engl. J. Med. 2013; 368: 107-116
        • Mulder S.D.
        • Nielsen H.M.
        • Blankenstein M.A.
        • Eikelenboom P.
        • Veerhuis R.
        Apolipoproteins E and J interfere with amyloid-beta uptake by primary human astrocytes and microglia in vitro.
        Glia. 2014; 62: 493-503
        • Cole G.M.
        • Beech W.
        • Frautschy S.A.
        • Sigel J.
        • Glasgow C.
        • Ard M.D.
        Lipoprotein effects on Abeta accumulation and degradation by microglia in vitro.
        J. Neurosci. Res. 1999; 57: 504-520
        • Bell R.D.
        • Sagare A.P.
        • Friedman A.E.
        • Bedi G.S.
        • Holtzman D.M.
        • Deane R.
        • Zlokovic B.V.
        Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system.
        J. Cereb. Blood Flow Metab. 2007; 27: 909-918
        • Ignatius M.J.
        • Gebicke-Harter P.J.
        • Skene J.H.
        • Schilling J.W.
        • Weisgraber K.H.
        • Mahley R.W.
        • Shooter E.M.
        Expression of apolipoprotein E during nerve degeneration and regeneration.
        Proc. Natl. Acad. Sci. USA. 1986; 83: 1125-1129
        • Washington P.M.
        • Burns M.P.
        The effect of the APOE4 gene on accumulation of Aβ40 after brain injury cannot be reversed by increasing apoE4 protein.
        J. Neuropathol. Exp. Neurol. 2016; (Epub ahead of print. June 12, doi:10.1093/jnen/nlw049)
        • Arendt T.
        • Schindler C.
        • Bruckner M.K.
        • Eschrich K.
        • Bigl V.
        • Zedlick D.
        • Marcova L.
        Plastic neuronal remodeling is impaired in patients with Alzheimer's disease carrying apolipoprotein epsilon 4 allele.
        J. Neurosci. 1997; 17: 516-529
        • Ringheim G.E.
        • Szczepanik A.M.
        Brain inflammation, cholesterol, and glutamate as interconnected participants in the pathology of Alzheimer's disease.
        Curr. Pharm. Des. 2006; 12: 719-738
        • Courtney R.
        • Landreth G.E.
        LXR regulation of brain cholesterol: from development to disease.
        Trends Endocrinol. Metab. 2016; 27: 404-414
        • Castellano J.M.
        • Kim J.
        • Stewart F.R.
        • Jiang H.
        • DeMattos R.B.
        • Patterson B.W.
        • Fagan A.M.
        • Morris J.C.
        • Mawuenyega K.G.
        • Cruchaga C.
        • et al.
        Human apoE isoforms differentially regulate brain amyloid-β peptide clearance.
        Sci. Transl. Med. 2011; 3: 89ra57
        • Cruchaga C.
        • Kauwe J.S.
        • Nowotny P.
        • Bales K.
        • Pickering E.H.
        • Mayo K.
        • Bertelsen S.
        • Hinrichs A.
        • Alzheimer's Disease Neuroimaging Initiative
        • Fagan A.M.
        • et al.
        Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease.
        Hum. Mol. Genet. 2012; 21: 4558-4571
        • Sullivan P.M.
        • Han B.
        • Liu F.
        • Mace B.E.
        • Ervin J.F.
        • Wu S.
        • Koger D.
        • Paul S.
        • Bales K.R.
        Reduced levels of human apoE4 protein in an animal model of cognitive impairment.
        Neurobiol. Aging. 2011; 32: 791-801
        • Riddell D.R.
        • Zhou H.
        • Atchison K.
        • Warwick H.K.
        • Atkinson P.J.
        • Jefferson J.
        • Xu L.
        • Aschmies S.
        • Kirksey Y.
        • Hu Y.
        • et al.
        Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels.
        J. Neurosci. 2008; 28: 11445-11453
        • Harris F.M.
        • Brecht W.J.
        • Xu Q.
        • Tesseur I.
        • Kekonius L.
        • Wyss-Coray T.
        • Fish J.D.
        • Masliah E.
        • Hopkins P.C.
        • Scearce-Levie K.
        • et al.
        Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice.
        Proc. Natl. Acad. Sci. USA. 2003; 100: 10966-10971
        • Bien-Ly N.
        • Andrews-Zwilling Y.
        • Xu Q.
        • Bernardo A.
        • Wang C.
        • Huang Y.
        C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-beta (Abeta) and acts in concert with Abeta to elicit neuronal and behavioral deficits in mice.
        Proc. Natl. Acad. Sci. USA. 2011; 108: 4236-4241
        • Brecht W.J.
        • Harris F.M.
        • Chang S.
        • Tesseur I.
        • Yu G.Q.
        • Xu Q.
        • Dee Fish J.
        • Wyss-Coray T.
        • Buttini M.
        • Mucke L.
        • et al.
        Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice.
        J. Neurosci. 2004; 24: 2527-2534
        • Huang Y.
        • Liu X.Q.
        • Wyss-Coray T.
        • Brecht W.J.
        • Sanan D.A.
        • Mahley R.W.
        Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons.
        Proc. Natl. Acad. Sci. USA. 2001; 98: 8838-8843
        • Wernette-Hammond M.E.
        • Lauer S.J.
        • Corsini A.
        • Walker D.
        • Taylor J.M.
        • Rall Jr, S.C.
        Glycosylation of human apolipoprotein E. The carbohydrate attachment site is threonine 194.
        J. Biol. Chem. 1989; 264: 9094-9101
        • DiBattista A.M.
        • Dumanis S.B.
        • Newman J.
        • Rebeck G.W.
        Identification and modification of amyloid-independent phenotypes of APOE4 mice.
        Exp. Neurol. 2016; 280: 97-105
        • Tolar M.
        • Keller J.N.
        • Chan S.
        • Mattson M.P.
        • Marques M.A.
        • Crutcher K.A.
        Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity.
        J. Neurosci. 1999; 19: 7100-7110
        • Teter B.
        • Xu P.T.
        • Gilbert J.R.
        • Roses A.D.
        • Galasko D.
        • Cole G.M.
        Defective neuronal sprouting by human apolipoprotein E4 is a gain-of-negative function.
        J. Neurosci. Res. 2002; 68: 331-336
        • Rodriguez G.A.
        • Burns M.P.
        • Weeber E.J.
        • Rebeck G.W.
        Young APOE4 targeted replacement mice exhibit poor spatial learning and memory, with reduced dendritic spine density in the medial entorhinal cortex.
        Learn. Mem. 2013; 20: 256-266
        • Bour A.
        • Grootendorst J.
        • Vogel E.
        • Kelche C.
        • Dodart J.C.
        • Bales K.
        • Moreau P.H.
        • Sullivan P.M.
        • Mathis C.
        Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks.
        Behav. Brain Res. 2008; 193: 174-182
        • Grootendorst J.
        • Bour A.
        • Vogel E.
        • Kelche C.
        • Sullivan P.M.
        • Dodart J.C.
        • Bales K.
        • Mathis C.
        Human apoE targeted replacement mouse lines: h-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior.
        Behav. Brain Res. 2005; 159: 1-14
        • Knoferle J.
        • Yoon S.Y.
        • Walker D.
        • Leung L.
        • Gillespie A.K.
        • Tong L.M.
        • Bien-Ly N.
        • Huang Y.
        Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice.
        J. Neurosci. 2014; 34: 14069-14078
        • Dumanis S.B.
        • Tesoriero J.A.
        • Babus L.W.
        • Nguyen M.T.
        • Trotter J.H.
        • Ladu M.J.
        • Weeber E.J.
        • Turner R.S.
        • Xu B.
        • Rebeck G.W.
        • et al.
        ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo.
        J. Neurosci. 2009; 29: 15317-15322
        • Wang C.
        • Wilson W.A.
        • Moore S.D.
        • Mace B.E.
        • Maeda N.
        • Schmechel D.E.
        • Sullivan P.M.
        Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology.
        Neurobiol. Dis. 2005; 18: 390-398
        • Gillespie A.K.
        • Jones E.A.
        • Lin Y.H.
        • Karlsson M.P.
        • Kay K.
        • Yoon S.Y.
        • Tong L.M.
        • Nova P.
        • Carr J.S.
        • Frank L.M.
        • et al.
        Apolipoprotein E4 causes age-dependent disruption of slow gamma oscillations during hippocampal sharp-wave ripples.
        Neuron. 2016; 90: 740-751
        • Leung L.
        • Andrews-Zwilling Y.
        • Yoon S.Y.
        • Jain S.
        • Ring K.
        • Dai J.
        • Wang M.M.
        • Tong L.
        • Walker D.
        • Huang Y.
        Apolipoprotein E4 causes age- and sex-dependent impairments of hilar GABAergic interneurons and learning and memory deficits in mice.
        PLoS One. 2012; 7: e53569
        • Klein R.C.
        • Acheson S.K.
        • Mace B.E.
        • Sullivan P.M.
        • Moore S.D.
        Altered neurotransmission in the lateral amygdala in aged human apoE4 targeted replacement mice.
        Neurobiol. Aging. 2014; 35: 2046-2052
        • Klein R.C.
        • Mace B.E.
        • Moore S.D.
        • Sullivan P.M.
        Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2.
        Neuroscience. 2010; 171: 1265-1272
        • Dolejší E.
        • Liraz O.
        • Rudajev V.
        • Zimcik P.
        • Dolezal V.
        • Michaelson D.M.
        Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice.
        J. Neurochem. 2016; 136: 503-509
        • Ji Y.
        • Gong Y.
        • Gan W.
        • Beach T.
        • Holtzman D.M.
        • Wisniewski T.
        Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients.
        Neuroscience. 2003; 122: 305-315
        • Dumanis S.B.
        • DiBattista A.M.
        • Miessau M.
        • Moussa C.E.
        • Rebeck G.W.
        APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals.
        J. Neurochem. 2013; 124: 4-14
        • Gilat-Frenkel M.
        • Boehm-Cagan A.
        • Liraz O.
        • Xian X.
        • Herz J.
        • Michaelson D.M.
        Involvement of the Apoer2 and Lrp1 receptors in mediating the pathological effects of ApoE4 in vivo.
        Curr. Alzheimer Res. 2014; 11: 549-557
        • Caselli R.J.
        • Reiman E.M.
        • Osborne D.
        • Hentz J.G.
        • Baxter L.C.
        • Hernandez J.L.
        • Alexander G.G.
        Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele.
        Neurology. 2004; 62: 1990-1995
        • Acevedo S.F.
        • Piper B.J.
        • Craytor M.J.
        • Benice T.S.
        • Raber J.
        Apolipoprotein E4 and sex affect neurobehavioral performance in primary school children.
        Pediatr. Res. 2010; 67: 293-299
        • Filippini N.
        • Rao A.
        • Wetten S.
        • Gibson R.A.
        • Borrie M.
        • Guzman D.
        • Kertesz A.
        • Loy-English I.
        • Williams J.
        • Nichols T.
        • et al.
        Anatomically-distinct genetic associations of APOE epsilon4 allele load with regional cortical atrophy in Alzheimer's disease.
        Neuroimage. 2009; 44: 724-728
        • Rusted J.M.
        • Evans S.L.
        • King S.L.
        • Dowell N.
        • Tabet N.
        • Tofts P.S.
        APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures.
        Neuroimage. 2013; 65: 364-373
        • Green A.E.
        • Gray J.R.
        • Deyoung C.G.
        • Mhyre T.R.
        • Padilla R.
        • Dibattista A.M.
        • William Rebeck G.
        A combined effect of two Alzheimer's risk genes on medial temporal activity during executive attention in young adults.
        Neuropsychologia. 2014; 56: 1-8
        • Borghesani P.R.
        • Johnson L.C.
        • Shelton A.L.
        • Peskind E.R.
        • Aylward E.H.
        • Schellenberg G.D.
        • Cherrier M.M.
        Altered medial temporal lobe responses during visuospatial encoding in healthy APOE*4 carriers.
        Neurobiol. Aging. 2008; 29: 981-991
        • Kunz L.
        • Schroder T.N.
        • Lee H.
        • Montag C.
        • Lachmann B.
        • Sariyska R.
        • Reuter M.
        • Stirnberg R.
        • Stocker T.
        • Messing-Floeter P.C.
        • et al.
        Reduced grid-cell-like representations in adults at genetic risk for Alzheimer's disease.
        Science. 2015; 350: 430-433
        • Dean III, D.C.
        • Jerskey B.A.
        • Chen K.
        • Protas H.
        • Thiyyagura P.
        • Roontiva A.
        • O'Muircheartaigh J.
        • Dirks H.
        • Waskiewicz N.
        • Lehman K.
        • et al.
        Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study.
        JAMA Neurol. 2014; 71: 11-22
        • Knickmeyer R.C.
        • Wang J.
        • Zhu H.
        • Geng X.
        • Woolson S.
        • Hamer R.M.
        • Konneker T.
        • Lin W.
        • Styner M.
        • Gilmore J.H.
        Common variants in psychiatric risk genes predict brain structure at birth.
        Cereb. Cortex. 2014; 24: 1230-1246
        • Di Battista A.M.
        • Heinsinger N.M.
        • Rebeck G.W.
        Alzheimer's disease genetic risk factor APOE-ε4 also affects normal brain function.
        Curr. Alzheimer Res. 2016; 13: 1200-1207
        • Matura S.
        • Prvulovic D.
        • Jurcoane A.
        • Hartmann D.
        • Miller J.
        • Scheibe M.
        • O'Dwyer L.
        • Oertel-Knochel V.
        • Knochel C.
        • Reinke B.
        • et al.
        Differential effects of the ApoE4 genotype on brain structure and function.
        Neuroimage. 2014; 89: 81-91
        • O'Dwyer L.
        • Lamberton F.
        • Matura S.
        • Tanner C.
        • Scheibe M.
        • Miller J.
        • Rujescu D.
        • Prvulovic D.
        • Hampel H.
        Reduced hippocampal volume in healthy young ApoE4 carriers: an MRI study.
        PLoS One. 2012; 7: e48895
        • Stevens B.W.
        • DiBattista A.M.
        • William Rebeck G.
        • Green A.E.
        A gene-brain-cognition pathway for the effect of an Alzheimers risk gene on working memory in young adults.
        Neuropsychologia. 2014; 61: 143-149
        • Han S.D.
        • Bondi M.W.
        Revision of the apolipoprotein E compensatory mechanism recruitment hypothesis.
        Alzheimers Dement. 2008; 4: 251-254
        • Laskowitz D.T.
        • Vitek M.P.
        Apolipoprotein E and neurological disease: therapeutic potential and pharmacogenomic interactions.
        Pharmacogenomics. 2007; 8: 959-969
        • Cornelius C.
        • Fastbom J.
        • Winblad B.
        • Viitanen M.
        Aspirin, NSAIDs, risk of dementia, and influence of the apolipoprotein E epsilon 4 allele in an elderly population.
        Neuroepidemiology. 2004; 23: 135-143
        • Lindsay J.
        • Laurin D.
        • Verreault R.
        • Hebert R.
        • Helliwell B.
        • Hill G.B.
        • McDowell I.
        Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging.
        Am. J. Epidemiol. 2002; 156: 445-453
        • Stewart W.F.
        • Kawas C.
        • Corrada M.
        • Metter E.J.
        Risk of Alzheimer's disease and duration of NSAID use.
        Neurology. 1997; 48: 626-632
        • Zandi P.P.
        • Anthony J.C.
        • Hayden K.M.
        • Mehta K.
        • Mayer L.
        • Breitner J.C.
        • Cache County Study Investigators
        Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study.
        Neurology. 2002; 59: 880-886
        • in't Veld B.A.
        • Ruitenberg A.
        • Hofman A.
        • Stricker B.H.
        • Breteler M.M.
        Antihypertensive drugs and incidence of dementia: the Rotterdam Study.
        Neurobiol. Aging. 2001; 22: 407-412
        • Pasqualetti P.
        • Bonomini C.
        • Dal Forno G.
        • Paulon L.
        • Sinforiani E.
        • Marra C.
        • Zanetti O.
        • Rossini P.M.
        A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer's disease.
        Aging Clin. Exp. Res. 2009; 21: 102-110
        • Breitner J.C.
        • Baker L.D.
        • Montine T.J.
        • Meinert C.L.
        • Lyketsos C.G.
        • Ashe K.H.
        • Brandt J.
        • Craft S.
        • Evans D.E.
        • Green R.C.
        • et al.
        Extended results of the Alzheimer's disease anti-inflammatory prevention trial.
        Alzheimers Dement. 2011; 7: 402-411
        • Hayden K.M.
        • Zandi P.P.
        • Khachaturian A.S.
        • Szekely C.A.
        • Fotuhi M.
        • Norton M.C.
        • Tschanz J.T.
        • Pieper C.F.
        • Corcoran C.
        • Lyketsos C.G.
        • et al.
        Does NSAID use modify cognitive trajectories in the elderly? The Cache County Study.
        Neurology. 2007; 69: 275-282
        • Szekely C.A.
        • Breitner J.C.
        • Fitzpatrick A.L.
        • Rea T.D.
        • Psaty B.M.
        • Kuller L.H.
        • Zandi P.P.
        NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type.
        Neurology. 2008; 70: 17-24
        • Yip A.G.
        • Green R.C.
        • Huyck M.
        • Cupples L.A.
        • Farrer L.A.
        • Group M.S.
        Nonsteroidal anti-inflammatory drug use and Alzheimer's disease risk: the MIRAGE study.
        BMC Geriatr. 2005; 5: 2
        • Hong C.
        • Tontonoz P.
        Liver X receptors in lipid metabolism: opportunities for drug discovery.
        Nat. Rev. Drug Discov. 2014; 13: 433-444
        • Eckert G.P.
        • Vardanian L.
        • Rebeck G.W.
        • Burns M.P.
        Regulation of central nervous system cholesterol homeostasis by the liver X receptor agonist TO-901317.
        Neurosci. Lett. 2007; 423: 47-52
        • Donkin J.J.
        • Stukas S.
        • Hirsch-Reinshagen V.
        • Namjoshi D.
        • Wilkinson A.
        • May S.
        • Chan J.
        • Fan J.
        • Collins J.
        • Wellington C.L.
        ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice.
        J. Biol. Chem. 2010; 285: 34144-34154
        • Fitz N.F.
        • Castranio E.L.
        • Carter A.Y.
        • Kodali R.
        • Lefterov I.
        • Koldamova R.
        Improvement of memory deficits and amyloid-β clearance in aged APP23 mice treated with a combination of anti-amyloid-β antibody and LXR agonist.
        J. Alzheimers Dis. 2014; 41: 535-549
        • Sandoval-Hernández A.G.
        • Buitrago L.
        • Moreno H.
        • Cardona-Gomez G.P.
        • Arboleda G.
        Role of liver X receptor in AD pathophysiology.
        PLoS One. 2015; 10: e0145467
        • Cramer P.E.
        • Cirrito J.R.
        • Wesson D.W.
        • Lee C.Y.
        • Karlo J.C.
        • Zinn A.E.
        • Casali B.T.
        • Restivo J.L.
        • Goebel W.D.
        • James M.J.
        • et al.
        ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.
        Science. 2012; 335: 1503-1506
        • Corona A.W.
        • Kodoma N.
        • Casali B.T.
        • Landreth G.E.
        ABCA1 is necessary for bexarotene-mediated clearance of soluble amyloid beta from the hippocampus of APP/PS1 mice.
        J. Neuroimmune Pharmacol. 2016; 11: 61-72
        • Sperling R.
        • Mormino E.
        • Johnson K.
        The evolution of preclinical Alzheimer's disease: implications for prevention trials.
        Neuron. 2014; 84: 608-622