Abstract
There is now a large body of evidence suggesting that apolipoprotein E (apoE) genotype is the single most important genetic risk factor for the most common (sporadic) form of Alzheimer’s disease. Yet in proportion to the total number of investigations in this field, relatively few groups are studying the contribution of this cholesterol-binding protein to disease risk and severity. Of those that are, a major focus is on the impact of apoE on amyloid-related mechanisms of disease. I argue here that apoE should be considered a major culprit in its own right, not simply in a supporting role. The argument is based on several lines of evidence, including the fact that apoE is associated with both plaques and tangles, the overwhelming evidence for genetic risk of the disease attributed to apoE, increasing evidence that apoE might also modify risk of other nonamyloidogenic neurological diseases, neurotoxicity attributed to apoE and/or proteolytic fragments of apoE, negative consequences of transgenic expression of apoE4 in mice, and genetic evidence for polymorphisms that increase both apoE expression and disease risk, regardless of isoform.
Similar content being viewed by others
References
Aizawa Y., Fukatsu R., Takamaru Y., Tsuzuki K., Chiba H., Kobayashi K., et al. (1997) Amino-terminus truncated apolipoprotein E is the major species in amyloid deposits in Alzheimer’s disease-affected brains: a possible role for apolipoprotein E in Alzheimer’s disease. Brain Res. 768, 208–214.
Artiga M. J., Bullido M. J., Frank A., Sastre I., Recuero M., Garcia M. A., et al. (1998) Risk for Alzheimer’s disease correlates with transcriptional activity of the APOE gene. Hum. Mol. Genet. 7, 1887–1892.
Artiga M. J., Bullido M. J., Sastre I., Recuero M., Garcia M. A., Aldudo J., et al. (1998) Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. FEBS Lett. 421, 105–108.
Ashford J. W. and Mortimer J. A. (2002) Non-familial Alzheimer’s disease is mainly due to genetic factors. J. Alzheimers Dis. 4, 169–177.
Bales K. R., Verina T., Cummins D. J., Du Y., Dodel R. C., Saura J., et al. (1999) Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 96, 15233–15238.
Bales K. R., Verina T., Dodel R. C., Du Y., Altstiel L., Bender M., et al. (1997) Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat. Genet. 17, 263–264.
Becker K. G. (2001) APOE genotype is a major predictor of long-term progression of disability in MS. Neurology 57, 2148,2149.
Bedlack R. S., Edelman D., Gibbs J. W. III, Kelling D., Strittmatter W., Saunders A. M., and Morgenlander J. (2003) APOE genotype is a risk factor for neuropathy severity in diabetic patients. Neurology 60, 1022–1024.
Bedlack R. S., Strittmatter W. J., and Morgenlander J. C. (2000) Apolipoprotein E and neuromuscular disease: a critical review of the literature. Arch. Neurol. 57, 1561–1565.
Bellosta S., Nathan B. P., Orth M., Dong L. M., Mahley R. W., and Pitas R.E. (1995) Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth. J. Biol. Chem. 270, 27063–27071.
Boyles J. K., Pitas R. E., Wilson E., Mahley R. W., and Taylor J. M. (1985) Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J. Clin. Invest. 76, 1501–1513.
Boyles J. K., Zoellner C. D., Anderson L. J., Kosik L. M., Pitas R. E., Weisgraber K. H., et al. (1989) A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J. Clin. Invest. 83, 1015–1031.
Bullido M. J. and Valdivieso F. (2000) Apolipoprotein E gene promoter polymorphisms in Alzheimer’s disease. Microsc. Res. Tech. 50, 261–267.
Buttini M., Akeefe H., Lin C., Mahley R. W., Pitas R. E., Wyss-Coray T., and Mucke L. (2000) Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease. Neuroscience 97, 207–210.
Cambon K., Davies H. A., and Stewart M. G. (2000) Synaptic loss is accompanied by an increase in synaptic area in the dentate gyrus of aged human apolipoprotein E4 transgenic mice. Neuroscience 97, 685–692.
Cedazo-Minguez A., Huttinger M., and Cowburn R. F. (2001) Beta-VLDL protects against A beta(1–42) and apoE toxicity in human SH-SY5Y neuroblastoma cells. Neuroreport 12, 201–206.
Chapman J., Vinokurov S., Achiron A., Karussis D. M., Mitosek-Szewczyk K., Birnbaum M., et al. (2001) APOE genotype is a major predictor of long-term progression of disability in MS. Neurology 56, 312–316.
Cho H. S., Hyman B. T., Greenberg S. M., and Rebeck G. W. (2001) Quantitation of apoE domains in Alzheimer disease brain suggests a role for apoE in Abeta aggregation. J. Neuropathol. Exp. Neurol. 60, 342–349.
Citron M. (2000) Secretases as targets for the treatment of Alzheimer’s disease. Mol. Med. Today 6, 392–397.
Corder E. H., Robertson K., Lannfelt L., Bogdanovic N., Eggertsen G., Wilkins J., and Hall C. (1998) HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat. Med. 4, 1182–1184.
Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923.
Crawford F. C., Vanderploeg R. D., Freeman M. J., Singh S., Waisman M., Michaels L., et al. (2002) APOE genotype influences acquisition and recall following traumatic brain injury. Neurology 58, 1115–1118.
Crutcher K. A., Clay M. A., Scott S. A., Tian X., Tolar M., and Harmony J. A. K. (1994) Neurite degeneration elicited by apolipoprotein E peptides. Exp. Neurol. 130, 120–126.
de Chaves E. I., Rusinol A. E., Vance D. E., Campenot R. B., and Vance J. E. (1997) Role of lipoproteins in the delivery of lipids to axons during axonal regeneration. J. Biol. Chem. 272, 30766–30773.
DeMattos R. B., Thorngate F. E., and Williams D. L. (1999) A test of the cytosolic apolipoprotein E hypothesis fails to detect the escape of apolipoprotein E from the endocytic pathway into the cytosol and shows that direct expression of apolipoprotein E in the cytosol is cytotoxic. J. Neurosci. 19, 2464–2473.
Drory V. E., Birnbaum M., Korczyn A. D., and Chapman J. (2001) Association of APOE epsilon4 allele with survival in amyotrophic lateral sclerosis. J. Neurol. Sci. 190, 17–20.
Fazekas F., Strasser-Fuchs S., Kollegger H., Berger T., Kristoferitsch W., Schmidt H., et al. (2001) Apolipoprotein E epsilon4 is associated with rapid progression of multiple sclerosis. Neurology 57, 853–857.
Friedman G., Froom P., Sazbon L., Grinblatt I., Shochina M., Tsenter J., et al. (1999) Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology 52, 244–248.
Genden E. M., Watanabe O., Mackinnon S. E., Hunter D. A., and Strasberg S. R. (2002) Peripheral nerve regeneration in the apolipoprotein-E-deficient mouse. J. Reconstr. Microsurg. 18, 495–502.
Goodrum J. F., Bouldin T. W., Zhang S. H., Maeda N., and Popko B. (1995) Nerve regeneration and cholesterol reutilization occur in the absence of apolipoproteins E and A-I in mice. J. Neurochem. 64, 408–416.
Han S. H., Hulette C., Saunders A. M., Einstein G., Pericak V. M., Strittmatter W. J., et al. (1994) Apolipoprotein E is present in hippocampal neurons without neurofibrillary tangles in Alzheimer’s disease and in age-matched controls. Exp. Neurol. 128, 13–26.
Harris F. M., Brecht W. J., Xu, Q., Tesseur I., Wekonius L., Fish J. D., et al. (2003) Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc. Natl. Acad. Sci. 100, 10966–10971.
Hartman R. E., Wozniak D. F., Nardi A., Olney J. W., Sartorius L., and Holtzman D. M. (2001) Behavioral phenotyping of GFAP-apoE3 and -apoE4 transgenic mice: apoE4 mice show profound working memory impairments in the absence of Alzheimer’s-like neuropathology. Exp. Neurol. 170, 326–344.
Hashimoto Y., Jiang H., Niikura T., Ito Y., Hagiwara A., Umezawa K., et al. (2000) Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases. J. Neurosci. 20, 8401–8409.
Hogh P., Oturai A., Schreiber K., Blinkenberg M., Jorgensen O. S., Ryder L., et al. (2000) Apoliprotein E and multiple sclerosis: impact of the epsilon-4 allele on susceptibility, clinical type and progression rate. Mult. Scler. 6, 226–230.
Holtzman D. M., Bales K. R., Tenkova T., Fagan A. M., Parsadanian M., Sartorius L. J., et al. (2000a) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 97, 2892–2897.
Holtzman D. M., Fagan A. M., Mackey B., Tenkova T., Sartorius L., Paul S. M., et al. (2000b) Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann. Neurol. 47, 739–747.
Huang Y., Liu X. Q., Wyss-Coray T., Brecht W. J., Sanan D. A., and Mahley R. W. (2001) Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc. Natl. Acad. Sci. USA 98, 8838–8843.
Ignatius M. J., Gebicke H. P., Skene J. H., Schilling J. W., Weisgraber K. H., Mahley R. W., and Shooter E. M. (1986) Expression of apolipoprotein E during nerve degeneration and regeneration. Proc. Natl. Acad. Sci. USA 83, 1125–1129.
Irizarry M. C., Cheung B. S., Rebeck G. W., Paul S. M., Bales K. R., and Hyman B. T. (2000) Apolipoprotein E affects the amount, form, and anatomical distribution of amyloid beta-peptide deposition in homozygous APP(V717F) transgenic mice. Acta Neuropathol. (Berl.) 100, 451–458.
Jordan B. D., Relkin N. R., Ravdin L. D., Jacobs A. R., Bennett A., and Gandy S. (1997) Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA 278, 136–140.
Jordan J., Galindo M. F., Miller R. J., Reardon C. A., Getz G. S., and LaDu M. J. (1998) Isoform-specific effect of apolipoprotein E on cell survival and beta-amyloid-induced toxicity in rat hippocampal pyramidal neuronal cultures. J. Neurosci. 18, 195–204.
Kokubo Y., Chowdhury A. H., Date C., Yokoyama T., Sobue H., and Tanaka H. (2000) Age-dependent association of apolipoprotein E genotypes with stroke subtypes in a Japanese rural population. Stroke 31, 1299–1306.
Lacomblez L., Doppler V., Beucler I., Costes G., Salachas F., Raisonnier A., et al. (2002) APOE: a potential marker of disease progression in ALS. Neurology 58, 1112–1114.
LaDu M. J., Falduto M. T., Manelli A. M., Reardon C. A., Getz G. S., and Frail D. E. (1994) Isoform-specific binding of apolipoprotein E to beta-amyloid. J. Biol. Chem. 269, 23403–23406.
Laffont I., Takahashi M., Shibukawa Y., Honke K., Shuvaev V. V., Siest G., et al. (2002) Apolipoprotein E activates Akt pathway in neuro-2a in an isoform-specific manner. Biochem. Biophys. Res. Commun. 292, 83–87.
Lambert J. C., Pasquier F., Cottel D., Frigard B., Amouyel P., and Chartier-Harlin M. C. (1998a) A new polymorphism in the APOE promoter associated with risk of developing Alzheimer’s disease. Hum. Mol. Genet. 7, 533–540.
Lambert J. C., Berr C., Pasquier F., Delacourte A., Frigard B., Cottel D., et al. (1998b) Pronounced impact of Th1/E47cs mutation compared with −491 AT mutation on neural APOE gene expression and risk of developing Alzheimer’s disease. Hum. Mol. Genet. 7, 1511–1516.
Liu Y., Laakso M. P., Karonen J. O., Vanninen R. L., Nuutinen J., Soimakallio S., and Aronen H. J. (2002) Apolipoprotein E polymorphism and acute ischemic stroke: a diffusion- and perfusion-weighted magnetic resonance imaging study. J. Cereb. Blood Flow Metab. 22, 1336–1342.
Luthra K., Prasad K., Kumar P., Dwivedi M., Pandey R. M., and Das N. (2002) Apolipoprotein E gene polymorphism in cerebrovascular disease: a case-control study. Clin. Genet. 62, 39–44.
Mahley R. W. and Huang Y. (1999) Apolipoprotein E: from atherosclerosis to Alzheimer’s disease and beyond. Curr. Opin. Lipidol. 10, 207–217.
Marques M. A., Tolar M., and Crutcher K. A. (1996) A thrombin cleavage fragment of apolipoprotein E exhibits isoform-specific neurotoxicity. Neuroreport 7, 2529–2532.
Marques M. A., Tolar M., and Crutcher K. A. (1997) Apolipoprotein E exhibits isoform-specific neurotoxicity. Alzheimers Res. 3, 1–6.
Michikawa M. and Yanagisawa K. (1998) Apolipoprotein E4 induces neuronal cell death under conditions of suppressed de novo cholesterol synthesis. J. Neurosci. Res. 54, 58–67.
Nadig P., Fine R., and McKee A. (1996) Relative invulnerability of apoE knockout mouse hippocampal neurons to amyloid beta toxicity. Soc. Neurosci. Abstr. 22, 1696.
Naidu A., Catalano R., Bales K., Wu S., Paul S. M., and Cordell B. (2001) Conversion of brain apolipoprotein E to an insoluble form in a mouse model of Alzheimer disease. Neuroreport 12, 1265–1270.
Namba Y., Tomonaga M., Kawasaki H., Otomo E., and Ikeda K. (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeld-Jacob disease. Brain Res. 541, 163–166.
Naslund J., Thyberg J., Tjernberg L. O., Wernstedt C., Karlstrom A. R., Bogdanovic N., et al. (1995) Characterization of stable complexes involving apolipoprotein E and the amyloid beta peptide in Alzheimer’s disease brain. Neuron 15, 219–228.
Nathan B. P., Bellosta S., Sanan D. A., Weisgraber K. H., Mahley R. W., and Pitas R. E. (1994) Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 264, 850–852.
Nathan B. P., Chang K. C., Bellosta S., Brisch E., Ge N., Mahley R. W., and Pitas R. E. (1995) The inhibitory effect of apolipoprotein E4 on neurite outgrowth is associated with microtubule depolymerization. J. Biol. Chem. 270, 19791–19799.
Nathan B. P., Jiang Y., Wong G., Shen F., Brewer G., and Struble R. G. (2002) Apolipoprotein E4 inhibits, and apolipoprotein E3 promotes neurite outgrowth in cultured adult mouse cortical neurons through the low-density lipoprotein receptor-related protein. Brain Res. 928, 96–105.
Nixon R.A. (2000) A “protease activation cascade” in the pathogenesis of Alzheimer’s disease. Ann. NY Acad. Sci. 924, 117–131.
Ohkubo N., Mitsuda N., Tamatani M., Yamaguchi A., Lee Y. D., Ogihara T., et al. (2000) Apolipoprotein E4 stimulates CREB’s transcriptional activity through the ERK pathway. J. Biol. Chem. 276, 3046–3053.
Popko B., Goodrum J. F., Bouldin T. W., Zhang S. H., and Maeda N. (1993) Nerve regeneration occurs in the absence of apolipoprotein E in mice. J. Neurochem. 60, 1155–1158.
Roks G., Cruts M., Bullido M. J., Backhovens H., Artiga M. J., Hofman A., et al. (1998) The -491 A/T polymorphism in the regulatory region of the apolipoprotein E gene and early-onset Alzheimer’s disease. Neurosci. Lett. 258, 65–68.
Roks G., Cruts M., Houwing-Duistermaat J. J., Dermaut B., Serneels S., Havekes L. M., et al. (2002) Effect of the APOE-491A/T promoter polymorphism on apolipoprotein E levels and risk of Alzheimer disease: the Rotterdam Study. Am. J. Med. Genet. 114, 570–573.
Schmidt S., Barcellos L. F., DeSombre K., Rimmler J. B., Lincoln R. R., Bucher P., et al. (2002) Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis. Am. J. Hum. Genet. 70, 708–717.
Slooter A. J., Tang M. X., van Duijn C. M., Stern Y., Ott A., Bell K., et al. (1997) Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation. JAMA 277, 818–821.
Smith C., Graham D. I., Murray L., and Nicoll J. A. (2002) Association of APOE polymorphisms and pathological features in traumatic brain injury. Neuropathol. Appl. Neurobiol. 28, 151,152.
Strittmatter W. J., Saunders A. M., Goedert M., Weisgraber K. H., Dong L. M., Jakes R., et al. (1994) Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc. Natl. Acad. Sci. USA 91, 11183–11186.
Strittmatter W. J., Saunders A. M., Schmechel D., Pericak V. M., Enghild J., Salvesen G. S., and Roses A. D. (1993a) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 1977–1981.
Strittmatter W. J., Weisgraber K. H., Huang D. Y., Dong L. M., Salvesen G. S., Pericak V. M., et al. (1993b) Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 8098–8102.
Szolnoki Z., Somogyvari F., Kondacs A., Szabo M., and Fodor L. (2002) Evaluation of the interactions of common genetic mutations in stroke subtypes. J. Neurol. 249, 1391–1397.
Tesseur I., Van Dorpe J., Bruynseels K., Bronfman F., Sciot R., Van Lommel A., and Van Leuven F. (2000a) Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am. J. Pathol. 157, 1495–1510.
Tesseur I., Van Dorpe J., Spittaels K., Van den Haute C., Moechars D., and Van Leuven F. (2000b) Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am. J. Pathol. 156, 951–964.
Tolar M., Keller J. N., Chan S., Mattson M. P., Marques M. A., and Crutcher K. A. (1999) Truncated apolipoprotein E (apoE) causes increased intracellular calcium and may mediate apoE neurotoxicity. J. Neurosci. 19, 7100–7110.
Tsuzuki S., Murano T., Watanabe H., Itoh Y., Miyashita Y., and Shirai K. (1998) The examination of apoE phenotypes in diabetic patients with peripheral neuropathy. Rinsho Byori 46, 829–833.
Uchihara T., Duyckaerts C., He Y., Kobayashi K., Seilhean D., Amouyel P., and Hauw J.-J. (1995) ApoE immuno-reactivity and microglial cells in Alzheimer’s disease brain. Neurosci. Lett. 195, 5–8.
Veinbergs I., Everson A., Sagara Y., and Masliah E. (2002) Neurotoxic effects of apolipoprotein E4 are mediated via dysregulation of calcium homeostasis. J. Neurosci. Res. 67, 379–387.
Weir C. J., McCarron M. O., Muir K. W., Dyker A. G., Bone I., Lees K. R. and Nicoll J. A. (2001) Apolipoprotein E genotype, coagulation, and survival following acute stroke. Neurology 57, 1097–1000.
Weisgraber K. H., Roses A. D., and Strittmatter W. J. (1994) The role of apolipoprotein E in the nervous system. Curr. Opin. Lipidol. 5, 110–116.
Wetterau J. R., Aggerbeck L. P., Rall S. J., and Weisgraber K. H. (1988) Human apolipoprotein E3 in aqueous solution. I. Evidence for two structural domains. J. Biol. Chem. 263, 6240–6248.
Wisniewski T., Lalowski M., Golabek A., Vogel T., and Frangione B. (1995) Is Alzheimer’s disease an apolipoprotein E amyloidosis? Lancet 345, 956–958.
Woo D., Sauerbeck L. R., Kissela B. M., Khoury J. C., Szaflarski J. P., Gebel J., et al. (2002) Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke 33, 1190–1195.
Zhang D., McQuade J.-A., Shockley K., Levin L., Marques M., and Crutcher K. (2001) Proteolysis of apolipoprotein E and Alzheimer’s disease pathology. Alzheimers Rep. 4, 67–80.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Crutcher, K.A. Apolipoprotein E is a prime suspect, not just an accomplice, in Alzheimer’s disease. J Mol Neurosci 23, 181–188 (2004). https://doi.org/10.1385/JMN:23:3:181
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/JMN:23:3:181