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The APOE gene and cognitive function in non-demented and Alzheimer's disease patients

Published online by Cambridge University Press:  19 October 2009

Antony Payton*
Affiliation:
Centre for Integrated Genomic Medical Research, University of Manchester, UK
*
Address for correspondence: Dr Antony Payton, Centre for Integrated Genomic Medical Research, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK. Email: [email protected]

Summary

This review discusses the role that the APOE gene plays in cognitive dysfunction both in demented and non-demented elderly people. The increasing problem of cognitive impairment in developed countries makes finding new and effective treatments a research priority. Understanding the biological basis of this impairment is therefore paramount. APOE has received much attention in the field of cognitive genetics due to it being a major susceptibility gene for Alzheimer's disease, which itself is characterized by a rapid and irreversible loss in memory function. Over the past 14 years this has generated a considerable number of publications that have produced conflicting findings, making it difficult for the reader to interpret whether the APOE gene regulates cognition or not. This review attempts to summarize the mass of information on this gene in relation to cognition, by weighting the pros and cons of the methodologies used, and offers suggestions for future study designs.

Type
Biological gerontology
Copyright
Copyright © Cambridge University Press 2009

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References

1Comas-Herrera, A, Wittenberg, R, Pickard, L, Knapp, M. Cognitive impairment in older people: future demand for long-term care services and the associated costs. Int J Geriatr Psychiatry 2007; 22: 1037–45.CrossRefGoogle ScholarPubMed
2Payton, A. The impact of genetic research on our understanding of normal cognitive ageing: 1995 to 2009. Neuropsychology Reviews 2009 (in press; Epub 19 Sept).CrossRefGoogle Scholar
3Spearman, C. ‘General intelligence’ objectively determined and measured. Am J Psychol 1904; 15: 201–93.CrossRefGoogle Scholar
4Carroll, JB. Human Cognitive Abilities: a Survey of Factor Analytic Studies. Cambridge: Cambridge University Press, 1993.CrossRefGoogle Scholar
5Wechsler, D. Manual for the Wechsler Adult Intelligence Scale-III, Psychological Corporation, 1997.CrossRefGoogle Scholar
6Deary, IJ. Human intelligence differences: a recent history. Trends Cogn Sci 2001; 5: 127–30.CrossRefGoogle ScholarPubMed
7Jones, JJ, van Schaik, P, Witts, P. A factor analysis of the Wechsler Adult Intelligence Scale 3rd Edition (WAIS-III) in a low IQ sample. Br J Clin Psychol 2006; 45: 145–52.CrossRefGoogle Scholar
8Devlin, B, Daniels, M, Roeder, K. The heritability of IQ. Nature 1997; 388: 468–71.CrossRefGoogle ScholarPubMed
9Bouchard, TJ Jr, McGue, M. Genetic and environmental influences on human psychological differences. J Neurobiol 2003; 54: 445.CrossRefGoogle ScholarPubMed
10Qi, L, Cho, YA. Gene–environment interaction and obesity. Nutr Rev 2008; 66: 684–94.CrossRefGoogle ScholarPubMed
11Thorgeirsson, TE, Geller, F, Sulem, P et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 2008; 452: 638–42.CrossRefGoogle ScholarPubMed
12Kim, JH, Elwood, PE, Asher, MI. Diet and asthma: looking back, moving forward. Respir Res 2009; 10: 49.CrossRefGoogle ScholarPubMed
13Caspi, A, Williams, B, Kim-Cohen, J et al. Moderation of breastfeeding effects on the IQ by genetic variation in fatty acid metabolism. Proc Natl Acad Sci USA 2007; 104: 18860–65.CrossRefGoogle ScholarPubMed
14Wang, FT, Hu, H, Schwartz, J et al. Modifying effects of the HFE polymorphisms on the association between lead burden and cognitive decline. Environ Health Perspect 2007; 115: 1210–15.CrossRefGoogle ScholarPubMed
15Morales, E, Sunyer, J, Castro-Giner, F et al. Influence of glutathione S-transferase polymorphisms on cognitive functioning effects induced by p, p’-DDT among preschoolers. Environ Health Perspect 2008; 116: 1581–15.CrossRefGoogle ScholarPubMed
16Johnson, W, Harris, SE, Starr, JM, Whalley, LJ, Deary, IJ. PPARG Pro12Ala genotype and risk of cognitive decline in elders? Maybe with diabetes. Neurosci Lett 2008; 434: 5055.CrossRefGoogle ScholarPubMed
17Ridley, M.Nature via Nurture. Harper Collins, New York, 2003.Google Scholar
18McClearn, GE, Johansson, B, Berg, S, Pedersen, NL, Ahern, F, Petrill, SA, Plomin, R. Substantial genetic influence on cognitive abilities in twins 80 or more years old. Science 1997; 276: 1560–63.CrossRefGoogle ScholarPubMed
19Spinath, FM, Ronald, A, Harlaar, N, Price, TS, Plomin, R. Phenotypic g early in life: on the etiology of general cognitive ability in a large population sample of twin children aged 2–4 years. Intelligence 2003; 31: 195210.CrossRefGoogle Scholar
20Giubilei, F, Medda, E, Fagnani, C et al. Heritability of neurocognitive functioning in the elderly: evidence from an Italian twin study. Age Ageing 2008; 37: 640–46.CrossRefGoogle ScholarPubMed
21Peper, JS, Brouwer, RM, Boomsma, DI, Kahn, RS, Hulshoff, HE. Genetic influences on human brain structure: a review of brain imaging studies in twins. Hum Brain Map 2007; 28: 464–73.CrossRefGoogle ScholarPubMed
22Posthuma, D, Baaré, WF, Hulshoff Pol, HE, Kahn, RS, Boomsma, DI, De Geus, EJ. Genetic correlations between brain volumes and the WAIS-III dimensions of verbal comprehension, working memory, perceptual organization, and processing speed. Twin Res 2003; 6: 131–39.CrossRefGoogle ScholarPubMed
23Panizzon, MS, Fennema-Notestine, C, Eyler, LT et al. . Distinct genetic influences on cortical surface area and cortical thickness. Cereb Cortex 2009 (in press; Epub 18 Mar).CrossRefGoogle Scholar
24Fatokun, AA, Stone, TW, Smith, RA. Oxidative stress in neurodegeneration and available means of protection. Front Biosci 2008; 13: 3288–311.CrossRefGoogle ScholarPubMed
25Godbout, JP, Johnson, RW. Age and neuroinflammation: a lifetime of psychoneuroimmune consequences. Neurol Clin 2006; 24: 521–38.CrossRefGoogle ScholarPubMed
26Mauch, DH, Nägler, K, Schumacher, S, Göritz, C, Müller, EC, Otto, A, Pfrieger, FW. CNS synaptogenesis promoted by glia-derived cholesterol. Science 2001; 294: 1354–57.CrossRefGoogle ScholarPubMed
27Mahley, RW. Apolipoprotein, E: cholesterol transport protein with expanding role in cell biology. Science 1988; 240: 622–30.CrossRefGoogle ScholarPubMed
28Small, BJ, Rosnick, CB, Fratiglioni, L, Bäckman, L. Apolipoprotein E and cognitive performance: a meta-analysis. Psychol Aging 2004; 19: 592600.CrossRefGoogle ScholarPubMed
29Bertram, L, Tanzi, RE. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nature Rev Neurosci 2008; 9: 768–78.CrossRefGoogle ScholarPubMed
30Munoz, DG, Feldman, H.Causes of Alzheimer's disease. CMAJ 2000; 162: 6572.Google ScholarPubMed
31Raber, J, Huang, Y, Ashford, JW. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol Aging 2004; 25: 641–50.CrossRefGoogle ScholarPubMed
32Khachaturian, AS, Corcoran, CD, Mayer, LS, Zandi, PP, Breitner, JC. Apolipoprotein E ɛ4 count affects age at onset of Alzheimer's disease, but not lifetime susceptibility: the Cache County Study. Arch Gen Psychiatry 2004; 61: 518–24.CrossRefGoogle Scholar
33Bu, G. Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 2009; 10: 333–44.CrossRefGoogle ScholarPubMed
34Nathan, BP, Bellosta, S, Sanan, DA, Weisgraber, KH, Mahley, RW, Pitas, RE. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 1994; 264: 850–52.CrossRefGoogle ScholarPubMed
35Nathan, BP, Jiang, Y, Wong, GK, Shen, F, Brewer, GJ, Struble, RG. 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 2002; 22: 96105.CrossRefGoogle Scholar
36Teter, B, Xu, PT, Gilbert, JR, Roses, AD, Galasko, D, Cole, GM. Defective neuronal sprouting by human apolipoprotein E4 is a gain-of negative function. J Neurosci Res 2002; 68: 331–36.CrossRefGoogle ScholarPubMed
37Kutner, KC, Erlanger, DM, Tsai, J, Jordan, B, Relkin, NR. Lower cognitive performance of older football players possessing apolipoprotein E ɛ4. Neurosurgery 2000; 47: 651–57.Google Scholar
38Jordan, BD, Relkin, NR, Ravdin, LD, Jacobs, AR, Bennett, A, Gandy, S. Apolipoprotein E ɛ4 associated with chronic traumatic brain injury in boxing. JAMA 1997; 278: 136–40.CrossRefGoogle ScholarPubMed
39Strittmatter, WJ, Weisgraber, KH, Huang, DY et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer's disease. Proc Natl Acad Sci USA 1993; 90: 8098–102.CrossRefGoogle Scholar
40Rebeck, GW, Reiter, JS, Strickland, DK, Hyman, BT. Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron 1993; 11: 575–80.CrossRefGoogle ScholarPubMed
41Bennett, DA, Wilson, RS, Schneider, JA et al. Apolipoprotein E ɛ4 allele, AD pathology, and the clinical expression of Alzheimer's disease. Neurology 2003; 60: 246–52.CrossRefGoogle ScholarPubMed
42Polvikoski, T, Sulkava, R, Haltia, M et al. Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med 1995; 333: 1242–47.CrossRefGoogle ScholarPubMed
43Drzezga, A, Grimmer, T, Henriksen, G et al. Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer's disease. Neurology 2009; 72: 1487–94.CrossRefGoogle Scholar
44Marques, MA, Tolar, M, Harmony, JA, Crutcher, KA. A thrombin cleavage fragment of apolipoprotein E exhibits isoform-specific neurotoxicity. Neuroreport 1996; 7: 2529–32.CrossRefGoogle ScholarPubMed
45Tolar, M, Marques, MA, Harmony, JA, Crutcher, KA. Neurotoxicity of the 22 kDa thrombincleavage fragment of apolipoprotein E and related synthetic peptides is receptor-mediated. J Neurosci 1997; 17: 5678–86.CrossRefGoogle ScholarPubMed
46Huang, Y, Liu, XQ, Wyss-Coray, T, Brecht, WJ, Sanan, DA, Mahley, RW. Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci USA 2001; 98: 8838–43.CrossRefGoogle ScholarPubMed
47Eddins, D, Klein, RC, Yakel, JL, Levin, ED. Hippocampal infusions of apolipoprotein E peptides induce long-lasting cognitive impairment. Brain Res Bull 2009; 79: 111–15.CrossRefGoogle ScholarPubMed
48Corder, EH, Saunders, AM, Strittmatter, WJ et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261: 921–23.CrossRefGoogle ScholarPubMed
49Bookheimer, S, Burggren, A. APOE-4 genotype and neurophysiological vulnerability to Alzheimer's and cognitive aging. Ann Rev Clin Psychol 2009; 5: 343–62.CrossRefGoogle ScholarPubMed
50Wisdom, NM, Callahan, JL, Hawkins, KA. The effects of apolipoprotein E on non-impaired cognitive functioning: A meta-analysis. Neurobiol Aging 2009 (in press; Epub 12 Mar).Google Scholar
51Breitner, JC, Wyse, BW, Anthony, JC et al. APOE-ɛ4 count predicts age when prevalence of AD increases, then declines: the Cache County Study. Neurology 1999; 53: 321–31.CrossRefGoogle Scholar
52Farrer, LA, Cupples, LA, Haines, JL et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer's disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997; 278: 1349–56.CrossRefGoogle ScholarPubMed
53Corder, EH, Ghebremedhin, E, Thal, DR, Ohm, TG, Braak, H. Alzheimer pathogenesis for men and women. Alzheimer Dis Res J 2008; 2: 3952.Google Scholar
54Deary, IJ, Whiteman, MC, Pattie, A et al. Cognitive change and the APOE ɛ4 allele. Nature 2002; 418: 932.CrossRefGoogle Scholar
55Heim, AW. Intelligence and Personality: Their Assessment and Relationship. Harmondsworth: Penguin, 1970.Google Scholar
56Folstein, MF, Folstein, SE, McHugh, PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 313: 1419–20.Google Scholar
57Deary, IJ, Whiteman, MC, Starr, JM, Whalley, LJ, Fox, HC. The impact of childhood intelligence on later life: following up the Scottish mental Surveys of 1932 and 1947. J Pers Soc Psychol 2004; 86: 130–47.CrossRefGoogle ScholarPubMed
58Mueller, SG, Schuff, N, Raptentsetsang, S, Elman, J, Weiner, MW. Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T. Neuroimage 2008; 42: 4248.CrossRefGoogle Scholar
59Bartzokis, G, Lu, PH, Geschwind, DH et al. Apolipoprotein E affects both myelin breakdown and cognition: implications for age-related trajectories of decline into dementia. Biol Psychiatry 2007; 62: 1380–87.CrossRefGoogle ScholarPubMed
60Burggren, AC, Zeineh, MM, Ekstrom, AD, Braskie, MN, Thompson, PM, Small, GW, Bookheimer, SY. Reduced cortical thickness in hippocampal subregions among cognitively normal apolipoprotein E e4 carriers. Neuroimage 2008; 41: 1177–83.CrossRefGoogle ScholarPubMed
61Tombaugh, TN, McIntyre, NJ. The mini-mental state examination: a comprehensive review. J Am Geriatr Soc 1992; 40: 922–35.CrossRefGoogle ScholarPubMed
62Rabbitt, P, Lowe, C. Patterns of cognitive ageing. Psychol Res 2000; 63: 308–16.CrossRefGoogle ScholarPubMed
63Finkel, D, Reynolds, CA, McArdle, JJ, Pedersen, NL. Age changes in processing speed as a leading indicator of cognitive aging. Psychol Aging 2007; 22: 558–68.CrossRefGoogle ScholarPubMed
64Rabbitt, P, Diggle, P, Holland, F, McInnes, L. Practice and drop-out effects during a 17-year longitudinal study of cognitive aging. J Gerontol B Psychol Sci Soc Sci 2004; 59: 8497.CrossRefGoogle ScholarPubMed
65Savitz, J, Solms, M, Ramesar, R. Apolipoprotein E variants and cognition in healthy individuals: a critical opinion. Brain Res Rev 2006; 51: 125–35.CrossRefGoogle ScholarPubMed
66Packard, CJ, Westendorp, RG, Stott, DJ et al. Prospective study of pravastatin in the elderly at risk group. Association between apolipoprotein E4 and cognitive decline in elderly adults. J Am Geriatr Soc 2007; 55: 1777–85.CrossRefGoogle ScholarPubMed
67Cargin, JW, Maruff, P, Collie, A, Shafiq-Antonacci, R, Masters, C. Decline in verbal memory in non-demented older adults. J Clin Exp Neuropsychol 2007; 29: 706–18.CrossRefGoogle ScholarPubMed
68Tupler, LA, Krishnan, KR, Greenberg, DL et al. Predicting memory decline in normal elderly: genetics, MRI, and cognitive reserve. Neurobiol Aging 2007; 28: 1644–56.CrossRefGoogle ScholarPubMed
69Christensen, H, Batterham, PJ, Mackinnon, AJ et al. The association of APOE genotype and cognitive decline in interaction with risk factors in a 65–69 year old community sample. BMC Geriatr 2008; 8: 14.CrossRefGoogle Scholar
70Kozauer, NA, Mielke, MM, Chan, GK, Rebok, GW, Lyketsos, CG. Apolipoprotein E genotype and lifetime cognitive decline. Int Psychogeriatr 2008; 20: 109–23.CrossRefGoogle ScholarPubMed
71Niti, M, Yap, KB, Kua, EH, Ng, TP. APOE-ɛ4, depressive symptoms, and cognitive decline in Chinese older adults: Singapore Longitudinal Aging Studies. J Gerontol A Biol Sci Med Sci 2009; 64: 306–11.CrossRefGoogle Scholar
72Caselli, RJ, Dueck, AC, Osborne, D et al. Longitudinal modeling of age-related memory decline and the APOE ɛ4 effect. N Engl J Med 2009; 361: 255–63.CrossRefGoogle ScholarPubMed
73van Vliet, P, Oleksik, AM, Mooijaart, SP, de Craen, AJ, Westendorp, RG. APOE genotype modulates the effect of serum calcium levels on cognitive function in old age. Neurology 2009; 72: 821–28.CrossRefGoogle ScholarPubMed
74Nagy, Z, Esiri, MM, Jobst, KA, Johnston, C, Litchfield, S, Sim, E, Smith, AD. Influence of the apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer's disease. Neuroscience 1995; 69: 757–61.CrossRefGoogle ScholarPubMed
75Ohm, TG, Kirca, M, Bohl, J, Scharnagl, H, Gross, W, März, W. Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation. Neuroscience 1995; 66: 583–87.CrossRefGoogle Scholar
76Cherbuin, N, Leach, LS, Christensen, H, Anstey, KJ. Neuroimaging and APOE genotype: a systematic qualitative review. Dement Geriatr Cogn Disord 2007; 24: 348–62.CrossRefGoogle ScholarPubMed
77Marra, C, Bizzarro, A, Daniele, A et al. Apolipoprotein E ɛ4 allele differently affects the patterns of neuropsychological presentation in early- and late-onset Alzheimer's disease patients. Dement Geriatr Cogn Disord 2004; 18: 125–31.CrossRefGoogle ScholarPubMed
78Lam, LC, Tang, NL, Ma, SL, Lui, VW, Chan, AS, Leung, PY, Chiu, HF. Apolipoprotein ɛ-4 allele and the two-year progression of cognitive function in Chinese subjects with late-onset Alzheimer's disease. Am J Alzheimers Dis Other Demen 2006; 21: 9299.CrossRefGoogle ScholarPubMed
79Cosentino, S, Scarmeas, N, Helzner, E, Glymour, MM, Brandt, J, Albert, M, Blacker, D, Stern, Y. APOE ɛ4 allele predicts faster cognitive decline in mild Alzheimer's disease. Neurology 2008; 70: 1842–49.CrossRefGoogle Scholar
80Van Der Vlies, AE, Koedam, EL, Pijnenburg, YA, Twisk, JW, Scheltens, P, Van Der Flier, WM. Most rapid cognitive decline in APOE ɛ4 negative Alzheimer's disease with early onset. Psychol Med 2009; 1: 15.Google Scholar
81Morris, JC, Edland, S, Clark, C et al. The consortium to establish a registry for Alzheimer's disease (CERAD). Part IV. Rates of cognitive change in the longitudinal assessment of probable Alzheimer's disease. Neurology 1993; 43: 2457–65.CrossRefGoogle Scholar
82Han, L, Cole, M, Bellavance, F, McCusker, J, Primeau, F. Tracking cognitive decline in Alzheimer's disease using the mini-mental state examination: a meta-analysis. Int Psychogeriatr 2000; 12: 231–47.CrossRefGoogle ScholarPubMed
83Plassman, BL, Breitner, JC. Apolipoprotein E and cognitive decline in Alzheimer's disease. Neurology 1996; 47: 317–20.CrossRefGoogle ScholarPubMed
84Bekris, LM, Galloway, NM, Montine, TJ, Schellenberg, GD, Yu, CE. APOE mRNA and protein expression in post-mortem brain are modulated by an extended haplotype structure. Am J Med Genet B Neuropsychiatr Genet 2009 (in press; Epub 24 June).Google Scholar
85Basun, H, Grut, M, Winblad, B, Lannfelt, L. Apolipoprotein ɛ4 allele and disease progression in patients with late-onset Alzheimer's disease. Neurosci Lett 1995; 183: 3234.CrossRefGoogle Scholar
86Asada, T, Kariya, T, Yamagata, Z, Kinoshita, T, Asaka, A. ApoE ɛ4 allele and cognitive decline in patients with Alzheimer's disease. Neurology 1996; 47: 603.CrossRefGoogle Scholar
87Holmes, C, Levy, R, McLoughlin, DM, Powell, JF, Lovestone, S. Apolipoprotein E: non-cognitive symptoms and cognitive decline in late onset Alzheimer's disease. J Neurol Neurosurg Psychiatry 1996; 61: 580–83.CrossRefGoogle ScholarPubMed
88Dal Forno, G, Rasmusson, DX, Brandt, J, Carson, KA, Brookmeyer, R, Troncoso, J, Kawas, CH. Apolipoprotein E genotype and rate of decline in probable Alzheimer's disease. Arch Neurol 1996; 53: 345–50.CrossRefGoogle ScholarPubMed
89Kurz, A, Egensperger, R, Haupt, M, Lautenschlager, N, Romero, B, Graeber, MB, Müller, U. Apolipoprotein E ɛ4 allele, cognitive decline, and deterioration of everyday performance in Alzheimer's disease. Neurology 1996; 47: 440–43.CrossRefGoogle Scholar
90Growdon, JH, Locascio, JJ, Corkin, S, Gomez-Isla, T, Hyman, BT. Apolipoprotein E genotype does not influence rates of cognitive decline in Alzheimer's disease. Neurology 1996; 47: 444–48.CrossRefGoogle Scholar
91Murphy, GM Jr, Taylor, J, Kraemer, HC, Yesavage, J, Tinklenberg, JR. No association between apolipoprotein E ɛ4 allele and rate of decline in Alzheimer's disease. Am J Psychiatry 1997; 154: 603–8.Google ScholarPubMed
92Jonker, C, Schmand, B, Lindeboom, J, Havekes, LM, Launer, LJ. Association between apolipoprotein E ɛ4 and the rate of cognitive decline in community-dwelling elderly individuals with and without dementia. Arch Neurol 1998; 55: 1065–69.CrossRefGoogle Scholar
93Lehtovirta, M, Kuikka, J, Helisalmi, S et al. Longitudinal SPECT study in Alzheimer's disease: relation to apolipoprotein E polymorphism. J Neurol Neurosurg Psychiatry 1998; 64: 742–46.CrossRefGoogle ScholarPubMed
94Farlow, MR, Cyrus, PA, Nadel, A, Lahiri, DK, Brashear, A, Gulanski, B. Metrifonate treatment of AD: influence of APOE genotype. Neurology 1999; 53: 2010–16.CrossRefGoogle ScholarPubMed
95Slooter, AJ, Houwing-Duistermaat, JJ, van Harskamp, F et al. Apolipoprotein E genotype and progression of Alzheimer's disease: the Rotterdam Study. J Neurol 1999; 246: 304–8.CrossRefGoogle ScholarPubMed
96Aerssens, J, Raeymaekers, P, Lilienfeld, S, Geerts, H, Konings, F, Parys, W. APOE genotype: no influence on galantamine treatment efficacy nor on rate of decline in Alzheimer's disease. Dement Geriatr Cogn Disord 2001; 12: 6977.CrossRefGoogle ScholarPubMed
97Mori, E, Lee, K, Yasuda, M, Hashimoto, M, Kazui, H, Hirono, N, Matsui, M. Accelerated hippocampal atrophy in Alzheimer's disease with apolipoprotein E ɛ4 allele. Ann Neurol 2002; 51: 209–14.CrossRefGoogle Scholar
98Kleiman, T, Zdanys, K, Black, B et al. Apolipoprotein E ɛ4 allele is unrelated to cognitive or functional decline in Alzheimer's disease: retrospective and prospective analysis. Dement Geriatr Cogn Disord 2006; 22: 7382.CrossRefGoogle ScholarPubMed
99Chuu, JY, Taylor, JL, Tinklenberg, J, Noda, A, Yesavage, J, Murphy, GM Jr. The brain-derived neurotrophic factor Val66Met polymorphism and rate of decline in Alzheimer's disease. J Alzheimers Dis 2006; 9: 4349.CrossRefGoogle ScholarPubMed
100Bracco, L, Piccini, C, Baccini, M et al. Pattern and progression of cognitive decline in Alzheimer's disease: role of premorbid intelligence and ApoE genotype. Dement Geriatr Cogn Disord 2007; 24: 483–91.CrossRefGoogle ScholarPubMed
101Craft, S, Teri, L, Edland, SD et al. Accelerated decline in apolipoprotein E-ɛ4 homozygotes with Alzheimer's disease. Neurology 1998; 51: 149–53.CrossRefGoogle Scholar
102Kanai, M, Shizuka, M, Urakami, K, Matsubara, E, Harigaya, Y, Okamoto, K, Shoji, M. Apolipoprotein E4 accelerates dementia and increases cerebrospinal fluid tau levels in Alzheimer's disease. Neurosci Lett 1999; 267: 6568.CrossRefGoogle ScholarPubMed
103Hirono, N, Hashimoto, M, Yasuda, M, Kazui, H, Mori, E. Accelerated memory decline in Alzheimer's disease with apolipoprotein ɛ4 allele. J Neuropsychiatry Clin Neurosci 2003; 15: 354–58.CrossRefGoogle Scholar
104Martins, CA, Oulhaj, A, de Jager, CA, Williams, JH. APOE alleles predict the rate of cognitive decline in Alzheimer's disease: a non-linear model. Neurology 2005; 65: 1888–93.CrossRefGoogle Scholar
105Frisoni, GB, Govoni, S, Geroldi, C, Bianchetti, A, Calabresi, L, Franceschini, G, Trabucchi, M. Gene dose of the ɛ4 allele of apolipoprotein E and disease progression in sporadic late-onset Alzheimer's disease. Ann Neurol 1995; 37: 596604.CrossRefGoogle Scholar
106Stern, Y, Brandt, J, Albert, M, Jacobs, DM, Liu, X, Bell, K, Marder, K, Sano, M, Albert, S, Del-Castillo Castenada, C, Bylsma, F, Tycko, B, Mayeux, R. The absence of an apolipoprotein ɛ4 allele is associated with a more aggressive form of Alzheimer's disease. Ann Neurol 1997; 41: 615–20.CrossRefGoogle ScholarPubMed
107Hoyt, BD, Massman, PJ, Schatschneider, C, Cooke, N, Doody, RS. Individual growth curve analysis of APOE ɛ4-associated cognitive decline in Alzheimer's disease. Arch Neurol 2005; 62: 454–59.CrossRefGoogle Scholar