The Correlation of Levels of Serum Lipid, Homocysteine, and Folate with Volumes of Hippocampus, Amygdala, Corpus Callosum, and Thickness of Entorhinal Cortex in Patients with Amnestic Mild Cognitive Impairment or Dementia of Alzheimer's Type

기억성 경도인지장애 및 알츠하이머 치매 환자에서 해마, 편도체, 뇌들보, 내후각 피질과 혈중 지질, 호모시스테인, 엽산 농도와의 연관성

  • Lee, Sang Jun (Department of Psychiatry, Inje University Haeundae Paik Hospital, Inje University College of Medicine) ;
  • Kim, Tae Hyung (Department of Biomedical Engineering, and U-Health Care Research Center, Inje University) ;
  • Huh, Lyang (Department of Psychiatry, Inje University Haeundae Paik Hospital, Inje University College of Medicine) ;
  • Choi, Seung Eun (Department of Psychology, Inje University Haeundae Paik Hospital) ;
  • Lee, Bong Ju (Department of Psychiatry, Inje University Haeundae Paik Hospital, Inje University College of Medicine) ;
  • Kim, Gyung Mee (Department of Psychiatry, Inje University Haeundae Paik Hospital, Inje University College of Medicine) ;
  • Lee, Jung Goo (Department of Psychiatry, Inje University Haeundae Paik Hospital, Inje University College of Medicine) ;
  • Kim, Hong Dae (Department of Radiology, Inje University Haeundae Paik Hospital, Inje University College of Medicine) ;
  • Mun, Chi Woong (Department of Biomedical Engineering, and U-Health Care Research Center, Inje University) ;
  • Kim, Young Hoon (Department of Psychiatry, Inje University Haeundae Paik Hospital, Inje University College of Medicine)
  • 이상준 (인제대학교 의과대학 해운대백병원 정신건강의학과) ;
  • 김태형 (인제대학교 의용공학과, UHRC) ;
  • 허량 (인제대학교 의과대학 해운대백병원 정신건강의학과) ;
  • 최승은 (인제대학교 해운대백병원 정신건강의학과 임상심리학실) ;
  • 이봉주 (인제대학교 의과대학 해운대백병원 정신건강의학과) ;
  • 김경미 (인제대학교 의과대학 해운대백병원 정신건강의학과) ;
  • 이정구 (인제대학교 의과대학 해운대백병원 정신건강의학과) ;
  • 김홍대 (인제대학교 의과대학 해운대백병원 영상의학과) ;
  • 문치웅 (인제대학교 의용공학과, UHRC) ;
  • 김영훈 (인제대학교 의과대학 해운대백병원 정신건강의학과)
  • Received : 2015.10.10
  • Accepted : 2015.10.29
  • Published : 2015.11.30

Abstract

Objectives In this study, the authors evaluated the correlation between levels of serum lipid, homocysteine, and folate with volumes of hippocampus, amygdala, corpus callosum, and in patients with amnestic mild cognitive impairment (aMCI) or Alzheimer's disease (AD) type. Methods The study recruited patients who visited the dementia clinic of Haeundae Paik Hospital in Korea between March 2010 and June 2014. Among those, patients who had taken the neurocognitive test, brain magnetic resonance imaing, tests for serum lipid, homocysteine, folate, and apolipoprotein E (APOE) genotyping and diagnosed with aMCI or AD were included for analysis. Bilateral hippocampus, entorhinal cortex, amygdala and corpus callosum were selected for region of interest (ROI). The cross-sectional relationships between serum lipid, homocysteine, folate and ROI were assessed by partial correlation analysis and multiple linear regression analysis. Results In patients with aMCI, old age (> 80) and APOE ${\varepsilon}4$ carrier were associated with AD [odds ration (OR) : 12.80 ; 95% confidence interval (CI) : 2.25-72.98 and OR : 4.48 ; 95% CI : 1.58-12.67, respectively]. In patients with aMCI or AD, volumes and thickness of ROI were inversely correlated with levels of serum lipid and homocysteine. In multiple linear regression analyses, higher total cholesterol level was related to lower left, right hippocampus volume and left amygdala volume ; higher low-density lipoprotein cholesterol was related to lower right entorhinal cortex thickness ; higher homocysteine level was related to lower corpus callosum volume. Conclusions Higher serum lipid and homocysteine levels are associated with decreased volume of hippocampus, amygdala, corpus callosum and entorhinal cortex thickness in patients with aMCI or AD. These findings suggest that serum lipid and homocysteine levels are associated with AD as a modifiable risk factor.

Keywords

References

  1. van der Flier WM, Scheltens P. Epidemiology and risk factors of dementia. J Neurol Neurosurg Psychiatry 2005;76 Suppl 5:v2-v7. https://doi.org/10.1136/jnnp.2005.082867
  2. Hugo J, Ganguli M. Dementia and cognitive impairment: epidemiology, diagnosis, and treatment. Clin Geriatr Med 2014;30:421-442. https://doi.org/10.1016/j.cger.2014.04.001
  3. Jack CR Jr. Alzheimer disease: new concepts on its neurobiology and the clinical role imaging will play. Radiology 2012;263:344-361. https://doi.org/10.1148/radiol.12110433
  4. Kim KW, Park JH, Kim MH, Kim MD, Kim BJ, Kim SK, et al. A nationwide survey on the prevalence of dementia and mild cognitive impairment in South Korea. J Alzheimers Dis 2011;23:281-291. https://doi.org/10.3233/JAD-2010-101221
  5. Hong CH. Mild cognitive impairment. In: Korean association for geriatric psychiatry. Geriatric Psychiatry. 2nd ed. Seoul: ML Communication Co. Ltd.;2015. p.228-229.
  6. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56:303-308. https://doi.org/10.1001/archneur.56.3.303
  7. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256:183-194. https://doi.org/10.1111/j.1365-2796.2004.01388.x
  8. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, et al. Current concepts in mild cognitive impairment. Arch Neurol 2001;58:1985-1992. https://doi.org/10.1001/archneur.58.12.1985
  9. Petersen RC, Roberts RO, Knopman DS, Boeve BF, Geda YE, Ivnik RJ, et al. Mild cognitive impairment: ten years later. Arch Neurol 2009;66:1447-1455.
  10. Bruscoli M, Lovestone S. Is MCI really just early dementia? A systematic review of conversion studies. Int Psychogeriatr 2004;16:129-140. https://doi.org/10.1017/S1041610204000092
  11. Boyle PA, Wilson RS, Aggarwal NT, Tang Y, Bennett DA. Mild cognitive impairment: risk of Alzheimer disease and rate of cognitive decline. Neurology 2006;67:441-445. https://doi.org/10.1212/01.wnl.0000228244.10416.20
  12. Mitchell AJ, Shiri-Feshki M. Temporal trends in the long term risk of progression of mild cognitive impairment: a pooled analysis. J Neurol Neurosurg Psychiatry 2008;79:1386-1391. https://doi.org/10.1136/jnnp.2007.142679
  13. American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-V. 5th ed. Washington, DC: American Psychiatric Association;2013.
  14. Li J, Wang YJ, Zhang M, Xu ZQ, Gao CY, Fang CQ, et al. Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. Neurology 2011;76:1485-1491. https://doi.org/10.1212/WNL.0b013e318217e7a4
  15. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow- up study. Lancet Neurol 2006;5:228-234. https://doi.org/10.1016/S1474-4422(06)70355-6
  16. Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, et al. Conversion of mild cognitive impairment to dementia: predictive role of mild cognitive impairment subtypes and vascular risk factors. Dement Geriatr Cogn Disord 2006;21:51-58. https://doi.org/10.1159/000089515
  17. Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 2002;33:341-355. https://doi.org/10.1016/S0896-6273(02)00569-X
  18. Fischl B, Salat DH, van der Kouwe AJ, Makris N, Segonne F, Quinn BT, et al. Sequence-independent segmentation of magnetic resonance images. Neuroimage 2004;23 Suppl 1:S69-S84. https://doi.org/10.1016/j.neuroimage.2004.07.016
  19. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239-259. https://doi.org/10.1007/BF00308809
  20. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 2006;112:389-404. https://doi.org/10.1007/s00401-006-0127-z
  21. Fox NC, Schott JM. Imaging cerebral atrophy: normal ageing to Alzheimer's disease. Lancet 2004;363:392-394. https://doi.org/10.1016/S0140-6736(04)15441-X
  22. Apostolova LG, Dinov ID, Dutton RA, Hayashi KM, Toga AW, Cummings JL, et al. 3D comparison of hippocampal atrophy in amnestic mild cognitive impairment and Alzheimer's disease. Brain 2006;129(Pt 11):2867-2873. https://doi.org/10.1093/brain/awl274
  23. Singh V, Chertkow H, Lerch JP, Evans AC, Dorr AE, Kabani NJ. Spatial patterns of cortical thinning in mild cognitive impairment and Alzheimer's disease. Brain 2006;129(Pt 11):2885-2893. https://doi.org/10.1093/brain/awl256
  24. Seo SW, Im K, Lee JM, Kim YH, Kim ST, Kim SY, et al. Cortical thickness in single- versus multiple-domain amnestic mild cognitive impairment. Neuroimage 2007;36:289-297. https://doi.org/10.1016/j.neuroimage.2007.02.042
  25. Chetelat G, Landeau B, Eustache F, Mezenge F, Viader F, de la Sayette V, et al. Using voxel-based morphometry to map the structural chanees associated with rapid conversion in MCI: a longitudinal MRI study. Neuroimage 2005;27:934-946. https://doi.org/10.1016/j.neuroimage.2005.05.015
  26. Hamalainen A, Tervo S, Grau-Olivares M, Niskanen E, Pennanen C, Huuskonen J, et al. Voxel-based morphometry to detect brain atrophy in progressive mild cognitive impairment. Neuroimage 2007;37:1122-1131. https://doi.org/10.1016/j.neuroimage.2007.06.016
  27. Ferreira LK, Diniz BS, Forlenza OV, Busatto GF, Zanetti MV. Neurostructural predictors of Alzheimer’s disease: a meta-analysis of VBM studies. Neurobiol Aging 2011;32:1733-1741. https://doi.org/10.1016/j.neurobiolaging.2009.11.008
  28. Velayudhan L, Proitsi P, Westman E, Muehlboeck JS, Mecocci P, Vellas B, et al. Entorhinal cortex thickness predicts cognitive decline in Alzheimer's disease. J Alzheimers Dis 2013;33:755-766. https://doi.org/10.3233/JAD-2012-121408
  29. Braak H, Braak E. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging 1995;16:271-278; discussion 278-284. https://doi.org/10.1016/0197-4580(95)00021-6
  30. Risacher SL, Shen L, West JD, Kim S, McDonald BC, Beckett LA, et al. Longitudinal MRI atrophy biomarkers: relationship to conversion in the ADNI cohort. Neurobiol Aging 2010;31:1401-1418. https://doi.org/10.1016/j.neurobiolaging.2010.04.029
  31. LeDoux JE, Schiller D. The human amygdala: insights from other animals. In: Whalen PJ, Phelps EA, editors. The Human Amygdala. New York: Guilford Press;2009. p.43-60.
  32. Miller MI, Younes L, Ratnanather JT, Brown T, Trinh H, Lee DS, et al. Amygdalar atrophy in symptomatic Alzheimer's disease based on diffeomorphometry: the BIOCARD cohort. Neurobiol Aging 2015;36 Suppl 1:S3-S10. https://doi.org/10.1016/j.neurobiolaging.2014.06.032
  33. Tsuchiya K, Kosaka K. Neuropathological study of the amygdala in presenile Alzheimer’s disease. J Neurol Sci 1990;100:165-173. https://doi.org/10.1016/0022-510X(90)90029-M
  34. Scott SA, DeKosky ST, Scheff SW. Volumetric atrophy of the amygdala in Alzheimer's disease: quantitative serial reconstruction. Neurology 1991;41:351-356. https://doi.org/10.1212/WNL.41.3.351
  35. Scott SA, DeKosky ST, Sparks DL, Knox CA, Scheff SW. Amygdala cell loss and atrophy in Alzheimer’s disease. Ann Neurol 1992;32:555-563. https://doi.org/10.1002/ana.410320412
  36. Poulin SP, Dautoff R, Morris JC, Barrett LF, Dickerson BC; Alzheimer’s Disease Neuroimaging Initiative. Amygdala atrophy is prominent in early Alzheimer’s disease and relates to symptom severity. Psychiatry Res 2011;194:7-13. https://doi.org/10.1016/j.pscychresns.2011.06.014
  37. Qiu A, Fennema-Notestine C, Dale AM, Miller MI; Alzheimer's Disease Neuroimaging Initiative. Regional shape abnormalities in mild cognitive impairment and Alzheimer's disease. Neuroimage 2009;45:656-661. https://doi.org/10.1016/j.neuroimage.2009.01.013
  38. Cavedo E, Boccardi M, Ganzola R, Canu E, Beltramello A, Caltagirone C, et al. Local amygdala structural differences with 3T MRI in patients with Alzheimer disease. Neurology 2011;76:727-733. https://doi.org/10.1212/WNL.0b013e31820d62d9
  39. Aboitiz F, Scheibel AB, Fisher RS, Zaidel E. Fiber composition of the human corpus callosum. Brain Res 1992;598:143-153. https://doi.org/10.1016/0006-8993(92)90178-C
  40. Hoptman MJ, Davidson RJ. How and why do the two cerebral hemispheres interact? Psychol Bull 1994;116:195-219. https://doi.org/10.1037/0033-2909.116.2.195
  41. Sidtis JJ, Volpe BT, Holtzman JD, Wilson DH, Gazzaniga MS. Cognitive interaction after staged callosal section: evidence for transfer of semantic activation. Science 1981;212:344-346. https://doi.org/10.1126/science.6782673
  42. Innocenti GM. General organization of callosal connections in the cerebral cortex. In: Jones EG, Peters A, editors. Sensory-motor areas and aspects of cortical connectivity. Vol 5. New York: Springer;1986. p.291-353.
  43. de Lacoste MC, Kirkpatrick JB, Ross ED. Topography of the human corpus callosum. J Neuropathol Exp Neurol 1985;44:578-591. https://doi.org/10.1097/00005072-198511000-00004
  44. Hofer S, Frahm J. Topography of the human corpus callosum revisited--comprehensive fiber tractography using diffusion tensor magnetic resonance imaging. Neuroimage 2006;32:989-994. https://doi.org/10.1016/j.neuroimage.2006.05.044
  45. Elahi S, Bachman AH, Lee SH, Sidtis JJ, Ardekani BA; Alzheimer's Disease Neuroimaging Initiative. Corpus callosum atrophy rate in mild cognitive impairment and prodromal Alzheimer's disease. J Alzheimers Dis 2015;45:921-931. https://doi.org/10.3233/JAD-142631
  46. Di Paola M, Caltagirone C, Spalletta G. What does the corpus callosum tell us about brain changes in the elderly? Expert Rev Neurother 2011;11:1557-1560. https://doi.org/10.1586/ern.11.130
  47. Ryberg C, Rostrup E, Paulson OB, Barkhof F, Scheltens P, van Straaten EC, et al. Corpus callosum atrophy as a predictor of age-related cognitive and motor impairment: a 3-year follow-up of the LADIS study cohort. J Neurol Sci 2011;307:100-105. https://doi.org/10.1016/j.jns.2011.05.002
  48. Di Paola M, Di Iulio F, Cherubini A, Blundo C, Casini AR, Sancesario G, et al. When, where, and how the corpus callosum changes in MCI and AD: a multimodal MRI study. Neurology 2010;74:1136-1142. https://doi.org/10.1212/WNL.0b013e3181d7d8cb
  49. Bachman AH, Lee SH, Sidtis JJ, Ardekani BA. Corpus callosum shape and size changes in early Alzheimer's disease: a longitudinal MRI study using the OASIS brain database. J Alzheimers Dis 2014;39:71-78.
  50. Teipel SJ, Bayer W, Alexander GE, Zebuhr Y, Teichberg D, Kulic L, et al. Progression of corpus callosum atrophy in Alzheimer disease. Arch Neurol 2002;59:243-248. https://doi.org/10.1001/archneur.59.2.243
  51. Zhu M, Wang X, Gao W, Shi C, Ge H, Shen H, et al. Corpus callosum atrophy and cognitive decline in early Alzheimer’s disease: longitudinal MRI study. Dement Geriatr Cogn Disord 2014;37:214-222. https://doi.org/10.1159/000350410
  52. Wang XD, Ren M, Zhu MW, Gao WP, Zhang J, Shen H, et al. Corpus callosum atrophy associated with the degree of cognitive decline in patients with Alzheimer's dementia or mild cognitive impairment: a meta-analysis of the region of interest structural imaging studies. J Psychiatr Res 2015;63:10-19. https://doi.org/10.1016/j.jpsychires.2015.02.005
  53. Povova J, Ambroz P, Bar M, Pavukova V, Sery O, Tomaskova H, et al. Epidemiological of and risk factors for Alzheimer's disease: a review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2012;156:108-114. https://doi.org/10.5507/bp.2012.055
  54. Prasad K, Wiryasaputra L, Ng A, Kandiah N. White matter disease independently predicts progression from mild cognitive impairment to Alzheimer's disease in a clinic cohort. Dement Geriatr Cogn Disord 2011;31:431-434. https://doi.org/10.1159/000330019
  55. Solomon A, Kareholt I, Ngandu T, Winblad B, Nissinen A, Tuomilehto J, et al. Serum cholesterol changes after midlife and late-life cognition: twenty-one-year follow-up study. Neurology 2007;68:751-756. https://doi.org/10.1212/01.wnl.0000256368.57375.b7
  56. Li G, Shofer JB, Kukull WA, Peskind ER, Tsuang DW, Breitner JC, et al. Serum cholesterol and risk of Alzheimer disease: a community-based cohort study. Neurology 2005;65:1045-1050. https://doi.org/10.1212/01.wnl.0000178989.87072.11
  57. Han X, Holtzman DM, McKeel DW Jr. Plasmalogen deficiency in early Alzheimer's disease subjects and in animal models: molecular characterization using electrospray ionization mass spectrometry. J Neurochem 2001;77:1168-1180. https://doi.org/10.1046/j.1471-4159.2001.00332.x
  58. Goodenowe DB, Cook LL, Liu J, Lu Y, Jayasinghe DA, Ahiahonu PW, et al. Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer's disease and dementia. J Lipid Res 2007;48:2485-2498. https://doi.org/10.1194/jlr.P700023-JLR200
  59. Igarashi M, Ma K, Gao F, Kim HW, Rapoport SI, Rao JS. Disturbed choline plasmalogen and phospholipid fatty acid concentrations in Alzheimer’s disease prefrontal cortex. J Alzheimers Dis 2011;24:507-517. https://doi.org/10.3233/JAD-2011-101608
  60. Cooper C, Sommerlad A, Lyketsos CG, Livingston G. Modifiable predictors of dementia in mild cognitive impairment: a systematic review and meta-analysis. Am J Psychiatry 2015;172:323-334. https://doi.org/10.1176/appi.ajp.2014.14070878
  61. Sohn JH, Lee SY, Kim HC, Lee SM, Choi HC. Relationship between homocysteine level, white matter lesion and cognitive decline. J Korean Geriatr Soc 2007;11:31-37.
  62. Loscalzo J. Homocysteine and dementias. N Engl J Med 2002;346:466-468. https://doi.org/10.1056/NEJM200202143460702
  63. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288:2015-2022. https://doi.org/10.1001/jama.288.16.2015
  64. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:2693-2698. https://doi.org/10.1001/jama.1993.03510220049033
  65. Goodwin JS, Goodwin JM, Garry PJ. Association between nutritional status and cognitive functioning in a healthy elderly population. JAMA 1983;249:2917-2921. https://doi.org/10.1001/jama.1983.03330450047024
  66. McCaddon A, Hudson P, Davies G, Hughes A, Williams JH, Wilkinson C. Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord 2001;12:309-313. https://doi.org/10.1159/000051275
  67. Morris MS, Jacques PF, Rosenberg IH, Selhub J; National Health and Nutrition Examination Survey. Hyperhomocysteinemia associated with poor recall in the third National Health and Nutrition Examination Survey. Am J Clin Nutr 2001;73:927-933. https://doi.org/10.1093/ajcn/73.5.927
  68. Budge M, Johnston C, Hogervorst E, de Jager C, Milwain E, Iversen SD, et al. Plasma total homocysteine and cognitive performance in a volunteer elderly population. Ann N Y Acad Sci 2000;903:407-410. https://doi.org/10.1111/j.1749-6632.2000.tb06392.x
  69. Blasko I, Hinterberger M, Kemmler G, Jungwirth S, Krampla W, Leitha T, et al. Conversion from mild cognitive impairment to dementia: influence of folic acid and vitamin B12 use in the VITA cohort. J Nutr Health Aging 2012;16:687-694. https://doi.org/10.1007/s12603-012-0051-y
  70. Hankey GJ. Is homocysteine a causal and treatable risk factor for vascular diseases of the brain (cognitive impairment and stroke)? Ann Neurol 2002;51:279-281. https://doi.org/10.1002/ana.10134
  71. Schmidt R, Fazekas F, Kleinert G, Offenbacher H, Gindl K, Payer F, et al. Magnetic resonance imaging signal hyperintensities in the deep and subcortical white matter. A comparative study between stroke patients and normal volunteers. Arch Neurol 1992;49:825-827. https://doi.org/10.1001/archneur.1992.00530320049011
  72. Matsui T, Arai H, Yuzuriha T, Yao H, Miura M, Hashimoto S, et al. Elevated plasma homocysteine levels and risk of silent brain infarction in elderly people. Stroke 2001;32:1116-1119. https://doi.org/10.1161/01.STR.32.5.1116
  73. Vermeer SE, van Dijk EJ, Koudstaal PJ, Oudkerk M, Hofman A, Clarke R, et al. Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam scan study. Ann Neurol 2002;51:285-289. https://doi.org/10.1002/ana.10111
  74. Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol 2006;5:949-960. https://doi.org/10.1016/S1474-4422(06)70598-1
  75. Hughes CF, Ward M, Hoey L, McNulty H. Vitamin B12 and ageing: current issues and interaction with folate. Ann Clin Biochem 2013;50(Pt 4):315-329. https://doi.org/10.1177/0004563212473279
  76. Obadia Y, Rotily M, Degrand-Guillaud A, Guelain J, Ceccaldi M, Severo C, et al. The PREMAP Study: prevalence and risk factors of dementia and clinically diagnosed Alzheimer's disease in Provence, France. Prevalence of Alzheimer's disease in Provence. Eur J Epidemiol 1997;13:247-253. https://doi.org/10.1023/A:1007300305507
  77. Roses AD. Apolipoprotein E affects the rate of Alzheimer disease expression: beta-amyloid burden is a secondary consequence dependent on APOE genotype and duration of disease. J Neuropathol Exp Neurol 1994;53:429-437. https://doi.org/10.1097/00005072-199409000-00002
  78. Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC. Impact of APOE in mild cognitive impairment. Neurology 2004;63:1898-1901. https://doi.org/10.1212/01.WNL.0000144279.21502.B7
  79. Ramakers IH, Visser PJ, Aalten P, Bekers O, Sleegers K, van Broeckhoven CL, et al. The association between APOE genotype and memory dysfunction in subjects with mild cognitive impairment is related to age and Alzheimer pathology. Dement Geriatr Cogn Disord 2008;26:101-108. https://doi.org/10.1159/000144072
  80. Blom ES, Giedraitis V, Zetterberg H, Fukumoto H, Blennow K, Hyman BT, et al. Rapid progression from mild cognitive impairment to Alzheimer's disease in subjects with elevated levels of tau in cerebrospinal fluid and the APOE epsilon4/epsilon4 genotype. Dement Geriatr Cogn Disord 2009;27:458-464. https://doi.org/10.1159/000216841