Fall 2014 – Alzheimer’s Disease: A Clinical and Basic Science Review

Alzheimer’s Disease: A Clinical and Basic Science Review. 

Author: Igor O. Korolev

Author Affiliations: College of Osteopathic Medicine and Neuroscience Program, Michigan State University, East Lansing, MI, USA

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Corresponding Author: Igor O. Korolev; korolevi[at]msu.edu

Key Words: Alzheimer’s disease; mild cognitive impairment; dementia; neurodegeneration; neuroimaging; biomarkers.

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia in older adults and an important public health problem. The purpose of this review article is to provide a brief introduction to AD and the related concept of mild cognitive impairment (MCI). The article emphasizes clinical and neurobiological aspects of AD and MCI that medical students should be familiar with. In addition, the article describes advances in the use of biomarkers for diagnosis of AD and highlights ongoing efforts to develop novel therapies.

Published on date: September 31, 2014

Senior Editor: Liza Gill

Junior Editor: Timothy Smith

DOI: Pending

Citation: Korolev IO. Alzheimer’s Disease: A Clinical and Basic Science Review.  Medical Student Research Journal. 2014;4(Fall):24-33.

References:

  1. Alzheimer A. About a Peculiar Disease of the Cerebral Cortex. Allg Z Psychiatr. 1907; 64: 146-148.
  2. Alzheimer A. About a Peculiar Disease of the Cerebral Cortex. Alzheimer Dis Assoc Disord. 1987; 1: 3-8.
  3. Maurer K, Volk S, Gerbaldo H. Auguste D and Alzheimer’s Disease. Lancet. May 1997; 349(9064): 1546-1549. doi: 10.1016/S0140-6736(96)10203-8
  4. Gilman, S. Oxford American Handbook of Neurology. Oxford, England: Oxford University Press; 2010.
  5. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, et al. The diagnosis of dementia due to Alzheimer’s disease: Rocommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. May 2011; 7(3): 263-269. doi: 10.1016/j.jalz.2011.03.005
  6. Shadlen M, Larson E (2012) Evaluation of cognitive impairment and dementia. In: Basow D, editor. UpToDate. Waltham, MA: UpToDate.
  7. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, et al. Prevalence of Dementia in the United States: The Aging, Demographics, and Memory Study. Neuroepidemiology. 2007; 29: 125–132. doi:10.1159/000109998
  8. Thies W, Bleiler. 2013 Alzheimer’s disease facts and figures. Alzheimers Dement. 2013; 9: 208–245. doi:10.1016/j.jalz.2013.02.003
  9. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, et al. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013; 9: 63–75.e2. doi:10.1016/j.jalz.2012.11.007
  10. Ott A, Breteler MM, van Harskamp F, Claus JJ, van der Cammen TJ, et al. Prevalence of Alzheimer’s disease and vascular dementia: association with education. The Rotterdam study. BMJ 1995; 310: 970–973.
  11. Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010; 362: 329–344. doi:10.1056/NEJMra0909142
  12. Holtzman DM, Morris JC, Goate AM. Alzheimer’s disease: the challenge of the second century. Sci Transl Med. 2011; 3: 77sr1. doi:10.1126/scitranslmed.3002369
  13. Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, et al. Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. Proc Natl Acad Sci. USA 2005; 102: 8299–8302. doi:10.1073/pnas.0500579102
  14. Hebert LE, Scherr PA, McCann JJ, Beckett LA, Evans DA. Is the Risk of Developing Alzheimer’s Disease Greater for Women than for Men? Am J Epidemiol. 2001; 153: 132–136. doi:10.1093/aje/153.2.132
  15. Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol 2012; 11: 1006–1012. doi:10.1016/S1474-4422(12)70191-6
  16. Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 2011; 10: 819–828. doi:10.1016/S1474-4422(11)70072-2
  17. Mann DM. Pyramidal nerve cell loss in Alzheimer’s disease. 1996; 5: 423–427.
  18. Norfray JF, Provenzale JM. Alzheimer’s disease: neuropathologic findings and recent advances in imaging. AJR Am J Roentgenol. 2004; 182: 3–13. doi:10.2214/ajr.182.1.1820003
  19. Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science. 2002; 298: 789–791. doi:10.1126/science.1074069
  20. Jack CR, Petersen RC, Xu YC, Waring SC, O’Brien PC, et al. Medial temporal atrophy on MRI in normal aging and very mild Alzheimer’s disease. Neurology. 1997; 49: 786–794.
  21. Bozoki AC, Korolev IO, Davis NC, Hoisington LA, Berger KL. Disruption of limbic white matter pathways in mild cognitive impairment and Alzheimer’s disease: a DTI/FDG-PET study. Hum Brain Mapp. 2012; 33: 1792–1802. doi:10.1002/hbm.21320
  22. Braak H, Thal DR, Ghebremedhin E, Del Tredici K.Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011; 70: 960–969. doi:10.1097/NEN.0b013e318232a379
  23. Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol. 2012; 71: 266–273. doi:10.1097/NEN.0b013e31824b211b
  24. McKhann G, Drachman D, Folstein M, Katzman R, Price D, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984; 34: 939–944.
  25. Camicioli R. Distinguishing different dementias. Canadian Review of Alzheimer’s Disease and Other Dementias. 2006; 9: 4–11.
  26. Knopman DS, DeKosky ST, Cummings JL, Chui H, Corey-Bloom J, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001; 56: 1143–1153.
  27. S. Department of Health and Human Services, National Institutes of Health, National Institute on Aging, Alzheimer’s Disease Education & Referral (ADEAR) Center (2014) Alzheimer’s Disease Medications Fact Sheet (NIH Publication No. 08-3431). National Institute on Aging. Available: http://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-medications-fact-sheet. Accessed 15 April 2014.
  28. Tomita T. Secretase inhibitors and modulators for Alzheimer’s disease treatment. Expert Rev Neurother. 2009; 9: 661–679. doi:10.1586/ern.09.24
  29. De Strooper B, Vassar R, Golde T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol. 2010; 6: 99–107. doi:10.1038/nrneurol.2009.218
  30. Schenk D, Basi GS, Pangalos MN. Treatment strategies targeting amyloid β-protein. Cold Spring Harb Perspect Med. 2012; 2: a006387. doi:10.1101/cshperspect.a006387
  31. Wischik CM, Harrington CR, Storey JMD. Tau-aggregation inhibitor therapy for Alzheimer’s disease. Biochem Pharmacol. 2014; 88: 529–539. doi:10.1016/j.bcp.2013.12.008
  32. Selkoe DJ. Resolving controversies on the path to Alzheimer’s therapeutics. Nat Med. 2011; 17: 1060–1065. doi:10.1038/nm.2460
  33. Mullane K, Williams M. Alzheimer’s therapeutics: continued clinical failures question the validity of the amyloid hypothesis-but what lies beyond? Biochem Pharmacol. 2013; 85: 289–305. doi:10.1016/j.bcp.2012.11.014
  34. Corbett A, Williams G, Ballard C. Drug Repositioning: An Opportunity to Develop Novel Treatments for Alzheimer’s Disease. 2013; 6: 1304–1321. doi:10.3390/ph6101304.
  35. Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature. 2009; 461: 916–922. doi:10.1038/nature08538
  36. Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, et al. Report of the task force on designing clinical trials in early (predementia) AD. 2011; 76: 280–286. doi:10.1212/WNL.0b013e318207b1b9
  37. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7: 280–292. doi:10.1016/j.jalz.2011.03.003
  38. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2014; 256: 183–194. doi:10.1111/j.1365-2796.2004.01388.x
  39. Petersen RC, Roberts RO, Knopman DS, Boeve BF, Geda YE, et al. Mild cognitive impairment: ten years later. Arch Neurol. 2009; 66: 1447–1455. doi:10.1001/archneurol.2009.266
  40. Busse A, Hensel A, Guhne U, Angermeyer MC, Riedel-Heller SG. Mild cognitive impairment: Long-term course of four clinical subtypes. 2006; 67: 2176–2185. doi:10.1212/01.wnl.0000249117.23318.e1
  41. Manly JJ, Tang M-X, Schupf N, Stern Y, Vonsattel J-PG, et al. Frequency and course of mild cognitive impairment in a multiethnic community. Ann Neurol. 2008; 63: 494–506. doi:10.1002/ana.21326
  42. Farias ST, Mungas D, Reed BR, Harvey D, DeCarli C. Progression of mild cognitive impairment to dementia in clinic- vs community-based cohorts. Arch Neurol. 2009; 66: 1151–1157. doi:10.1001/archneurol.2009.106
  43. Mitchell AJ, Shiri-Feshki M. Temporal trends in the long term risk of progression of mild cognitive impairment: a pooled analysis. J Neurol Neurosurg Psychiatr. 2008; 79: 1386–1391. doi:10.1136/jnnp.2007.142679
  44. Bozoki A, Giordani B, Heidebrink JL, Foster NL. Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss. Arch Neurol. 2001; 58: 411–416.
  45. Gauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, et al. Mild cognitive impairment. Lancet. 2006; 367: 1262–1270. doi:10.1016/S0140-6736(06)68542-5
  46. He J, Farias S, Martinez O, Reed B, Mungas D, et al. Differences in brain volume, hippocampal volume, cerebrovascular risk factors, and apolipoprotein E4 among mild cognitive impairment subtypes. Arch Neurol. 2009; 66: 1393–1399. doi:10.1001/archneurol.2009.252
  47. Rabinovici GD, Seeley WW, Kim EJ, Gorno-Tempini ML, Rascovsky K, et al. Distinct MRI Atrophy Patterns in Autopsy-Proven Alzheimer’s Disease and Frontotemporal Lobar Degeneration. Am J Alzheimers Dis Other Demen. 2007; 22: 474–488. doi:10.1177/1533317507308779
  48. Whitwell JL, Petersen RC, Negash S, Weigand SD, Kantarci K, et al. Patterns of atrophy differ among specific subtypes of mild cognitive impairment. Arch Neurol. 2007; 64: 1130–1138. doi:10.1001/archneur.64.8.1130
  49. Devanand DP, Pradhaban G, Liu X, Khandji A, De Santi S, et al. Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease. 2007; 68: 828–836. doi:10.1212/01.wnl.0000256697.20968.d7
  50. Nestor SM, Rupsingh R, Borrie M, Smith M, Accomazzi V, et al. Ventricular enlargement as a possible measure of Alzheimer’s disease progression validated using the Alzheimer’s disease neuroimaging initiative database. 2008; 131: 2443–2454. doi:10.1093/brain/awn146
  51. Mori S, Zhang J. Principles of diffusion tensor imaging and its applications to basic neuroscience research. 2006; 51: 527–539. doi:10.1016/j.neuron.2006.08.012
  52. Zhu DC, Majumdar S, Korolev IO, Berger KL, Bozoki AC. Alzheimer’s disease and amnestic mild cognitive impairment weaken connections within the default-mode network: a multi-modal imaging study. J Alzheimers Dis. 2013; 34: 969–984. doi:10.3233/JAD-121879
  53. Cole DM, Smith SM, Beckmann CF. Advances and pitfalls in the analysis and interpretation of resting-state FMRI data. Front Syst Neurosci. 2010; 4: 8. doi:10.3389/fnsys.2010.00008
  54. Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, et al. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol. 1997; 42: 85–94. doi:10.1002/ana.410420114
  55. Mosconi L, Tsui WH, Herholz K, Pupi A, Drzezga A, et al. Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer’s disease, and other dementias. J Nucl Med. 2008; 49: 390–398. doi:10.2967/jnumed.107.045385
  56. Foster NL, Heidebrink JL, Clark CM, Jagust WJ, Arnold SE, et al. FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer’s disease. 2007; 130: 2616–2635. doi:10.1093/brain/awm177
  57. Jack CR, Lowe VJ, Senjem ML, Weigand SD, Kemp BJ, et al. 11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment. 2008; 131: 665–680. doi:10.1093/brain/awm336
  58. Yang L, Rieves D, Ganley C. Brain Amyloid Imaging — FDA Approval of Florbetapir F18 Injection. New England Journal of Medicine. 2012; 367: 885–887. doi:10.1056/NEJMp1208061
  59. Pearson SD, Ollendorf DA, Colby JA. Amyloid-β positron emission tomography in the diagnostic evaluation of Alzheimer disease: Summary of primary findings and conclusions. JAMA Intern Med. 2014; 174: 133–134. doi:10.1001/jamainternmed.2013.11711
  60. S. Department of Health and Human Services, Centers for Medicare and Medicaid Services, (2013) Decision Memo for Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N). Available: http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=265. Accessed 21 April 2014.
  61. Vemuri P, Wiste HJ, Weigand SD, Shaw LM, Trojanowski JQ, et al. MRI and CSF biomarkers in normal, MCI, and AD subjects: diagnostic discrimination and cognitive correlations. Neurology. 2009; 73: 287–293. doi:10.1212/WNL.0b013e3181af79e5
  62. Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, et al. The Alzheimer’s Disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimers Dement. 2012; 8: S1–68. doi:10.1016/j.jalz.2011.09.172
  63. Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, et al. Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry. 2012; 69: 98–106. doi:10.1001/archgenpsychiatry.2011.155
  64. Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, et al. Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med. 2007; 13: 1359–1362. doi:10.1038/nm1653
  65. Johnstone D, Milward EA, Berretta R, Moscato P. Multivariate protein signatures of pre-clinical Alzheimer’s disease in the Alzheimer’s disease neuroimaging initiative (ADNI) plasma proteome dataset. PLoS ONE. 2007; 7: e34341. doi:10.1371/journal.pone.0034341
  66. Björkqvist M, Ohlsson M, Minthon L, Hansson O. Evaluation of a Previously Suggested Plasma Biomarker Panel to Identify Alzheimer’s Disease. PLoS ONE. 2012; 7: e29868. doi:10.1371/journal.pone.0029868
  67. Doecke JD, Laws SM, Faux NG, Wilson W, Burnham SC, et al. Blood-Based Protein Biomarkers for Diagnosis of Alzheimer Disease. Archives of Neurology. 2012: 1–8. doi:10.1001/archneurol.2012.1282
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Jessica Wummel

Executive Editor
Jessica Wummel is a third year medical student at Michigan State University’s College of Human Medicine. She received her B.S. in Human Biology with a specialization in Bioethics, Humanities, and Society also from Michigan State University in 2011 from the Lyman Briggs College. She is interested in pursuing a career in Med/Peds and would eventually like to be involved in academic medicine later in her career.