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On the path to 2025: understanding the Alzheimer’s disease continuum

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Aisen, Paul S., Cummings, Jeffrey, Jack, Clifford R., Morris, John C., Sperling, Reisa, Frölich, Lutz, Jones, Roy W., Dowsett, Sherie A. +4 more·2017·Alzheimer's Research & Therapy
DOI 10.1186/s13195-017-0283-5PMC PMC5549378
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Abstract

Basic research advances in recent years have furthered our understanding of the natural history of Alzheimer's disease (AD). It is now recognized that pathophysiological changes begin many years prior to clinical manifestations of disease and the spectrum of AD spans from clinically asymptomatic to severely impaired. Defining AD purely by its clinical presentation is thus artificial and efforts have been made to recognize the disease based on both clinical and biomarker findings. Advances with biomarkers have also prompted a shift in how the disease is considered as a clinico-pathophysiological entity, with an increasing appreciation that AD should not only be viewed with discrete and defined clinical stages, but as a multifaceted process moving along a seamless continuum. Acknowledging this concept is critical to understanding the development process for disease-modifying therapies, and for initiating effective diagnostic and disease management options. In this article, we discuss the concept of a disease continuum from pathophysiological, biomarker, and clinical perspectives, and highlight the importance of considering AD as a continuum rather than discrete stages. While the pathophysiology of AD has still not been elucidated completely, there is ample evidence to support researchers and clinicians embracing the view of a disease continuum in their study, diagnosis, and management of the disease.

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  • As Alzheimer's disease progresses, downstream clinical features of memory loss, social dependence and motor abnormalities eventually become manifest.

    “As the disease progresses, downstream clinical features of memory loss, social dependence and motor abnormalities eventually become manifest [5, 6].”

    From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [5]

    In “Advancing along the clinical continuum” (page unavailable), the paper describes progressive memory loss and declining ability to perform daily activities, which broadly supports increasing dependence. It does not identify motor abnormalities as a feature of progression, and it cautions that not everyone progresses through all dementia stages during their lifetime. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Alzheimer's disease is characterized by a long asymptomatic preclinical phase, and cognitively normal individuals can also have the disease.

    “AD is also characterized by a long asymptomatic preclinical phase, and cognitively normal individuals can also have the disease [5].”

    From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [5]

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Research works printed but not linked: 54

  1. [1]Essay HJ A hundred years of Alzheimer's disease research Neuron. 2006 52 3 13 10.1016/j.neuron.2006.09.016 17015223 · DOI · Paper page
  2. [2]Glenner GG Wong CW Quaranta V Eanes ED The amyloid deposits in Alzheimer's disease: their nature and pathogenesis Appl Pathol. 1984 2 357 69 6242724
  3. [3]Brion JP, Passareiro H, Nunez J, Flament-Durand J. Mise en evidence de la immunologique de la protein tau au lesions de degeneresescence neurofibrillaire de la maladie. Arch Biol (Brux). 1985;95:229–35.
  4. [4]Cummings J, Aisen PS, DuBois B, Frölich L, Jack Jr CR, Jones RW, et al. Drug development in Alzheimer's disease: the path to 2025. Alzheimers Res Ther. 2016. vol. 8. doi:10.1186/s13195-016-0207-9. PMC5028936 27646601 · DOI · Paper page
  5. [11]Raskin J Cummings J Hardy J Schuh K Dean RA Neurobiology of Alzheimer's disease: integrated molecular, physiological, anatomical, biomarker, and cognitive dimensions Curr Alzheimer Res. 2015 12 712 22 10.2174/1567205012666150701103107 26412218 PMC5384474 · DOI
  6. [12]Ittner LM Götz J Amyloid-β and tau—a toxic pas de deux in Alzheimer's disease Nat Rev Neurosci. 2011 12 65 72 10.1038/nrn2967 21193853 · DOI
  7. [13]Arendt T Stieler JT Holzer M Tau and tauopathies Brain Res Bull. 2016 126 238 92 10.1016/j.brainresbull.2016.08.018 27615390 · DOI · Paper page
  8. [14]Crary JF Trojanowski JQ Schneider JA Primary age-related tauopathy (PART): a common pathology associated with human aging Acta Neuropathol. 2014 128 755 66 10.1007/s00401-014-1349-0 25348064 PMC4257842 · DOI · Paper page
  9. [15]Jellinger KA Alafuzoff I Attems J Beach TG Cairns NJ Crary JF PART, a distinct tauopathy, different from classical sporadic Alzheimer disease Acta Neuropathol. 2015 129 757 62 10.1007/s00401-015-1407-2 25778618 PMC4534004 · DOI · Paper page
  10. [16]Sperling RA Aisen P Beckett L Bennett DA Craft S Fagan AM Towards defining the preclinical stage of Alzheimer’s disease: recommendations from the National Institute on Aging and the Alzheimer’s Association workgroup Alzheimers Dement. 2011 7 280 92 10.1016/j.jalz.2011.03.003 21514248 PMC3220946 · DOI · Paper page
  11. [17]Mormino EC, Betensky RA, Hedden T, Schultz AP, Ward A, Huijbers W, et al. Amyloid and APOE ε4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology. 2014;82:1760–7. doi:10.1212/WNL.0000000000000431. PMC4035706 24748674 · DOI
  12. [20]Rusanen M Kivipelto M Quesenberry CP Jr Zhou J Whitmer RA Heavy smoking in midlife and long-term risk of Alzheimer disease and vascular dementia Arch Intern Med. 2011 171 333 9 10.1001/archinternmed.2010.393 20975015 · DOI
  13. [21]Solomon A, Mangialasche F, Richard E, Andrieu S, Bennett DA, Breteler M, et al. Advances in the prevention of Alzheimer's disease and dementia. J Intern Med. 2014;275:229–50. doi:10.1111/joim.1217. PMC4390027 24605807 · DOI
  14. [23]Dubois B Feldman HH Jacova C Hampel H Molinuevo JL Blennow K Dubois B Feldman HH Jacova C Hampel H Molinuevo J Dubois B Feldman HH Jacova C Hampel H Molinuevo J Blennow K Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria Lancet Neurol 2014 13 614 29 10.1016/S1474-4422(14)70090-0 24849862 · DOI · Paper page
  15. [24]Jack Jr CR, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al. Alzheimer's Disease Neuroimaging Initiative. Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer's disease. Brain. 2010;133:3336–48. PMC2965425 20935035
  16. [25]Jack CR Jr Knopman DS Jagust WJ Petersen RC Weiner MW Aisen PS Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers Lancet Neurol. 2013 12 207 16 10.1016/S1474-4422(12)70291-0 23332364 PMC3622225 · DOI · Paper page
  17. [26]Bateman RJ Xiong C Benzinger TL Fagan AM Goate A Fox NC Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease N Engl J Med 2012 367 795 804 10.1056/NEJMoa1202753 22784036 PMC3474597 · DOI · Paper page
  18. [27]Benzinger TL, Blazey T, Jack Jr CR, Koeppe RA, Su Y, Xiong C, et al. Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease. Proc Natl Acad Sci U S A. 2013;110:E4502–9. doi:10.1073/pnas. PMC3839740 24194552 · DOI
  19. [28]Fleisher AS, Chen K, Quiroz YT, Jakimovich LJ, Gutierrez Gomez M, Langois CM, et al. Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study. JAMA Neurol. 2015;72:316–24. doi:10.1001/jamaneurol.2014.3314. PMC4355261 25580592 · DOI · Paper page
  20. [29]van Rossum IA Visser PJ Knol DL van der Flier WM Teunissen CE Barkhof F Injury markers but not amyloid markers are associated with rapid progression from mild cognitive impairment to dementia in Alzheimer's disease J Alzheimers Dis. 2012 29 319 27 22233766
  21. [30]Ossenkoppele R Schonhaut DR Schöll M Lockhart SN Ayakta N Baker SL Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease Brain. 2016 139 1551 67 10.1093/brain/aww027 26962052 PMC5006248 · DOI · Paper page
  22. [31]Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol. 2013;12:357–67. doi:10.1016/S1474-4422(13)70044-9. 23477989 · DOI · Paper page
  23. [33]Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015;313:1924–38. doi:10.1001/jama.2015.4668. PMC4486209 25988462 · DOI · Paper page
  24. [34]Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families Science. 1993 261 921 3 10.1126/science.8346443 8346443 · DOI · Paper page
  25. [35]Chartier-Harlin MC Parfitt M Legrain S Pérez-Tur J Brousseau T Evans A Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region Hum Mol Genet 1994 3 569 74 10.1093/hmg/3.4.569 8069300 · DOI
  26. [37]Johnson DK Storandt M Morris JC Galvin JE Longitudinal study of the transition from healthy aging to Alzheimer disease Arch Neurol. 2009 66 1254 9 10.1001/archneurol.2009.158 19822781 PMC2795328 · DOI
  27. [38]Donohue MC Sperling RA Salmon DP Rentz DM Raman R Thomas RG The preclinical Alzheimer cognitive composite: measuring amyloid-related decline JAMA Neurol. 2014 71 961 70 10.1001/jamaneurol.2014.803 24886908 PMC4439182 · DOI · Paper page
  28. [39]Jessen F Subjective and objective cognitive decline at the pre-dementia stage of Alzheimer's disease Eur Arch Psychiatry Clin Neurosci. 2014 264 S3 7 10.1007/s00406-014-0539-z 25238934 · DOI
  29. [40]Liu-Seifert H Siemers E Price K Han B Selzler KJ Henley D Cognitive impairment precedes and predicts functional impairment in mild Alzheimer’s disease J Alzheimers Dis. 2015 47 205 14 10.3233/JAD-142508 26402769 PMC4923754 · DOI
  30. [41]Dubois B Feldman HH Jacova C Dekosky ST Barberger-Gateau P Cummings J Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria Lancet Neurol. 2007 6 734 46 10.1016/S1474-4422(07)70178-3 17616482 · DOI · Paper page
  31. [44]Wagner M Wolf S Reischies FM Daerr M Wolfsgruber S Jessen F Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease Neurology. 2012 78 379 86 10.1212/WNL.0b013e318245f447 22238414 · DOI
  32. [45]Jekel K Damian M Wattmo C Hausner L Bullock R Connelly PJ Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review Alzheimers Res Ther. 2015 7 17 10.1186/s13195-015-0099-0 25815063 PMC4374414 · DOI · Paper page
  33. [46]Jack CR Jr Bennett DA Blennow K Carrillo MC Feldman HH Frisoni GB A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers Neurology. 2016 87 539 47 10.1212/WNL.0000000000002923 27371494 PMC4970664 · DOI · Paper page
  34. [48]Arnerić SP Batrla-Utermann R Beckett L Bittner T Blennow K Carter L Cerebrospinal fluid biomarkers for Alzheimer's disease: a view of the regulatory science qualification landscape from the Coalition Against Major Diseases CSF Biomarker Team J Alzheimers Dis. 2017 55 19 35 10.3233/JAD-160573 27662307 PMC5115607 · DOI
  35. [49]Chételat G, La Joie R, Villain N, Perrotin A, de La Sayette V, Eustache F, Vandenberghe R. Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer's disease. Neuroimage Clin. 2013;2:356–65. doi:10.1016/j.nicl.2013.02.006. PMC3777672 24179789 · DOI
  36. [50]Johnson KA Schultz A Betensky RA Becker JA Sepulcre J Rentz D Tau positron emission tomographic imaging in aging and early Alzheimer disease Ann Neurol. 2016 79 110 9 10.1002/ana.24546 26505746 PMC4738026 · DOI · Paper page
  37. [51]Siemers E Sundell K Carlson C Case M Sethuraman G Liu-Seifert H Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer’s disease patients Alzheimers Dement. 2016 12 110 20 10.1016/j.jalz.2015.06.1893 26238576 · DOI · Paper page
  38. [53]Galasko D Bennett D Sano M Ernesto C Thomas R Grundman M An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease. The Alzheimer’s disease Cooperative Study Alzheimer’s Disease and Associated Disorders 1997 11 S33 9 10.1097/00002093-199700112-00005 9236950 · DOI
  39. [54]Hamel R Köhler S Sistermans N Koene T Pijnenburg Y van der Flier W The trajectory of cognitive decline in the pre-dementia phase in memory clinic visitors: findings from the 4C-MCI study Psychol Med. 2015 45 1509 19 10.1017/S0033291714002645 25407094 · DOI
  40. [55]Walsh SP Raman R, Jones KB, Aisen PS, Alzheimer's Disease Cooperative Study Group. ADCS Prevention Instrument Project: the Mail-In Cognitive Function Screening Instrument (MCFSI) Alzheimer Dis Assoc Disord 2006 20 S170 8 10.1097/01.wad.0000213879.55547.57 17135810 · DOI
  41. [56]Marson DC Sawrie SM Snyder S McInturff B Stalvey T Boothe A Assessing financial capacity in patients with Alzheimer disease: a conceptual model and prototype instrument Arch Neurol. 2000 57 877 84 10.1001/archneur.57.6.877 10867786 · DOI
  42. [57]Buschke H, Kuslansky G, Katz M, Stewart WF, Sliwinski MJ, Eckholdt HM, Lipton RB Screening for dementia with the Memory Impairment Screen H. Neurology. 1999;52:231–8. doi:10.1212/WNL.52.2.231. 9932936 · DOI
  43. [58]Grober E Buschke H Genuine memory deficits in dementia Dev Neuropsychol. 1987 3 13 36 10.1080/87565648709540361 · DOI
  44. [59]Galvin JE Roe CM Powlishta KK Coats MA Muich SJ Grant E Miller JP Storandt M Morris JC The AD8: a brief informant interview to detect dementia Neurology. 2005 65 559 64 10.1212/01.wnl.0000172958.95282.2a 16116116 · DOI
  45. [60]Wang J, Logovinsky V, Hendrix S, Stanworth S, Perdoma C, Xu L, et al. ADCOMS: a composite clinical outcome for prodromal Alzheimer’s disease trials. J Neurol Neurosurg Psychiatry. 2016;87:993–9. doi:10.1136/jnnp-2015-312383. PMC5013117 27010616 · DOI · Paper page
  46. [61]Brodaty H Pond D Kemp NM Luscombe G Harding L Berman K Huppert FA The GPCOG: a new screening test for dementia designed for general practice J Am Geriatr Soc. 2002 50 530 4 10.1046/j.1532-5415.2002.50122.x 11943052 · DOI
  47. [62]Borson S Scanlan J Brush M Vitaliano P Dokmak A The mini-cog: a cognitive “vital signs” measure for dementia screening in multi-lingual elderly Int J Geriatr Psychiatry. 2000 15 1021 7 10.1002/1099-1166(200011)15:11<1021::AID-GPS234>3.0.CO;2-6 11113982 · DOI
  48. [63]Randolph C Tierney MC Mohr E Chase TN The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity J Clin Exp Neuropsych. 1988 20 310 9 10.1076/jcen.20.3.310.823 9845158 · DOI · Paper page
  49. [64]Dubois B Touchon J Portet F Ousset PJ Vellas B Michel B The “5-words”: a simple and sensitive test for the diagnosis of Alzheimer’s disease Presse Med. 2002 31 1696 9 12467149
  50. [65]Mormont E Jamart J Robaye L Validity of the five-word test for the evaluation of verbal episodic memory and dementia in a memory clinic setting J Geriatr Psychiatry Neurol. 2012 25 78 84 10.1177/0891988712445088 22689699 · DOI
  51. [66]Elwood RW The California Verbal Learning Test: psychometric characteristics and clinical application Neuropsychol Rev. 1995 5 173 201 10.1007/BF02214761 8653108 · DOI
  52. [68]Noone P. Addenbrooke’s Cognitive Examination-III. Occup Med (Lond). 2015;65:418–20. doi:10.1093/occmed/kqv041. 26187808 · DOI
  53. [71]Berg L Clinical Dementia Rating (CDR) Psychopharm Bull. 1988 24 637 9 3249765
  54. [72]Saxton J Swihart AA Neuropsychological assessment of the severely impaired elderly patient Clin Geriatr Med. 1989 5 531 43 2680032

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Authors
Aisen, P. S., Cummings, J., Jack, C. R., Morris, J. C., Sperling, R., Frölich, L., Jones, R. W., Dowsett, S. A., Matthews, B. R., Raskin, J., Scheltens, P., & Dubois, B.
Affiliations
  • University of Southern California (US)
  • Cleveland Clinic (US)
  • Mayo Clinic (US)
  • Washington University in St. Louis (US)
  • Brigham and Women's Hospital (US)
  • Heidelberg University (DE)
  • Royal United Hospital (GB)
  • Eli Lilly (United States) (US)
  • Eli Lilly (United Kingdom) (GB)
  • Vrije Universiteit Amsterdam (NL)
  • Institut des Sciences Moléculaires (FR)
Corresponding author
Aisen, Paul S.
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2017-08-09
Volume
9
Issue
1
Pages
60-60
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-017-0283-5
PMC
PMC5549378
OpenAlex
W2743373469
Cited by
556
References
19
Citations by year
2026: 47 · 2025: 91 · 2024: 90 · 2023: 67 · 2022: 65 · 2021: 73 · 2020: 51 · 2019: 43 · 2018: 27 · 2017: 2
FWCI
5.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
National Institute on Aging (K24AG035007, P01AG026276)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
Alzheimer's disease, disease continuum, biomarkers, disease stage, preclinical Alzheimer's disease, disease-modifying therapy, Alzheimer's disease diagnosis, pathophysiology
MeSH terms
Alzheimer Disease, Humans, Biomarkers, Disease Progression

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