4.7 Article

Atrophy subtypes in prodromal Alzheimer's disease are associated with cognitive decline

期刊

BRAIN
卷 141, 期 -, 页码 3443-3456

出版社

OXFORD UNIV PRESS
DOI: 10.1093/brain/awy264

关键词

Alzheimer's disease; non-negative matrix factorization; mild cognitive impairment; disease heterogeneity; prognosis

资金

  1. Stichting Alzheimer Nederland
  2. Stichting VUmc funds
  3. Stichting Dioraphte
  4. Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
  5. DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
  6. National Institute on Aging
  7. National Institute of Biomedical Imaging and Bioengineering
  8. AbbVie
  9. Alzheimer's Association
  10. Alzheimer's Drug Discovery Foundation
  11. Araclon Biotech
  12. BioClinica, Inc.
  13. Biogen
  14. Bristol-Myers Squibb Company
  15. CereSpir, Inc.
  16. Cogstate
  17. Eisai Inc.
  18. Elan Pharmaceuticals, Inc.
  19. Eli Lilly and Company
  20. EuroImmun
  21. F. Hoffmann-La Roche Ltd
  22. Genentech, Inc.
  23. Fujirebio
  24. GE Healthcare
  25. IXICO Ltd.
  26. Janssen Alzheimer Immunotherapy Research & Development, LLC.
  27. Johnson & Johnson Pharmaceutical Research & Development LLC.
  28. Lumosity
  29. Lundbeck
  30. Merck Co., Inc.
  31. Meso Scale Diagnostics, LLC.
  32. NeuroRx Research
  33. Neurotrack Technologies
  34. Novartis Pharmaceuticals Corporation
  35. Pfizer Inc.
  36. Piramal Imaging
  37. Servier
  38. Takeda Pharmaceutical Company
  39. Transition Therapeutics
  40. Canadian Institutes of Health Research
  41. EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant) [115372]
  42. ZonMW Memorabel grant programme [73305056, 733050824]
  43. NIHR biomedical research centre at UCLH

向作者/读者索取更多资源

Alzheimer's disease is a heterogeneous disorder. Understanding the biological basis for this heterogeneity is key for developing personalized medicine. We identified atrophy subtypes in Alzheimer's disease dementia and tested whether these subtypes are already present in prodromal Alzheimer's disease and could explain interindividual differences in cognitive decline. First we retrospectively identified atrophy subtypes from structural MRI with a data-driven cluster analysis in three datasets of patients with Alzheimer's disease dementia: discovery data (dataset 1: n = 299, age = 67 +/- 8, 50% female), and two independent external validation datasets (dataset 2: n = 181, age = 66 +/- 7, 52% female; dataset 3: n = 227, age = 74 +/- 8, 44% female). Subtypes were compared on clinical, cognitive and biological characteristics. Next, we classified prodromal Alzheimer's disease participants (n = 603, age = 72 +/- 8, 43% female) according to the best matching subtype to their atrophy pattern, and we tested whether subtypes showed cognitive decline in specific domains. In all Alzheimer's disease dementia datasets we consistently identified four atrophy subtypes: (i) medial-temporal predominant atrophy with worst memory and language function, older age, lowest CSF tau levels and highest amount of vascular lesions; (ii) parieto-occipital atrophy with poor executive/attention and visuospatial functioning and high CSF tau; (iii) mild atrophy with best cognitive performance, young age, but highest CSF tau levels; and (iv) diffuse cortical atrophy with intermediate clinical, cognitive and biological features. Prodromal Alzheimer's disease participants classified into one of these subtypes showed similar subtype characteristics at baseline as Alzheimer's disease dementia subtypes. Compared across subtypes in prodromal Alzheimer's disease, the medial-temporal subtype showed fastest decline in memory and language over time; the parieto-occipital subtype declined fastest on executive/attention domain; the diffuse subtype in visuospatial functioning; and the mild subtype showed intermediate decline in all domains. Robust atrophy subtypes exist in Alzheimer's disease with distinct clinical and biological disease expression. Here we observe that these subtypes can already be detected in prodromal Alzheimer's disease, and that these may inform on expected trajectories of cognitive decline.

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