AlzSWAN Knowledge Base

Powered by SWAN (Semantic Web Applications in Neuromedicine)

• Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
• Citation:
  Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
  

  Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.

  Lancet neurology. 2010 Jan;9(1):119-28
  [PubMed] [Alzforum]
• Source For Statements:
  • It is rational to select patients for inclusion in anti-Aβ therapy clinical trials on the basis of biomarker evidence of Aβ in the brain by use of either amyloid PET imaging or CSF Aβ42 although change in Aβ load over time has little relation to change in cognition.

    SHOW Details   Supporting(1)     Genes/Proteins: (2)

    Experimental Approach: Neuropsychology/Behavior,   Clinical trials,   Biomarkers,   Mechanism - biochemistry and structural biology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • The first phase of AD is pre-symptomatic, in which individuals are cognitively normal but have AD pathological changes, and would ultimately become symptomatic over time.

    SHOW Details   Supporting(3) 

    Experimental Approach: Epidemiology,   Neuropsychology/Behavior,   Biomarkers,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Price J, Morris J
      Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease.
      Annals of neurology. 1999 Mar;45(3):358-68
    • Savva G, Wharton S, Ince P, Forster G, Matthews F, Brayne C
      Age, neuropathology, and dementia.
      The New England journal of medicine. 2009 May 28;360(22):2302-9
    • Knopman D, Parisi J, Salviati A, Floriach-Robert M, Boeve B, Ivnik R, Smith G, Dickson D, Johnson K, Petersen L, McDonald W, Braak H, Petersen R
      Neuropathology of cognitively normal elderly.
      Journal of neuropathology and experimental neurology. 2003 Nov;62(11):1087-95
  • Cognitively normal individuals can accumulate substantial Aβ load with no immediate effect on gross brain structure or cognition, and have normal structural MRI studies.

    SHOW Details   Supporting(1)     Genes/Proteins: (2)

    Experimental Approach: Neuropsychology/Behavior,   Pathophysiology,   Mechanism - biochemistry and structural biology
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Jack C, Lowe V, Senjem M, Weigand S, Kemp B, Shiung M, Knopman D, Boeve B, Klunk W, Mathis C, Petersen R
      11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment.
      Brain : a journal of neurology. 2008 Mar;131(Pt 3):665-80

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • The direct substrate of memory impairment is hippocampal atrophy on MRI, and not Aβ deposition as measured by Pittsburgh compound B (PiB) imaging.

    SHOW Details   Supporting(2)     Genes/Proteins: (2)

    Experimental Approach: Mechanism - biochemistry and structural biology,   Biomarkers,   Neuropsychology/Behavior,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Mormino E, Kluth J, Madison C, Rabinovici G, Baker S, Miller B, Koeppe R, Mathis C, Weiner M, Jagust W
      Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects.
      Brain : a journal of neurology. 2009 May;132(Pt 5):1310-23
    • Frisoni G, Lorenzi M, Caroli A, Kemppainen N, Någren K, Rinne J
      In vivo mapping of amyloid toxicity in Alzheimer disease.
      Neurology. 2009 Apr 28;72(17):1504-11

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • The second prodromal phase of AD, mild cognitive impairment (MCI), is characterized by the onset of the earliest cognitive symptoms (typically deficits in episodic memory) that do not meet the criteria for dementia but rather varies from the earliest appearance of memory dysfunction to more widespread dysfunction in other cognitive domains.

    SHOW Details   Supporting(1) 

    Experimental Approach: Pathophysiology,   Neuropsychology/Behavior
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Petersen R
      Mild cognitive impairment as a diagnostic entity.
      Journal of internal medicine. 2004 Sep;256(3):183-94
  • Decreased fluorodeoxyglucose uptake measured by positron emission tomography (FDG-PET) and atrophy rate abnormalities, as measured by magnetic resonance imaging (MRI), precede any cognitive symptoms in individuals who later progress to AD; in patients who are in the mild cognitive impairment (MCI) phase of AD, MRI, FDG-PET, and CSF tau biomarkers are already abnormal.

    SHOW Details   Supporting(10) 

    Experimental Approach: Mechanism - molecular and cell,   Biomarkers,   Neuropsychology/Behavior,   Mechanism - biochemistry and structural biology,   Pathophysiology,   Mechanism - physiological systems
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Fox N, Warrington E, Rossor M
      Serial magnetic resonance imaging of cerebral atrophy in preclinical Alzheimer's disease.
      Lancet. 1999 Jun 19;353(9170):2125
    • Ewers M, Buerger K, Teipel S, Scheltens P, Schröder J, Zinkowski R, Bouwman F, Schönknecht P, Schoonenboom N, Andreasen N, Wallin A, DeBernardis J, Kerkman D, Heindl B, Blennow K, Hampel H
      Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI.
      Neurology. 2007 Dec 11;69(24):2205-12
    • Chételat G, Desgranges B, De La Sayette V, Viader F, Eustache F, Baron J
      Mapping gray matter loss with voxel-based morphometry in mild cognitive impairment.
      Neuroreport. 2002 Oct 28;13(15):1939-43
    • Shaw L, Vanderstichele H, Knapik-Czajka M, Clark C, Aisen P, Petersen R, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee V, Trojanowski J
      Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects.
      Annals of neurology. 2009 Apr;65(4):403-13
    • Minoshima S, Giordani B, Berent S, Frey K, Foster N, Kuhl D
      Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease.
      Annals of neurology. 1997 Jul;42(1):85-94
    • de Leon M, Convit A, Wolf O, Tarshish C, DeSanti S, Rusinek H, Tsui W, Kandil E, Scherer A, Roche A, Imossi A, Thorn E, Bobinski M, Caraos C, Lesbre P, Schlyer D, Poirier J, Reisberg B, Fowler J
      Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET).
      Proceedings of the National Academy of Sciences of the United States of America. 2001 Sep 11;98(19):10966-71
    • Kaye J, Swihart T, Howieson D, Dame A, Moore M, Karnos T, Camicioli R, Ball M, Oken B, Sexton G
      Volume loss of the hippocampus and temporal lobe in healthy elderly persons destined to develop dementia.
      Neurology. 1997 May;48(5):1297-304
    • Jagust W, Gitcho A, Sun F, Kuczynski B, Mungas D, Haan M
      Brain imaging evidence of preclinical Alzheimer's disease in normal aging.
      Annals of neurology. 2006 Apr;59(4):673-81
    • Sluimer J, Bouwman F, Vrenken H, Blankenstein M, Barkhof F, van der Flier W, Scheltens P
      Whole-brain atrophy rate and CSF biomarker levels in MCI and AD: a longitudinal study.
      Neurobiology of aging. 2010 May;31(5):758-64
    • Jack C, Shiung M, Gunter J, O'Brien P, Weigand S, Knopman D, Boeve B, Ivnik R, Smith G, Cha R, Tangalos E, Petersen R
      Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD.
      Neurology. 2004 Feb 24;62(4):591-600
  • Genes such as CR1, CLU, and PICALM , that amplify the effect of Aβ dysmetabolism on the neurodegenerative cascade might shift the cognitive decline curve closer to the amyloid curve since Clusterin (apolipoprotein J) seems to regulate the toxicity and solubility of Aβ and might modify its clearance at the blood–brain barrier; CR1 might also modify Aβ clearance and PICALM might be related to AD through a role in altering synaptic vesicle cycling or APP endocytosis.

    SHOW Details   Supporting(2)     Genes/Proteins: (4)

    Experimental Approach: Mechanism - physiological systems,   Pathophysiology,   Mechanism - biochemistry and structural biology,   Mechanism - molecular and cell,   Genetics
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Lambert J, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido M, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, de Pancorbo M, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues J, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P
      Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.
      Nature genetics. 2009 Oct;41(10):1094-9
    • Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere M, Pahwa J, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan A, Lovestone S, Powell J, Proitsi P, Lupton M, Brayne C, Rubinsztein D, Gill M, Lawlor B, Lynch A, Morgan K, Brown K, Passmore P, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith A, Love S, Kehoe P, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate A, Kauwe J, Cruchaga C, Nowotny P, Morris J, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn P, Van Broeckhoven C, Livingston G, Bass N, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw C, Tsolaki M, Singleton A, Guerreiro R, Mühleisen T, Nöthen M, Moebus S, Jöckel K, Klopp N, Wichmann H, Carrasquillo M, Pankratz V, Younkin S, Holmans P, O'Donovan M, Owen M, Williams J
      Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.
      Nature genetics. 2009 Oct;41(10):1088-93

    Genes/Proteins
    

    • Gene: PICALM phosphatidylinositol binding clathrin assembly protein [Homo sapiens]
    • Gene: CLU clusterin [Homo sapiens]
    • Gene: CR1 complement component (3b/4b) receptor 1 (Knops blood group) [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Measures of the neurodegenerative portion of the cascade (eg, CSF tau, FDG-PET, or structural MRI) should be used in AD therapeutic clinical trials as evidence of therapeutic modification of the neurodegenerative aspect of the AD pathological process and a combination of biomarkers might be needed in clinical trials to select appropriate participants and to follow disease progression.

    SHOW Details   Supporting(1) 

    Experimental Approach: Clinical trials,   Pathophysiology,   Mechanism - molecular and cell,   Biomarkers,   Mechanism - physiological systems
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • The presence of Aβ-plaque deposition alone, even in substantial quantities, is not sufficient to produce dementia, although abnormalities in biomarkers of Aβ deposition precede clinical/cognitive symptoms.

    SHOW Details   Supporting(5)     Genes/Proteins: (2)

    Experimental Approach: Biomarkers,   Mechanism - biochemistry and structural biology,   Neuropsychology/Behavior,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Gustafson D, Skoog I, Rosengren L, Zetterberg H, Blennow K
      Cerebrospinal fluid beta-amyloid 1-42 concentration may predict cognitive decline in older women.
      Journal of neurology, neurosurgery, and psychiatry. 2007 May;78(5):461-4
    • Stomrud E, Hansson O, Blennow K, Minthon L, Londos E
      Cerebrospinal fluid biomarkers predict decline in subjective cognitive function over 3 years in healthy elderly.
      Dementia and geriatric cognitive disorders. 2007;24(2):118-24
    • Fagan A, Roe C, Xiong C, Mintun M, Morris J, Holtzman D
      Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults.
      Archives of neurology. 2007 Mar;64(3):343-9
    • Li G, Sokal I, Quinn J, Leverenz J, Brodey M, Schellenberg G, Kaye J, Raskind M, Zhang J, Peskind E, Montine T
      CSF tau/Abeta42 ratio for increased risk of mild cognitive impairment: a follow-up study.
      Neurology. 2007 Aug 14;69(7):631-9
    • Fagan A, Head D, Shah A, Marcus D, Mintun M, Morris J, Holtzman D
      Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly.
      Annals of neurology. 2009 Feb;65(2):176-83

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • Although biomarkers of neurodegeneration correlate with clinical and pathological severity, they are not specific for AD and thus should not take precedence over Aβ biomarkers as inclusion criteria for patients in anti-amyloid therapeutic clinical trials, although an Aβ biomarker might be combined with MRI volumetrics to provide an indication of disease stage.

    SHOW Details   Supporting(1)     Genes/Proteins: (2)

    Experimental Approach: Mechanism - biochemistry and structural biology,   Biomarkers,   Clinical trials
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • Other diagnostic modalities (eg, functional MRI connectivity) will be added to this biomarker staging model as they mature.

    SHOW Details   Supporting(3) 

    Experimental Approach: Pathophysiology,   Biomarkers
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Buckner R, Sepulcre J, Talukdar T, Krienen F, Liu H, Hedden T, Andrews-Hanna J, Sperling R, Johnson K
      Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2009 Feb 11;29(6):1860-73
    • Buckner R, Snyder A, Shannon B, LaRossa G, Sachs R, Fotenos A, Sheline Y, Klunk W, Mathis C, Morris J, Mintun M
      Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005 Aug 24;25(34):7709-17
    • Sperling R, Laviolette P, O'Keefe K, O'Brien J, Rentz D, Pihlajamaki M, Marshall G, Hyman B, Selkoe D, Hedden T, Buckner R, Becker J, Johnson K
      Amyloid deposition is associated with impaired default network function in older persons without dementia.
      Neuron. 2009 Jul 30;63(2):178-88
  • FDG-PET changes might precede MRI changes in patients developing AD.

    SHOW Details   Supporting(3) 

    Experimental Approach: Biomarkers,   Pathophysiology,   Mechanism - physiological systems
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jagust W, Gitcho A, Sun F, Kuczynski B, Mungas D, Haan M
      Brain imaging evidence of preclinical Alzheimer's disease in normal aging.
      Annals of neurology. 2006 Apr;59(4):673-81
    • De Santi S, de Leon M, Rusinek H, Convit A, Tarshish C, Roche A, Tsui W, Kandil E, Boppana M, Daisley K, Wang G, Schlyer D, Fowler J
      Hippocampal formation glucose metabolism and volume losses in MCI and AD.
      Neurobiology of aging. 2001;22(4):529-39
    • Reiman E, Uecker A, Caselli R, Lewis S, Bandy D, de Leon M, De Santi S, Convit A, Osborne D, Weaver A, Thibodeau S
      Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer's disease.
      Annals of neurology. 1998 Aug;44(2):288-91
  • Evidence of disordered glucose uptake in cognitively normal young and middle-aged APOE ε4 carriers up to decades before disease-related clinical symptoms has no consensus interpretation, and these findings could be either neurodevelopmental in origin or early indicators of AD.

    SHOW Details   Supporting(4) 

    Experimental Approach: Pathophysiology,   Mechanism - physiological systems,   Biomarkers
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Reiman E, Chen K, Alexander G, Caselli R, Bandy D, Osborne D, Saunders A, Hardy J
      Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia.
      Proceedings of the National Academy of Sciences of the United States of America. 2004 Jan 6;101(1):284-9
    • Ghebremedhin E, Schultz C, Braak E, Braak H
      High frequency of apolipoprotein E epsilon4 allele in young individuals with very mild Alzheimer's disease-related neurofibrillary changes.
      Experimental neurology. 1998 Sep;153(1):152-5
    • Scarmeas N, Habeck C, Stern Y, Anderson K
      APOE genotype and cerebral blood flow in healthy young individuals.
      JAMA : the journal of the American Medical Association. 2003 Sep 24;290(12):1581-2
    • Reiman E, Chen K, Liu X, Bandy D, Yu M, Lee W, Ayutyanont N, Keppler J, Reeder S, Langbaum J, Alexander G, Klunk W, Mathis C, Price J, Aizenstein H, DeKosky S, Caselli R
      Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease.
      Proceedings of the National Academy of Sciences of the United States of America. 2009 Apr 21;106(16):6820-5
  • In AD patients who are rapidly declining clinically, MRI rates map well onto simultaneous cognitive deterioration, whereas neither rates of change in PiB staining nor CSF Aβ42 change significantly over time in patients with AD.

    SHOW Details   Supporting(2)     Genes/Proteins: (2)

    Experimental Approach: Biomarkers,   Mechanism - biochemistry and structural biology,   Pathophysiology,   Neuropsychology/Behavior
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, Wall A, Ringheim A, Långström B, Nordberg A
      Two-year follow-up of amyloid deposition in patients with Alzheimer's disease.
      Brain : a journal of neurology. 2006 Nov;129(Pt 11):2856-66
    • Jack C, Lowe V, Senjem M, Weigand S, Kemp B, Shiung M, Knopman D, Boeve B, Klunk W, Mathis C, Petersen R
      11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment.
      Brain : a journal of neurology. 2008 Mar;131(Pt 3):665-80

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • Increased CSF tau correlates with the presence of NFTs at autopsy.

    SHOW Details   Supporting(1)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - biochemistry and structural biology,   Biomarkers,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Tapiola T, Overmyer M, Lehtovirta M, Helisalmi S, Ramberg J, Alafuzoff I, Riekkinen P, Soininen H
      The level of cerebrospinal fluid tau correlates with neurofibrillary tangles in Alzheimer's disease.
      Neuroreport. 1997 Dec 22;8(18):3961-3

    Genes/Proteins
    

    • Protein: Microtubule-associated protein tau [Homo sapiens]
  • Abnormality in Aβ-plaque deposition biomarkers is an early event that nears a plateau before the appearance of both atrophy on MRI and cognitive symptoms, and remains relatively static thereafter.

    SHOW Details   Supporting(1)     Genes/Proteins: (2)

    Experimental Approach: Neuropsychology/Behavior,   Biomarkers,   Mechanism - biochemistry and structural biology,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • In a biphasic view of Alzheimer disease progression biomarkers of Aβ deposition become abnormal early, before neurodegeneration and clinical symptoms occur followed by biomarkers of neuronal injury, dysfunction, and neurodegeneration becoming abnormal later in the disease.

    SHOW Details   Supporting(1) 

    Experimental Approach: Pathophysiology,   Mechanism - biochemistry and structural biology,   Biomarkers,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • Rates of brain atrophy correlate well with pathological indices of neurofibrillary tangles (NFTs) and other neurodegenerative changes, but do not correlate with severity of Aβ deposition at autopsy.

    SHOW Details   Supporting(1)     Genes/Proteins: (3)

    Experimental Approach: Pathophysiology,   Biomarkers,   Mechanism - biochemistry and structural biology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Josephs K, Whitwell J, Ahmed Z, Shiung M, Weigand S, Knopman D, Boeve B, Parisi J, Petersen R, Dickson D, Jack C
      Beta-amyloid burden is not associated with rates of brain atrophy.
      Annals of neurology. 2008 Feb;63(2):204-12

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
    • Protein: Microtubule-associated protein tau [Homo sapiens]
  • Structural MRI measures cerebral atrophy, caused by dendritic pruning and synapse and neuron loss, with a strong correlation between the severity of atrophy and the severity of cognitive impairment from normal cognitive status to AD dementia as well as a correlation between the rates of neuronal and synaptic loss and the rates of cognitive decline.

    SHOW Details   Supporting(3)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell,   Pathophysiology,   Neuropsychology/Behavior,   Biomarkers,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Petersen R, O'Brien P, Tangalos E
      MR-based hippocampal volumetry in the diagnosis of Alzheimer's disease.
      Neurology. 1992 Jan;42(1):183-8
    • Bobinski M, de Leon M, Wegiel J, Desanti S, Convit A, Saint Louis L, Rusinek H, Wisniewski H
      The histological validation of post mortem magnetic resonance imaging-determined hippocampal volume in Alzheimer's disease.
      Neuroscience. 2000;95(3):721-5
    • Fox N, Scahill R, Crum W, Rossor M
      Correlation between rates of brain atrophy and cognitive decline in AD.
      Neurology. 1999 May 12;52(8):1687-9

    Genes/Proteins
    

    • Protein: Microtubule-associated protein tau [Homo sapiens]
  • Temporal ordering among the neurodegenerative biomarkers might ultimately differ from that in our proposed model since recent data suggest that MRI atrophy might precede increases in CSF tau.

    SHOW Details   Supporting(2)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - biochemistry and structural biology,   Pathophysiology,   Biomarkers
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Fagan A, Head D, Shah A, Marcus D, Mintun M, Morris J, Holtzman D
      Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly.
      Annals of neurology. 2009 Feb;65(2):176-83
    • Petersen R
      Alzheimer's disease: progress in prediction.
      Lancet neurology. 2010 Jan;9(1):4-5

    Genes/Proteins
    

    • Protein: Microtubule-associated protein tau [Homo sapiens]
  • Cognitive decline curve might shift closer to the Aβ curve (to the left) in individuals with comorbidities (eg, vascular disease), whereas the cognitive decline curve would shift away from the amyloid curve (to the right) in individuals with enhanced cognitive reserve.

    SHOW Details   Supporting(1)     Genes/Proteins: (2)

    Experimental Approach: Mechanism - physiological systems,   Mechanism - biochemistry and structural biology,   Epidemiology,   Neuropsychology/Behavior,   Pathophysiology
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Stern Y
      Cognitive reserve and Alzheimer disease.
      Alzheimer disease and associated disorders. 2006;20(2):112-7

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • The five most widely studied biomarkers of AD pathology, based on the current literature are decreased CSF Aβ42, increased CSF tau, decreased fluorodeoxyglucose uptake measured by positron emission tomography (FDG-PET), PET amyloid imaging, and structural magnetic resonance imaging (MRI) measures of cerebral atrophy.

    SHOW Details   Supporting(1) 

    Experimental Approach: Biomarkers,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • Although phosphotau might be a more specific indicator of AD, concentrations of both phosphotau and total tau increase in AD.

    SHOW Details   Supporting(1)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - biochemistry and structural biology,   Pathophysiology,   Biomarkers
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28

    Genes/Proteins
    

    • Protein: Microtubule-associated protein tau [Homo sapiens]
  • Fluorodeoxyglucose (FDG)-PET studies in patients with AD, as an indicator of impaired synaptic function, show a specific topographic pattern of decreased glucose uptake in a lateral temporal-parietal and posterior cingulate, precuneus distribution.

    SHOW Details   Supporting(1) 

    Experimental Approach: Pathophysiology,   Biomarkers,   Mechanism - molecular and cell,   Mechanism - physiological systems
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jagust W, Reed B, Mungas D, Ellis W, Decarli C
      What does fluorodeoxyglucose PET imaging add to a clinical diagnosis of dementia?
      Neurology. 2007 Aug 28;69(9):871-7
  • Although both MRI and CSF tau are predictive of future conversion from mild cognitive impairment (MCI) to AD, the predictive power of structural MRI is greater.

    SHOW Details   Supporting(1)     Genes/Proteins: (1)

    Experimental Approach: Pathophysiology,   Biomarkers,   Mechanism - biochemistry and structural biology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Vemuri P, Wiste H, Weigand S, Shaw L, Trojanowski J, Weiner M, Knopman D, Petersen R, Jack C
      MRI and CSF biomarkers in normal, MCI, and AD subjects: predicting future clinical change.
      Neurology. 2009 Jul 28;73(4):294-301

    Genes/Proteins
    

    • Protein: Microtubule-associated protein tau [Homo sapiens]
  • Carriers of APOE ε4 have an earlier age of onset of dementia than non-carriers, suggesting that APOE ε4 carriers will have a leftward (earlier in time) shift of both the Aβ-plaque and neurodegenerative biomarker cascades relative to non-carriers.

    SHOW Details   Supporting(2)     Genes/Proteins: (3)

    Experimental Approach: Biomarkers,   Mechanism - biochemistry and structural biology,   Neuropsychology/Behavior,   Pathophysiology,   Epidemiology,   Genetics
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Drzezga A, Grimmer T, Henriksen G, Mühlau M, Perneczky R, Miederer I, Praus C, Sorg C, Wohlschläger A, Riemenschneider M, Wester H, Foerstl H, Schwaiger M, Kurz A
      Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease.
      Neurology. 2009 Apr 28;72(17):1487-94
    • Roses A
      Apolipoprotein E affects the rate of Alzheimer disease expression: beta-amyloid burden is a secondary consequence dependent on APOE genotype and duration of disease.
      Journal of neuropathology and experimental neurology. 1994 Sep;53(5):429-37

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
    • Gene: APOE apolipoprotein E [Homo sapiens]
  • Both CSF Aβ42 and amyloid PET imaging are biomarkers of brain Aβ plaque deposition and nearly all patients who have a clinical diagnosis of AD are positive in amyloid imaging studies.

    SHOW Details   Supporting(3)     Genes/Proteins: (2)

    Experimental Approach: Pathophysiology,   Biomarkers,   Mechanism - biochemistry and structural biology,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Klunk W, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt D, Bergström M, Savitcheva I, Huang G, Estrada S, Ausén B, Debnath M, Barletta J, Price J, Sandell J, Lopresti B, Wall A, Koivisto P, Antoni G, Mathis C, Långström B
      Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.
      Annals of neurology. 2004 Mar;55(3):306-19
    • Rowe C, Ng S, Ackermann U, Gong S, Pike K, Savage G, Cowie T, Dickinson K, Maruff P, Darby D, Smith C, Woodward M, Merory J, Tochon-Danguy H, O'Keefe G, Klunk W, Mathis C, Price J, Masters C, Villemagne V
      Imaging beta-amyloid burden in aging and dementia.
      Neurology. 2007 May 15;68(20):1718-25
    • Edison P, Archer H, Hinz R, Hammers A, Pavese N, Tai Y, Hotton G, Cutler D, Fox N, Kennedy A, Rossor M, Brooks D
      Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study.
      Neurology. 2007 Feb 13;68(7):501-8

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • Non-linearity has been clearly shown in MRI studies, in which atrophy rates accelerate as patients approach clinical dementia.

    SHOW Details   Supporting(2) 

    Experimental Approach: Mechanism - molecular and cell,   Biomarkers,   Pathophysiology,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Chan D, Janssen J, Whitwell J, Watt H, Jenkins R, Frost C, Rossor M, Fox N
      Change in rates of cerebral atrophy over time in early-onset Alzheimer's disease: longitudinal MRI study.
      Lancet. 2003 Oct 4;362(9390):1121-2
    • Ridha B, Barnes J, Bartlett J, Godbolt A, Pepple T, Rossor M, Fox N
      Tracking atrophy progression in familial Alzheimer's disease: a serial MRI study.
      Lancet neurology. 2006 Oct;5(10):828-34
  • Nearly 100% concordance is present between abnormally low CSF Aβ42 and positive Pittsburgh compound B (PiB) amyloid imaging findings in AD patients who have undergone both tests.

    SHOW Details   Supporting(3)     Genes/Proteins: (2)

    Experimental Approach: Biomarkers,   Mechanism - biochemistry and structural biology,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Fagan A, Mintun M, Mach R, Lee S, Dence C, Shah A, LaRossa G, Spinner M, Klunk W, Mathis C, DeKosky S, Morris J, Holtzman D
      Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans.
      Annals of neurology. 2006 Mar;59(3):512-9
    • Jagust W, Landau S, Shaw L, Trojanowski J, Koeppe R, Reiman E, Foster N, Petersen R, Weiner M, Price J, Mathis C
      Relationships between biomarkers in aging and dementia.
      Neurology. 2009 Oct 13;73(15):1193-9
    • Grimmer T, Riemenschneider M, Förstl H, Henriksen G, Klunk W, Mathis C, Shiga T, Wester H, Kurz A, Drzezga A
      Beta amyloid in Alzheimer's disease: increased deposition in brain is reflected in reduced concentration in cerebrospinal fluid.
      Biological psychiatry. 2009 Jun 1;65(11):927-34

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • Biomarkers are physiological, biochemical, anatomical variables that can be measured in vivo by both imaging and biospecimen assay (ie, CSF) and that indicate specific features of disease-related pathological changes.

    SHOW Details   Supporting(1) 

    Experimental Approach: Biomarkers
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • Recent recommendations have suggested redefining research criteria for AD by labeling individuals with memory impairment plus accompanying biomarker evidence of AD as having early AD.

    SHOW Details   Supporting(1) 

    Experimental Approach: Pathophysiology,   Neuropsychology/Behavior,   Biomarkers,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Dubois B, Feldman H, Jacova C, Dekosky S, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser P, Scheltens P
      Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria.
      Lancet neurology. 2007 Aug;6(8):734-46
  • Among patients with MCI or AD alone, correlations with measures of general cognition are strong with structural MRI, but are not significant with CSF tau because CSF tau does not change appreciably over time in cognitively impaired patients and therefore correlations between cognition and CSF tau weaken as patients progress into the mid and late stages of the clinical AD spectrum.

    SHOW Details   Supporting(3)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - biochemistry and structural biology,   Biomarkers,   Neuropsychology/Behavior,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Bouwman F, van der Flier W, Schoonenboom N, van Elk E, Kok A, Rijmen F, Blankenstein M, Scheltens P
      Longitudinal changes of CSF biomarkers in memory clinic patients.
      Neurology. 2007 Sep 4;69(10):1006-11
    • Vemuri P, Wiste H, Weigand S, Shaw L, Trojanowski J, Weiner M, Knopman D, Petersen R, Jack C
      MRI and CSF biomarkers in normal, MCI, and AD subjects: predicting future clinical change.
      Neurology. 2009 Jul 28;73(4):294-301
    • Sunderland T, Wolozin B, Galasko D, Levy J, Dukoff R, Bahro M, Lasser R, Motter R, Lehtimäki T, Seubert P
      Longitudinal stability of CSF tau levels in Alzheimer patients.
      Biological psychiatry. 1999 Sep 15;46(6):750-5

    Genes/Proteins
    

    • Protein: Microtubule-associated protein tau [Homo sapiens]
  • Excellent correspondence has been seen between Pittsburgh compound B (PiB) binding (specifically for fibrillar Aβ, and not to soluble Aβ or to diffuse plaques) and fibrillar Aβ deposition in the brain (or cerebral vasculature) in most, but not all AD patients.

    SHOW Details   Supporting(3)     Genes/Proteins: (2)

    Experimental Approach: Mechanism - biochemistry and structural biology,   Pathophysiology,   Biomarkers,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Bacskai B, Frosch M, Freeman S, Raymond S, Augustinack J, Johnson K, Irizarry M, Klunk W, Mathis C, Dekosky S, Greenberg S, Hyman B, Growdon J
      Molecular imaging with Pittsburgh Compound B confirmed at autopsy: a case report.
      Archives of neurology. 2007 Mar;64(3):431-4
    • Rosen R, Ciliax B, Wingo T, Gearing M, Dooyema J, Lah J, Ghiso J, LeVine H, Walker L
      Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer's disease.
      Acta neuropathologica. 2010 Feb;119(2):221-33
    • Ikonomovic M, Klunk W, Abrahamson E, Mathis C, Price J, Tsopelas N, Lopresti B, Ziolko S, Bi W, Paljug W, Debnath M, Hope C, Isanski B, Hamilton R, DeKosky S
      Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease.
      Brain : a journal of neurology. 2008 Jun;131(Pt 6):1630-45

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • Low concentrations of CSF Aβ42 correlate with both the clinical diagnosis of AD and Aβ neuropathology at autopsy.

    SHOW Details   Supporting(3)     Genes/Proteins: (1)

    Experimental Approach:
    Pathogenic Narrative Tags:
    Supporting Evidence
    

    • Schoonenboom N, van der Flier W, Blankenstein M, Bouwman F, Van Kamp G, Barkhof F, Scheltens P
      CSF and MRI markers independently contribute to the diagnosis of Alzheimer's disease.
      Neurobiology of aging. 2008 May;29(5):669-75
    • Clark C, Xie S, Chittams J, Ewbank D, Peskind E, Galasko D, Morris J, McKeel D, Farlow M, Weitlauf S, Quinn J, Kaye J, Knopman D, Arai H, Doody R, DeCarli C, Leight S, Lee V, Trojanowski J
      Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses?
      Archives of neurology. 2003 Dec;60(12):1696-702
    • Strozyk D, Blennow K, White L, Launer L
      CSF Abeta 42 levels correlate with amyloid-neuropathology in a population-based autopsy study.
      Neurology. 2003 Feb 25;60(4):652-6

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
  • Evidence of therapeutic plaque removal in patients who already have dementia does not seem to correlate with a change in the trajectory of cognitive deterioration.

    SHOW Details   Supporting(1) 

    Experimental Approach: Pathophysiology,   Clinical trials,   Neuropsychology/Behavior,   Target validation,   Biomarkers
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones R, Bullock R, Love S, Neal J, Zotova E, Nicoll J
      Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial.
      Lancet. 2008 Jul 19;372(9634):216-23
  • Greater decreases in fluorodeoxyglucose (FDG) uptake correlate with greater cognitive impairment along the continuum from normal cognitive status to MCI to AD dementia with a good correlation between the ante-mortem FDG-PET diagnosis of AD and post-mortem confirmation.

    SHOW Details   Supporting(2) 

    Experimental Approach: Mechanism - physiological systems,   Mechanism - molecular and cell,   Biomarkers,   Neuropsychology/Behavior,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Minoshima S, Giordani B, Berent S, Frey K, Foster N, Kuhl D
      Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease.
      Annals of neurology. 1997 Jul;42(1):85-94
    • Hoffman J, Welsh-Bohmer K, Hanson M, Crain B, Hulette C, Earl N, Coleman R
      FDG PET imaging in patients with pathologically verified dementia.
      Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2000 Nov;41(11):1920-8
  • AD biomarkers can be used to predict conversion from mild cognitive impairment (MCI) to AD, demonstrated by prediction studies that show that individuals destined to develop AD can be identified earlier in the disease course by use of the MCI designation with the addition of imaging and CSF biomarkers to enhance diagnostic specificity.

    SHOW Details   Supporting(6) 

    Experimental Approach: Neuropsychology/Behavior,   Biomarkers,   Pathophysiology,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jagust W, Haan M, Eberling J, Wolfe N, Reed B
      Functional imaging predicts cognitive decline in Alzheimer's disease.
      Journal of neuroimaging : official journal of the American Society of Neuroimaging. 1996 Jul;6(3):156-60
    • Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka S, van der Flier W, Blankenstein M, Ewers M, Rich K, Kaiser E, Verbeek M, Tsolaki M, Mulugeta E, Rosén E, Aarsland D, Visser P, Schröder J, Marcusson J, de Leon M, Hampel H, Scheltens P, Pirttilä T, Wallin A, Jönhagen M, Minthon L, Winblad B, Blennow K
      CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment.
      JAMA : the journal of the American Medical Association. 2009 Jul 22;302(4):385-93
    • Yuan Y, Gu Z, Wei W
      Fluorodeoxyglucose-positron-emission tomography, single-photon emission tomography, and structural MR imaging for prediction of rapid conversion to Alzheimer disease in patients with mild cognitive impairment: a meta-analysis.
      AJNR. American journal of neuroradiology. 2009 Feb;30(2):404-10
    • Chételat G, Desgranges B, de la Sayette V, Viader F, Eustache F, Baron J
      Mild cognitive impairment: Can FDG-PET predict who is to rapidly convert to Alzheimer's disease?
      Neurology. 2003 Apr 22;60(8):1374-7
    • Visser P, Verhey F, Knol D, Scheltens P, Wahlund L, Freund-Levi Y, Tsolaki M, Minthon L, Wallin A, Hampel H, Bürger K, Pirttila T, Soininen H, Rikkert M, Verbeek M, Spiru L, Blennow K
      Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study.
      Lancet neurology. 2009 Jul;8(7):619-27
    • Jack C, Petersen R, Xu Y, O'Brien P, Smith G, Ivnik R, Boeve B, Waring S, Tangalos E, Kokmen E
      Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment.
      Neurology. 1999 Apr 22;52(7):1397-403
  • The suggested temporal order that amyloid markers precede tau biomarker change is inconsistent with the conclusion that NFT accumulation is the initiating event in AD, but the currently proposed model is supported by: (1) the genetics data in early-onset AD, which implicate disordered Aβ metabolism as the initiating event; (2) the fact that the final pathological picture is identical between late-onset and early-onset AD cases; and (3) the fact that the major genetic risk factor of late-onset AD (APOE ε4) is implicated in disordered trafficking of Aβ peptide.

    SHOW Details   Supporting(3) 

    Experimental Approach: Genetics,   Pathophysiology,   Biomarkers,   Mechanism - biochemistry and structural biology
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Corder E, Saunders A, Strittmatter W, Schmechel D, Gaskell P, Small G, Roses A, Haines J, Pericak-Vance M
      Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.
      Science (New York, N.Y.). 1993 Aug 13;261(5123):921-3
    • Duyckaerts C, Hauw J
      Prevalence, incidence and duration of Braak's stages in the general population: can we know?
      Neurobiology of aging. 1997;18(4):362-9; discussion 389-92
    • Braak H, Braak E
      Frequency of stages of Alzheimer-related lesions in different age categories.
      Neurobiology of aging. 1997;18(4):351-7
  • Structural MRI measures of atrophy correlates well with Braak staging at autopsy as distribution of atrophy on MRI maps well onto Braak’s staging of NFT pathology in patients who have undergone ante-mortem MRI and post-mortem AD staging.

    SHOW Details   Supporting(4) 

    Experimental Approach: Pathophysiology,   Mechanism - biochemistry and structural biology,   Biomarkers
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Whitwell J, Josephs K, Murray M, Kantarci K, Przybelski S, Weigand S, Vemuri P, Senjem M, Parisi J, Knopman D, Boeve B, Petersen R, Dickson D, Jack C
      MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study.
      Neurology. 2008 Sep 2;71(10):743-9
    • Braak H, Braak E
      Neuropathological stageing of Alzheimer-related changes.
      Acta neuropathologica. 1991;82(4):239-59
    • Silbert L, Quinn J, Moore M, Corbridge E, Ball M, Murdoch G, Sexton G, Kaye J
      Changes in premorbid brain volume predict Alzheimer's disease pathology.
      Neurology. 2003 Aug 26;61(4):487-92
    • Jack C, Dickson D, Parisi J, Xu Y, Cha R, O'Brien P, Edland S, Smith G, Boeve B, Tangalos E, Kokmen E, Petersen R
      Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia.
      Neurology. 2002 Mar 12;58(5):750-7
  • Increased CSF tau is not specific for AD, but does correlate with clinical disease severity, with higher concentrations associated with greater cognitive impairment in individuals on the normal–MCI–AD cognitive spectrum.

    SHOW Details   Supporting(2)     Genes/Proteins: (1)

    Experimental Approach: Biomarkers,   Pathophysiology,   Neuropsychology/Behavior
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Shaw L, Vanderstichele H, Knapik-Czajka M, Clark C, Aisen P, Petersen R, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee V, Trojanowski J
      Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects.
      Annals of neurology. 2009 Apr;65(4):403-13
    • Buerger K, Ewers M, Pirttilä T, Zinkowski R, Alafuzoff I, Teipel S, DeBernardis J, Kerkman D, McCulloch C, Soininen H, Hampel H
      CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease.
      Brain : a journal of neurology. 2006 Nov;129(Pt 11):3035-41

    Genes/Proteins
    

    • Protein: Microtubule-associated protein tau [Homo sapiens]
  • The presence of neurofibrillary tangles (NFTs) in asymptomatic individuals tends to be confined to the entorhinal cortex, Braak stage I–II, whereas NFTs in symptomatic individuals are far more widespread.

    SHOW Details   Supporting(4)     Genes/Proteins: (1)

    Experimental Approach: Biomarkers,   Mechanism - biochemistry and structural biology,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Savva G, Wharton S, Ince P, Forster G, Matthews F, Brayne C
      Age, neuropathology, and dementia.
      The New England journal of medicine. 2009 May 28;360(22):2302-9
    • Knopman D, Parisi J, Salviati A, Floriach-Robert M, Boeve B, Ivnik R, Smith G, Dickson D, Johnson K, Petersen L, McDonald W, Braak H, Petersen R
      Neuropathology of cognitively normal elderly.
      Journal of neuropathology and experimental neurology. 2003 Nov;62(11):1087-95
    • Braak H, Braak E
      Frequency of stages of Alzheimer-related lesions in different age categories.
      Neurobiology of aging. 1997;18(4):351-7
    • Price J, Morris J
      Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease.
      Annals of neurology. 1999 Mar;45(3):358-68

    Genes/Proteins
    

    • Protein: Microtubule-associated protein tau [Homo sapiens]
  • Serial Pittsburgh Compound B (PiB) imaging studies Aβ-plaque accumulation in individuals destined to become demented might begin as much as two decades before the manifestation of clinical symptoms and can be widespread in clinically asymptomatic individuals although both Aβ deposition and NFTs can be present in individuals with no symptoms.

    SHOW Details   Supporting(2)     Genes/Proteins: (2)

    Experimental Approach:
    Pathogenic Narrative Tags:
    Supporting Evidence
    

    • Jack C, Lowe V, Weigand S, Wiste H, Senjem M, Knopman D, Shiung M, Gunter J, Boeve B, Kemp B, Weiner M, Petersen R
      Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease.
      Brain : a journal of neurology. 2009 May;132(Pt 5):1355-65
    • Frisoni G, Lorenzi M, Caroli A, Kemppainen N, Någren K, Rinne J
      In vivo mapping of amyloid toxicity in Alzheimer disease.
      Neurology. 2009 Apr 28;72(17):1504-11

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • At present, the clinical diagnosis of AD requires the presence of dementia.

    SHOW Details   Supporting(1) 

    Experimental Approach: Neuropsychology/Behavior,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E
      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 Jul;34(7):939-44
  • In cognitively normal elderly individuals, correlations are seen between decreased FDG-PET uptake and both low CSF Aβ42 and increased CSF tau.

    SHOW Details   Supporting(1)     Genes/Proteins: (2)

    Experimental Approach: Pathophysiology,   Biomarkers,   Mechanism - physiological systems,   Mechanism - biochemistry and structural biology
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Petrie E, Cross D, Galasko D, Schellenberg G, Raskind M, Peskind E, Minoshima S
      Preclinical evidence of Alzheimer changes: convergent cerebrospinal fluid biomarker and fluorodeoxyglucose positron emission tomography findings.
      Archives of neurology. 2009 May;66(5):632-7

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Microtubule-associated protein tau [Homo sapiens]
  • The final phase in the evolution of AD is dementia, defined as impairments in multiple domains that are severe enough to produce loss of function.

    SHOW Details   Supporting(1) 

    Experimental Approach: Neuropsychology/Behavior,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • The current view of AD is that both AD pathological processes and clinical decline begin to develop decades before the earliest symptoms occur, with dementia representing the end stage.

    SHOW Details   Supporting(1) 

    Experimental Approach: Pathophysiology,   Neuropsychology/Behavior,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • Increases in CSF tau seem to indicate neuronal damage, and are seen in ischaemic and traumatic brain injury.

    SHOW Details   Supporting(2)     Genes/Proteins: (1)

    Experimental Approach: Biomarkers,   Pathophysiology,   Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Hesse C, Rosengren L, Andreasen N, Davidsson P, Vanderstichele H, Vanmechelen E, Blennow K
      Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke.
      Neuroscience letters. 2001 Jan 19;297(3):187-90
    • Ost M, Nylén K, Csajbok L, Ohrfelt A, Tullberg M, Wikkelsö C, Nellgård P, Rosengren L, Blennow K, Nellgård B
      Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury.
      Neurology. 2006 Nov 14;67(9):1600-4

    Genes/Proteins
    

    • Protein: Microtubule-associated protein tau [Homo sapiens]
  • Approximately 20–40% of cognitively normal elderly people have evidence of significant brain Aβ-plaque deposition, either from amyloid imaging or CSF Aβ42 concentrations.

    SHOW Details   Supporting(5)     Genes/Proteins: (2)

    Experimental Approach: Neuropsychology/Behavior,   Mechanism - biochemistry and structural biology,   Pathophysiology,   Biomarkers
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Aizenstein H, Nebes R, Saxton J, Price J, Mathis C, Tsopelas N, Ziolko S, James J, Snitz B, Houck P, Bi W, Cohen A, Lopresti B, DeKosky S, Halligan E, Klunk W
      Frequent amyloid deposition without significant cognitive impairment among the elderly.
      Archives of neurology. 2008 Nov;65(11):1509-17
    • Mintun M, Larossa G, Sheline Y, Dence C, Lee S, Mach R, Klunk W, Mathis C, DeKosky S, Morris J
      [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease.
      Neurology. 2006 Aug 8;67(3):446-52
    • Peskind E, Li G, Shofer J, Quinn J, Kaye J, Clark C, Farlow M, DeCarli C, Raskind M, Schellenberg G, Lee V, Galasko D
      Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition.
      Archives of neurology. 2006 Jul;63(7):936-9
    • Bouwman F, Schoonenboom N, Verwey N, van Elk E, Kok A, Blankenstein M, Scheltens P, van der Flier W
      CSF biomarker levels in early and late onset Alzheimer's disease.
      Neurobiology of aging. 2009 Dec;30(12):1895-901
    • Shaw L, Vanderstichele H, Knapik-Czajka M, Clark C, Aisen P, Petersen R, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee V, Trojanowski J
      Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects.
      Annals of neurology. 2009 Apr;65(4):403-13

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • Between-patient variation in the lag period between Aβ deposition and the neurodegenerative cascade is probably an indication of differences in Aβ processing, in the effects of abnormal Aβ processing on neuronal injury, and differences in brain resilience or cognitive reserve. Other pathological changes, particularly cerebrovascular, α-synuclein, and TAR DNA-binding protein 43 proteinopathy mechanisms, also contribute significantly to between-individual variations in clinical disease expression.

    SHOW Details   Supporting(2)     Genes/Proteins: (4)

    Experimental Approach: Pathophysiology,   Biomarkers,   Mechanism - biochemistry and structural biology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Stern Y
      Cognitive reserve and Alzheimer disease.
      Alzheimer disease and associated disorders. 2006;20(3 Suppl 2):S69-74
    • Nelson P, Abner E, Schmitt F, Kryscio R, Jicha G, Smith C, Davis D, Poduska J, Patel E, Mendiondo M, Markesbery W
      Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons.
      Brain pathology (Zurich, Switzerland). 2010 Jan;20(1):66-79

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
    • Protein: TAR DNA-binding protein 43 [Homo sapiens]
    • Protein: Alpha-synuclein [Homo sapiens]
  • PET imaging ligands and the magnetic resonance spectroscopy metabolite myo-inositol have been proposed as potential biomarkers of glial activation; however, neither is widely used.

    SHOW Details   Supporting(2) 

    Experimental Approach: Biomarkers,   Pathophysiology,   Mechanism - molecular and cell
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Edison P, Archer H, Gerhard A, Hinz R, Pavese N, Turkheimer F, Hammers A, Tai Y, Fox N, Kennedy A, Rossor M, Brooks D
      Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIB-PET study.
      Neurobiology of disease. 2008 Dec;32(3):412-9
    • Ross B, Bluml S, Cowan R, Danielsen E, Farrow N, Tan J
      In vivo MR spectroscopy of human dementia.
      Neuroimaging clinics of North America. 1998 Nov;8(4):809-22
  • Biomarkers indicate specific changes in AD that do not reach abnormal levels or peak simultaneously but do so in an ordered manner and can be measured and correlated to clinical symptoms in longitudinal observational studies.

    SHOW Details   Supporting(1) 

    Experimental Approach: Biomarkers,   Pathophysiology,   Epidemiology,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • Structural MRI measures of atrophy retain a highly significant correlation with observed clinical impairment in both the mild cognitive impairment (MCI) and dementia phases of AD, and furthermore, rates of atrophy on MRI are significantly greater in patients with AD than in cognitively normal elderly individuals.

    SHOW Details   Supporting(3) 

    Experimental Approach: Neuropsychology/Behavior,   Pathophysiology,   Biomarkers
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Vemuri P, Wiste H, Weigand S, Shaw L, Trojanowski J, Weiner M, Knopman D, Petersen R, Jack C
      MRI and CSF biomarkers in normal, MCI, and AD subjects: diagnostic discrimination and cognitive correlations.
      Neurology. 2009 Jul 28;73(4):287-93
    • Vemuri P, Wiste H, Weigand S, Shaw L, Trojanowski J, Weiner M, Knopman D, Petersen R, Jack C
      MRI and CSF biomarkers in normal, MCI, and AD subjects: predicting future clinical change.
      Neurology. 2009 Jul 28;73(4):294-301
    • Fox N, Freeborough P
      Brain atrophy progression measured from registered serial MRI: validation and application to Alzheimer's disease.
      Journal of magnetic resonance imaging : JMRI. 1997;7(6):1069-75
• Supporting:
  • In a biphasic view of Alzheimer disease progression biomarkers of Aβ deposition become abnormal early, before neurodegeneration and clinical symptoms occur followed by biomarkers of neuronal injury, dysfunction, and neurodegeneration becoming abnormal later in the disease.

    SHOW Details   Supporting(1) 

    Experimental Approach: Pathophysiology,   Mechanism - biochemistry and structural biology,   Biomarkers,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • Although biomarkers of neurodegeneration correlate with clinical and pathological severity, they are not specific for AD and thus should not take precedence over Aβ biomarkers as inclusion criteria for patients in anti-amyloid therapeutic clinical trials, although an Aβ biomarker might be combined with MRI volumetrics to provide an indication of disease stage.

    SHOW Details   Supporting(1)     Genes/Proteins: (2)

    Experimental Approach: Mechanism - biochemistry and structural biology,   Biomarkers,   Clinical trials
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • The final phase in the evolution of AD is dementia, defined as impairments in multiple domains that are severe enough to produce loss of function.

    SHOW Details   Supporting(1) 

    Experimental Approach: Neuropsychology/Behavior,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • It is rational to select patients for inclusion in anti-Aβ therapy clinical trials on the basis of biomarker evidence of Aβ in the brain by use of either amyloid PET imaging or CSF Aβ42 although change in Aβ load over time has little relation to change in cognition.

    SHOW Details   Supporting(1)     Genes/Proteins: (2)

    Experimental Approach: Neuropsychology/Behavior,   Clinical trials,   Biomarkers,   Mechanism - biochemistry and structural biology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • The current view of AD is that both AD pathological processes and clinical decline begin to develop decades before the earliest symptoms occur, with dementia representing the end stage.

    SHOW Details   Supporting(1) 

    Experimental Approach: Pathophysiology,   Neuropsychology/Behavior,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • The five most widely studied biomarkers of AD pathology, based on the current literature are decreased CSF Aβ42, increased CSF tau, decreased fluorodeoxyglucose uptake measured by positron emission tomography (FDG-PET), PET amyloid imaging, and structural magnetic resonance imaging (MRI) measures of cerebral atrophy.

    SHOW Details   Supporting(1) 

    Experimental Approach: Biomarkers,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • Although phosphotau might be a more specific indicator of AD, concentrations of both phosphotau and total tau increase in AD.

    SHOW Details   Supporting(1)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - biochemistry and structural biology,   Pathophysiology,   Biomarkers
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28

    Genes/Proteins
    

    • Protein: Microtubule-associated protein tau [Homo sapiens]
  • Measures of the neurodegenerative portion of the cascade (eg, CSF tau, FDG-PET, or structural MRI) should be used in AD therapeutic clinical trials as evidence of therapeutic modification of the neurodegenerative aspect of the AD pathological process and a combination of biomarkers might be needed in clinical trials to select appropriate participants and to follow disease progression.

    SHOW Details   Supporting(1) 

    Experimental Approach: Clinical trials,   Pathophysiology,   Mechanism - molecular and cell,   Biomarkers,   Mechanism - physiological systems
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • Abnormality in Aβ-plaque deposition biomarkers is an early event that nears a plateau before the appearance of both atrophy on MRI and cognitive symptoms, and remains relatively static thereafter.

    SHOW Details   Supporting(1)     Genes/Proteins: (2)

    Experimental Approach: Neuropsychology/Behavior,   Biomarkers,   Mechanism - biochemistry and structural biology,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • Biomarkers indicate specific changes in AD that do not reach abnormal levels or peak simultaneously but do so in an ordered manner and can be measured and correlated to clinical symptoms in longitudinal observational studies.

    SHOW Details   Supporting(1) 

    Experimental Approach: Biomarkers,   Pathophysiology,   Epidemiology,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
  • Biomarkers are physiological, biochemical, anatomical variables that can be measured in vivo by both imaging and biospecimen assay (ie, CSF) and that indicate specific features of disease-related pathological changes.

    SHOW Details   Supporting(1) 

    Experimental Approach: Biomarkers
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Jack C, Knopman D, Jagust W, Shaw L, Aisen P, Weiner M, Petersen R, Trojanowski J
      Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
      Lancet neurology. 2010 Jan;9(1):119-28
• Created On: Mon, May 10 15:53:46 EDT 2010
• Last Modified On: Mon May 10 15:53:46 EDT 2010