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International Working Group revises AD diagnosis, uses biomarkers to capture early stage
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[Courtesy of Bruno Dubois.]
Added value of biomarkers to diagnosis.
[Copyright 2010 Elsevier Limited.]
(From Dubois et al. 2010.)
[Copyright 2014 Elsevier Limited.]
IWG criteria propose a simplified algorithm, whereby in any condition and at any stage of the disease, the diagnosis of AD relies on the presence of a pathophysiological marker. (From Dubois et al. 2014.)
[Copyright 2016 Elsevier Limited.]
Toward a unified conception of preclinical AD based on both sets of proposed diagnostic criteria. (From Dubois et al. 2016.)
Primary Papers
- Dubois B, Feldman HH, Jacova C, Dekosky ST, 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 PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007 Aug;6(8):734-46. PubMed.
- Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010 Nov;9(11):1118-27. PubMed.
- Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, DeKosky ST, Gauthier S, Selkoe D, Bateman R, Cappa S, Crutch S, Engelborghs S, Frisoni GB, Fox NC, Galasko D, Habert MO, Jicha GA, Nordberg A, Pasquier F, Rabinovici G, Robert P, Rowe C, Salloway S, Sarazin M, Epelbaum S, de Souza LC, Vellas B, Visser PJ, Schneider L, Stern Y, Scheltens P, Cummings JL. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 2014 Jun;13(6):614-29. PubMed.
- Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, Bakardjian H, Benali H, Bertram L, Blennow K, Broich K, Cavedo E, Crutch S, Dartigues JF, Duyckaerts C, Epelbaum S, Frisoni GB, Gauthier S, Genthon R, Gouw AA, Habert MO, Holtzman DM, Kivipelto M, Lista S, Molinuevo JL, O'Bryant SE, Rabinovici GD, Rowe C, Salloway S, Schneider LS, Sperling R, Teichmann M, Carrillo MC, Cummings J, Jack CR Jr, Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer's Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA. Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement. 2016 Mar;12(3):292-323. PubMed.
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Aβ stress affects excitatory and inhibitory circuits
[Copyright 2007 Elsevier Inc.]
Aberrant synchronous neuronal network activity and spontaneous nonconvulsive seizures in hAPP-J20 mice. Chronic cortical and hippocampal EEG recordings were performed in freely moving, untreated J20 mice and non-transgenic controls. (A) In contrast to controls showing normal EEG activity (left), J20 mice had generalized cortical epileptiform spike discharges every five to 50 minutes. (B) Bilateral depth electrode recordings from the hippocampus detected occasional discharges of isolated hippocampal origin, e.g., here a prominent left-sided discharge. (C) Initiation (upper panel) and termination (lower) of a cortical seizure in a J20 mouse. Concurrent bilateral hippocampal depth electrode recordings show abnormal synchronization beginning as spike discharges (arrowheads) in the hippocampus and overlying posterior-parietal neocortex (LO-RO). Synchronous seizure activity then generalizes in the neocortex without behavioral signs of convulsive activity, followed by profound electroencephalographic postictal depression. (D) Model of Aβ-induced network dysfunction. High levels of Aβ induce aberrant excitatory neuronal activity, which triggers compensatory inhibitory mechanisms to counteract overexcitation. Both contribute to AD-related network dysfunction.(From Palop et al., 2007.)
Primary Papers
- Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007 Sep 6;55(5):697-711. PubMed.
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AD neurotoxicity attributed to tau missorting to dendritic compartment and interaction with Aβ oligomers
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[Courtesy of Eckhard and Eva Maria Mandelkow.]
In these hippocampal neurons, blockage of axonal transport by tau causes degeneration of dendritic spines.
[Copyright 2013 EMBO.]
Tau deficiency does not protect against Aβ association to dendrites and transient spine loss, but it does protect against loss of microtubules, neurofilament invasion, and loss of mitochondria. Left: Treating primary wild-type neurons with Aβ results in somatodendritic missorting of neurofilaments and increase in Ca++ and MAP2 (arrows). Right: Treating knockout hippocampal neurons with Aβ does not result in missorting of neurofilaments; MAP2 and Ca++ are slightly elevated. (From Zempel et at., 2013.)
[Copyright 2013 EMBO.]
Cascade of events leading from Aβ‐induced damage (loss of tau polarity, MTs and spines) to regeneration. Boxes in center indicate the cascade of events after exposure to Aβ oligomers, boxes on left indicate activators operating at different stages, boxes on right indicate inhibitors. Shaded boxes indicate steps that are bypassed in the absence of tau, implying that missorting of cytoskeletal elements such as neurofilaments or breakdown of microtubules are largely circumvented. (Zempel et al., 2013.)
Primary Papers
- Thies E, Mandelkow EM. Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1. J Neurosci. 2007 Mar 14;27(11):2896-907. PubMed.
- Zempel H, Luedtke J, Kumar Y, Biernat J, Dawson H, Mandelkow E, Mandelkow EM. Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 2013 Nov 13;32(22):2920-37. PubMed.
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Toll-like receptors in microglial activation
[Copyright 2009 Society of Neuroscience.]
Phagocytosis stimulated by fibrillar Aβ requires CD14, TLR4, and TLR2. (A) Microglia were pretreated with function-blocking antibodies before stimulation with fAβ, then fluorescent microspheres were added. (B) Microglia treated with fAβ-containing microspheres. (C) Primary microglia from wild-type, CD14−/−, TLR4−/−, or TLR2−/− mice were stimulated with fAβ, then incubated with fluorescent microspheres. (From Reed-Geaghan et al., 2009.)
Primary Papers
- Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, Fassbender K. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cell Physiol Biochem. 2007;20(6):947-56. PubMed.
- Richard KL, Filali M, Préfontaine P, Rivest S. Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer's disease. J Neurosci. 2008 May 28;28(22):5784-93. PubMed.
- Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci. 2009 Sep 23;29(38):11982-92. PubMed.
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Toxic halo of dystrophic neurites, lost synapses, Aβ oligomers surrounds plaque
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[Copyright 2008 Nature.]
Plaque appears rapidly. (a–c) Low-magnification overview of area of potential plaque formation. The angiogram (red), amyloid deposition (blue), and neurons (green) are visible on day of surgery (a) as well as one and two weeks later, allowing reimaging of the same sites over different imaging sessions. A new parenchymal amyloid plaque (arrow) was identified one (b) and two weeks (c) after first imaging. (d–i) Sequential daily imaging of a potential plaque-formation area revealed that plaques can form rapidly in a short time interval from one day to another (e). The initial plaque was joined by a novel plaque marked with arrows over six consecutive days (e–i). Note the formation of a dystrophy (arrowhead, i). Line diagram visualizes plaque size over time. (From Meyer-Luehmann et al., 2008.)
[Copyright 2009 National Academy of Sciences.]
Three-dimenstional reconstruction from array tomography images of APP/PS1 mouse cortex shows that a large volume of cortex around the dense core of the plaque (blue) is occupied by a halo of oligomeric Aβ (red). Postsynaptic densities (green) are lost within the plaque core (arrow; A), and in the surrounding area (arrowhead; C) within the halo of oligomeric Aβ (B, D). (From Koffie et al., 2009.)
Primary Papers
- Spires-Jones TL, Meyer-Luehmann M, Osetek JD, Jones PB, Stern EA, Bacskai BJ, Hyman BT. Impaired spine stability underlies plaque-related spine loss in an Alzheimer's disease mouse model. Am J Pathol. 2007 Oct;171(4):1304-11. PubMed.
- Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman BT. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature. 2008 Feb 7;451(7179):720-4. PubMed.
- Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M, Micheva KD, Smith SJ, Kim ML, Lee VM, Hyman BT, Spires-Jones TL. Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):4012-7. PubMed.
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APPsα aids neuronal survival, outgrowth, repair, but primary function in adult brain unknown
[Copyright 2007 Society of Neuroscience.]
In utero electroporation with APP constructs indicate that APP affects neuronal migration in the cortical plate. (From Young-Pearse et al., 2007.)
Primary Papers
- Ring S, Weyer SW, Kilian SB, Waldron E, Pietrzik CU, Filippov MA, Herms J, Buchholz C, Eckman CB, Korte M, Wolfer DP, Müller UC. The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice. J Neurosci. 2007 Jul 18;27(29):7817-26. PubMed.
- Young-Pearse TL, Bai J, Chang R, Zheng JB, LoTurco JJ, Selkoe DJ. A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J Neurosci. 2007 Dec 26;27(52):14459-69. PubMed.
First report of amyloid PET in autosominal-dominant AD
[University of Pittsburgh Amyloid Imaging Group.]
This image is a collage of three orthogonal views each of the first-ever scan of PS-1 mutation carrier (left) compared to a representative AD case (right). The spotty background represents a fluorescent amyloid stain of the striatum of a different PS-1 carrier. (Courtesy of William Klunk.)
Primary Papers
- Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Hoge JA, Cohen AD, Ikonomovic MD, Saxton JA, Snitz BE, Pollen DA, Moonis M, Lippa CF, Swearer JM, Johnson KA, Rentz DM, Fischman AJ, Aizenstein HJ, Dekosky ST. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. PubMed.
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First reports of amyloid PET in differential diagnosis; first F-18 tracer
[Courtesy of Chris Rowe.]
Distribution volume ratio PET transaxial (top) and sagittal images (bottom) of a 73-year-old healthy control participant, a 78-year-old patient with dementia with Lewy bodies, an 82-year-old patient with Alzheimer's disease, and an 80-year-old patient with frontotemporal dementia. Images show clear differences in regional Pittsburgh Compound B binding, with non-specific PiB binding in white matter in the control and FTD subjects compared with PiB binding in the frontal, temporal, and posterior cingulate/precuneus cortices of the AD and DLB patients. (From Rowe et al., 2007.)
Primary Papers
- Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, Cowie TF, Dickinson KL, Maruff P, Darby D, Smith C, Woodward M, Merory J, Tochon-Danguy H, O'Keefe G, Klunk WE, Mathis CA, Price JC, Masters CL, Villemagne VL. Imaging beta-amyloid burden in aging and dementia. Neurology. 2007 May 15;68(20):1718-25. PubMed.
- Rowe CC, Ackerman U, Browne W, Mulligan R, Pike KL, O'Keefe G, Tochon-Danguy H, Chan G, Berlangieri SU, Jones G, Dickinson-Rowe KL, Kung HP, Zhang W, Kung MP, Skovronsky D, Dyrks T, Holl G, Krause S, Friebe M, Lehman L, Lindemann S, Dinkelborg LM, Masters CL, Villemagne VL. Imaging of amyloid beta in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol. 2008 Feb;7(2):129-35. PubMed.
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Sorl1 variants increase risk of LOAD
[Copyright 2007 Macmillan Publishers Limited.]
Putative cell biological role and genetic architecture of SORL1. (a) Diagram of APP processing pathways. APP holoprotein synthesized in the endoplasmic reticulum (ER) and Golgi. Proteolytic cleavage through Aβ peptide domain by ADAM17 and other α-secretase enzymes generates N-terminal soluble APPsα and membrane-bound APP α C-terminal fragments. Sequential cleavage by BACE1 (β-secretase) generates N-terminal APPsβ and membrane-bound APP-CTFβ fragments. The latter undergo presenilin-dependent γ-secretase cleavage to generate Aβ and amyloid intracellular domain (AICD). SORL1 binds both APP holoprotein and VPS35 and acts as a sorting receptor for APP holoprotein. Absence of SORL1 switches APP holoprotein away from the retromer recycling pathway and instead directs APP into the β-secretase cleavage pathway, increasing APPsβ production and then into the γ-secretase cleavage pathway to generate Aβ. Blockade of the retromer complex by inhibiting proteins such as VPS26A or VPS35 has a similar effect, also increasing APPsβ and Aβ production. (b) Genomic map of SORL1 showing genotyped SNPs. Orange bars represent 5' UTR and 3' UTR, red bar represents intragenic regions, black vertical bars represent each of the 48 exons. (From Rogaeva et al., 2007.)
Primary Papers
- Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. PubMed.
- Lee JH, Cheng R, Schupf N, Manly J, Lantigua R, Stern Y, Rogaeva E, Wakutani Y, Farrer L, St George-Hyslop P, Mayeux R. The association between genetic variants in SORL1 and Alzheimer disease in an urban, multiethnic, community-based cohort. Arch Neurol. 2007 Apr;64(4):501-6. PubMed.
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First AD GWAS
[Copyright 2007 The American Society of Human Genetics.]
Stages of Phase 1 of a pooling-based GWA. (A) Stage 1: quality-check, quantify DNA, place into subpools. (B) Stage 2: transform and/or normalize paired probe-intensity data from both alleles into a value correlating with allelic frequency. (C) Stage 3: evaluate and rank each set of transformed-value scores to measure association between cohorts. (D) Stage 4: calculate multi-marker statistics, leveraging linkage disequilibrium between SNPs. (From Pearson et al., 2006.)
Primary Papers
- Pearson JV, Huentelman MJ, Halperin RF, Tembe WD, Melquist S, Homer N, Brun M, Szelinger S, Coon KD, Zismann VL, Webster JA, Beach T, Sando SB, Aasly JO, Heun R, Jessen F, Kolsch H, Tsolaki M, Daniilidou M, Reiman EM, Papassotiropoulos A, Hutton ML, Stephan DA, Craig DW. Identification of the genetic basis for complex disorders by use of pooling-based genomewide single-nucleotide-polymorphism association studies. Am J Hum Genet. 2007 Jan;80(1):126-39. PubMed.
Inducible tau transgenic mice
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[Copyright 2007 American Society for Biochemistry and Molecular Biology.]
Generation of inducible transgenic mice expressing the longest human tau isoform with pro- and anti-aggregation mutations. (A) Tau mutant transgenes. (B) Transgene expression in forebrain, mainly hippocampus, cortex, and striatum. (From Eckermann et al., 2007.)
[Copyright 2007 American Society of Biochemistry and Molecular Biology.]
Somatodendritic mislocalization of tau is reversable, tau levels are decreased, after switching off expression of pro-aggregation tau. Tau in pro-aggregation mouse with 10-month tau expression (A), no aggregates in mouse with 8.5-month expression and subsequent 1.5 month switch-off (B). (C) Western blots of soluble and insoluble fractions of the same animals show reduction in human pro-aggregation tau expression, whereas endogenous mouse tau levels remain stable. (D) Western blot quantification indicates disappearance of hTau40ΔK280 to control levels. (Eckermann et al., 2007.)
Primary Papers
- Eckermann K, Mocanu MM, Khlistunova I, Biernat J, Nissen A, Hofmann A, Schönig K, Bujard H, Haemisch A, Mandelkow E, Zhou L, Rune G, Mandelkow EM. The beta-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy. J Biol Chem. 2007 Oct 26;282(43):31755-65. Epub 2007 Aug 23 PubMed.
- Mocanu MM, Nissen A, Eckermann K, Khlistunova I, Biernat J, Drexler D, Petrova O, Schönig K, Bujard H, Mandelkow E, Zhou L, Rune G, Mandelkow EM. The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J Neurosci. 2008 Jan 16;28(3):737-48. PubMed.
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First demonstration of tau immunotherapy in mice
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[Copyright 2007 Society of Neuroscience.]
Neuronal tau aggregates were cleared in the dentate gyrus, the motor cortex, and brainstem in immunized P301L mice compared with controls. (From Asuni et al., 2007.)
[Copyright 2011 John Wiley & Sons, Inc.]
(a–c) PHF1 immunized P301L mice had less tau polyhelical filament pathology in the dentate gyrus, a trend for less in motor cortex, no change in brainstem. (From Boutajangout et al., 2011.)
[Copyright 2011 American Society for Biochemistry and Molecular Biology.]
Spinal cord and brain stem from P301S mice treated with control, MC1, and PHF1 anti-tau antibodies. The images show a reduction in PG5 staining in the anti-tau treated mice compared with control antibody-treated mice. (From Chai et al., 2011.)
Primary Papers
- Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci. 2007 Aug 22;27(34):9115-29. PubMed.
- Boutajangout A, Ingadottir J, Davies P, Sigurdsson EM. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem. 2011 Aug;118(4):658-67. PubMed.
- Chai X, Wu S, Murray TK, Kinley R, Cella CV, Sims H, Buckner N, Hanmer J, Davies P, O'Neill MJ, Hutton ML, Citron M. Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J Biol Chem. 2011 Sep 30;286(39):34457-67. PubMed.
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Atorvastatin fails in Phase 3
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