Journal Mobile Options
Table of Contents
Vol. 32, No. 1, 2011
Issue release date: September 2011
Dement Geriatr Cogn Disord 2011;32:45–54

Clinical Course of Patients with Familial Early-Onset Alzheimer’s Disease Potentially Lacking Senile Plaques Bearing the E693Δ Mutation in Amyloid Precursor Protein

Shimada H. · Ataka S. · Tomiyama T. · Takechi H. · Mori H. · Miki T.
Departments of aGeriatrics and Neurology and bNeuroscience, Osaka City University Graduate School of Medicine, Osaka, cCore Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, and dDepartment of Geriatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background/Aims: Oligomeric amyloid β (Aβ) is currently considered to induce Alzheimer’s disease (AD). We examined 2 patients with familial AD who possessed the Osaka (E693Δ) mutation in amyloid precursor protein. To the best of our knowledge, these patients are the first AD cases presumably affected with Aβ oligomers in the absence of senile plaques, and they support the Aβ oligomer hypothesis. Methods: We evaluated the clinical course, neuropsychological data, cerebrospinal fluid biomarker levels, magnetic resonance imaging (MRI) scans, fluorodeoxyglucose-positron emission tomography (PET) scans, and Pittsburgh compound B (PiB)-PET images of these patients. Results: In the early stages, these patients developed memory disturbances in a similar rate to patients with sporadic AD. Despite their memory disturbances, both patients showed only limited brain atrophy on MRI and little amyloid accumulation on PiB-PET. Subsequent to the development of memory disturbances, both patients suffered from motor dysfunction, probably due to cerebellar ataxia, and, within a few years, the patients fell into an apallic state. Conclusions: Familial AD patients with Osaka (E693Δ) mutation show severe dementia, cerebellar ataxia, and gait disturbances.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Selkoe DJ: Alzheimer’s disease is a synaptic failure. Science 2002;298:789–791.
  2. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH: Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci 2005;8:79–84.
  3. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH: A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006;440:352–357.
  4. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL: Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 2007;27:796–807.
  5. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL: Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 2007;27:2866–2875.
  6. Nimmrich V, Ebert U: Is Alzheimer’s disease a result of presynaptic failure? Synaptic dysfunctions induced by oligomeric beta-amyloid. Rev Neurosci 2009;20:1–12.
  7. Tomiyama T, Nagata T, Shimada H, Teraoka R, Fukushima A, Kanemitsu H, Takuma H, Kuwano R, Imagawa M, Ataka S, Wada Y, Yoshioka E, Nishizaki T, Watanabe Y, Mori H: A new amyloid beta variant favoring oligomerization in Alzheimer’s-type dementia. Ann Neurol 2008;63:377–387.
  8. Lopresti BJ, Klunk WE, Mathis CA, Hoge JA, Ziolko SK, Lu X, Meltzer CC, Schimmel K, Tsopelas ND, DeKosky ST, Price JC: Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis. J Nucl Med 2005;46:1959–1972.
  9. Price JC, Klunk WE, Lopresti BJ, Lu X, Hoge JA, Ziolko SK, Holt DP, Meltzer CC, DeKosky ST, Mathis CA: Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab 2005;25:1528–1547.
  10. Rouleau I, Salmon DP, Butters N, Kennedy C, McGuire K: Quantitative and qualitative analyses of clock drawings in Alzheimer’s and Huntington’s disease. Brain Cogn 1992;18:70–87.
  11. Funabiki Y, Takechi H, Akamatsu T, Kita T: Development of a short neuropsychological battery to screen early dementia in the elderly. Geriatr Gerontol Int 2003;2:179–186.

    External Resources

  12. Lezak MD: Neuropsychological Assessment, ed 3. New York, Oxford University Press, 1995.
  13. Takechi H, Dodge HH: Scenery Picture Memory Test: a new type of quick and effective screening test to detect early stage Alzheimer’s disease patients. Geriatr Gerontol Int 2010;10:183–190.
  14. Minoshima S, Frey KA, Koeppe RA, Foster NL, Kuhl DE: A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med 1995;36:1238–1248.
  15. Vemuri P, Wiste HJ, Weigand SD, Shaw LM, Trojanowski JQ, Weiner MW, Knopman DS, Petersen RC, Jack CR Jr: MRI and CSF biomarkers in normal, MCI, and AD subjects: diagnostic discrimination and cognitive correlations. Neurology 2009;73:287–293.
  16. Shoji M, Matsubara E, Murakami T, Manabe Y, Abe K, Kanai M, Ikeda M, Tomidokoro Y, Shizuka M, Watanabe M, Amari M, Ishiguro K, Kawarabayashi T, Harigaya Y, Okamoto K, Nishimura T, Nakamura Y, Takeda M, Urakami K, Adachi Y, Nakashima K, Arai H, Sasaki H, Kanemaru K, Yamanouchi H, Yoshida Y, Ichise K, Tanaka K, Hamamoto M, Yamamoto H, Matsubayashi T, Yoshida H, Toji H, Nakamura S, Hirai S: Cerebrospinal fluid tau in dementia disorders: a large scale multicenter study by a Japanese study group. Neurobiol Aging 2002;23:363–370.
  17. Ataka S, Tomiyama T, Takuma H, Yamashita T, Shimada H, Tsutada T, Kawabata K, Mori H, Miki T: A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease with spastic paraparesis. Arch Neurol 2004;61:1773–1776.

    External Resources

  18. Twells R, Yenchitsomanus PT, Sirinavin C, Allotey R, Poungvarin N, Viriyavejakul A, Cemal C, Weber J, Farrall M, Rodprasert P, et al: Autosomal dominant cerebellar ataxia with dementia: evidence for a fourth disease locus. Hum Mol Genet 1994;3:177–180.
  19. Oyanagi S: Hereditary dentatorubral-pallidoluysian atrophy. Neuropathology 2000;20(suppl):S42–S46.

    External Resources

  20. Filla A, De Michele G, Cocozza S, Patrignani A, Volpe G, Castaldo I, Ruggiero G, Bonavita V, Masters C, Casari G, Bruni A: Early onset autosomal dominant dementia with ataxia, extrapyramidal features, and epilepsy. Neurology 2002;58:922–928.
  21. Rolfs A, Koeppen AH, Bauer I, Bauer P, Buhlmann S, Topka H, Schols L, Riess O: Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (sca17). Ann Neurol 2003;54:367–375.
  22. Vale J, Bugalho P, Silveira I, Sequeiros J, Guimarães J, Coutinho P: Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal. Eur J Neurol 2010;17:124–128.
  23. Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K, Teraoka R, Sakama N, Yamashita T, Nishitsuji K, Ito K, Shimada H, Lambert MP, Klein WL, Mori H: A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci 2010;30:4845–4856.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50