We decided to try something novel and compile a roundup of the top news trends of the past year. We consulted our scientific advisors, eyeballed our news coverage, and pulled together this list, knowing fully well that it is the nature of such efforts to miss many worthwhile studies and end up with pie all over our face. We apologize in advance for any omissions and errors. We figured part of the fun will be to get readers to tell us what we missed. Please don't hesitate to correct and complain!

Clinical Trials Present a Mixed Picture
"The failed amyloid drug/vaccine studies, although not definitive, were some of the most galvanizing and concerning findings related to AD in 2009," according to an ARF Advisor. Will ApoE genotype help predict response to therapy? Other approaches show promise, including an α7 nicotinic acetylcholine receptor (nAChR) agonist EVP-6124 and Dimebon.

imageBapineuzumab Published, More AN1792 Presented

imageVienna: New Shoot Among Ashes of Drug Trials

imageDimebon: Bright Star or Black Hole?

Phase 2 Trial Launching for Prodromal AD
Bristol-Myers Squibb announced that it is recruiting for a 75-center Phase 2 trial of their new γ-secretase inhibitor, BMS-708163, in what that company calls “prodromal AD.”

imageVienna: New Genes, Anyone? ICAD Saves Best for Last

ADNI Reaping Fruit
Publication of ADNI data is enabling different imaging, CSF modalities, and neuropsychological tests to be compared in terms of power to detect treatment effects in AD and MCI clinical trials.

imageADNI: One-year Data Narrow Field of MRI, FDG-PET Approaches (Part 1)

imageADNI: Mission Creep From Alzheimer Disease to Healthy Senior? (Part 2)

Genomewide Association Studies Net Three New Genes
The two largest genomewide association studies of sporadic Alzheimer disease performed to date (Harold et al. and Williams et al.) fingered three new risk-factor genes—clusterin, CR1, PICALM. The most notable achievement of these studies lies in "the effort to collate data sets in support of larger samples, setting the trend we expect to see in the future," said an ARF Advisor.

imageVienna: In Genetics, Bigger Is Better—Data Sharing Nets Three New Hits

imagePaper Alert: GWAS Hits Clusterin, CR1, PICALM Formally Published

Growing Emphasis on Presymptomatic Detection
CSF biomarker and imaging studies pointed toward the possibility of detecting prodromal AD. A study from Washington University showing that Aβ dynamics are regulated by orexin and sleep-wake cycle "adds a new perspective to the use of CSF Aβ as a diagnostic marker, as the reference values may have to be adjusted to the sampling timepoints," according to an ARF Advisor.

imageCortical Hubs Found Capped With Amyloid (Buckner et al.)

imageBOLD New Look—Aβ Linked to Default Network Dysfunction

imageMulti-Paper Alert: More Data That Brain Amyloid Is Bad for You

imageSleep Deprivation Taxes Neurons, Racks Up Brain Aβ?

γ-Secretase Progress
Progress was made on elucidating the structure of γ-secretase. The paper by Serneels et al. described the role of the different Aph1 subtypes in the production of Aβ and in Notch-related toxicities. "With increasing numbers of failed clinical trials for γ-secretase inhibitors, this was especially important in (hopefully) injecting some renewed faith in γ-secretase as a viable target for AD drug development," an ARF Advisor opined.

imageEibsee: Channel Vanishes in Sharper Image

imageDouble Paper Alert—Keystone Presentations Now in Press

imageNew Spin on γ-Secretase—Tangled in Tetraspanin Web?

imageShelton CC, Zhu L, Chau D, Yang L, Wang R, Djaballah H, Zheng H, Li YM. Modulation of gamma-secretase specificity using small molecule allosteric inhibitors. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20228-33. Epub 2009 Nov 11. Abstract

imageMako Takami, Yu Nagashima, Yoshihisa Sano, Seiko Ishihara,1 Maho Morishima-Kawashima,4 Satoru Funamoto, and Yasuo Ihara. Gamma-Secretase: Successive Tripeptide and Tetrapeptide Release from the Transmembrane Domain of Beta-Carboxyl Terminal Fragment. J Neurosci 2009, 29:13042. Abstract

Insights Into Synaptic Plasticity, Cognition, and Role of Aβ

"The topic of synapses, β-amyloid, and synaptic/cognitive activity in AD continued to be a hot topic in the past year, with imaging and biological studies providing both new insights and questions," according to an ARF Advisor. A sampling:

imageAβ Boosts Memory; Mint/X11 Proteins Boost Aβ?

imageSpine Shrinkers: Aβ Oligomers Caught in the Act (Koffie et al.)

imageThe Many Misdeeds of Aβ—Seizures and Axonal Transport Interference

imageNeuronal Glutamate Fuels Aβ-induced LTD

imageThe Ups and Downs of Aβ: Synaptic Activity Yields Mixed Results

imageWhat’s My Line?—Fishing for the True Role of Aβ (Abramov et al.)

imageGarcia-Osta A, Alberini CM. Amyloid beta mediates memory formation. Learn Mem. 2009;16(4):267-72. Abstract

Transmissible Proteinopathy Hypothesis Is Spreading

imageAβ the Bad Apple? Seeding and Propagating Amyloidosis

imageTraveling Tau—A New Paradigm for Tau and Other Proteinopathies? (Clavaguera et al.)

imageKeystone: Tau, Huntingtin—Do Prion-like Properties Play a Role in Disease?

imageResearch Brief: α-synuclein Spoils the Neural Neighborhood

Recognizing Sports Concussion as Dementia Risk Factor

imageResearch Brief: Sixth Case of Brain Damage in NFL Player

imageTargeting Secretases Reduces Effects of Head Injury

imageNFL Survey on Dementia Splashes Across Front Pages

Stories to Watch in 2010

imageKeystone: Death Receptor Ligand—New Role for APP, New Model for AD?

imageVienna: In Genetics, Bigger Is Better—Data Sharing Nets Three New Hits

imageChicago: AD and Epilepsy—Joined at the Synapse?

imageKeystone: Partners in Crime—Do Aβ and Prion Protein Pummel Plasticity?

imageNO Joke: Viagra Lessens Aβ, Cognitive Problems in AD Mice

imageYeast Screen Implicates PARK9 in Synuclein Toxicity

imageBDNF the Next AD Gene Therapy?

imageBig Haul? A G Protein-coupled Receptor Regulates Aβ Production

Marci Kalif nominates as Top AD Trend paper for 2009:

Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. Abstract

Michael Marlatt nominates as Top AD Trend paper for 2009:

Ma L, Seager MA, Seager M, Wittmann M, Jacobson M, Bickel D, Burno M, Jones K, Graufelds VK, Xu G, Pearson M, McCampbell A, Gaspar R, Shughrue P, Danziger A, Regan C, Flick R, Pascarella D, Garson S, Doran S, Kreatsoulas C, Veng L, Lindsley CW, Shipe W, Kuduk S, Sur C, Kinney G, Seabrook GR, Ray WJ. Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation. Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15950-5. Abstract

Tim West nominates as Top AD Trend paper for 2009:

Bateman RJ, Siemers ER, Mawuenyega KG, Wen G, Browning KR, Sigurdson WC, Yarasheski KE, Friedrich SW, Demattos RB, May PC, Paul SM, Holtzman DM. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol. 2009 Jul;66(1):48-54. Abstract

Misha Nossov and Hyun Jin Kim nominate as Top AD Trend paper for 2009:

Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M, Bapineuzumab 201 Clinical Trial Investigators. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009 Dec 15;73(24):2061-70. Abstract

Misha Nossov and Dariusz Pytel nominate as Top AD Trend paper for 2009:

Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, 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 AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1088-93. Abstract

Lora Talley Watts nominates as Top AD Trend paper for 2009:

Schjeide BM, Hooli B, Parkinson M, Hogan MF, Divito J, Mullin K, Blacker D, Tanzi RE, Bertram L. GAB2 as an Alzheimer disease susceptibility gene: follow-up of genomewide association results. Arch Neurol. 2009 Feb;66(2):250-4. Abstract

Michael Shia nominates as Top AD Trend paper for 2009:

Britschgi M, Olin CE, Johns HT, Takeda-Uchimura Y, Lemieux MC, Rufibach K, Rajadas J, Zhang H, Tomooka B, Robinson WH, Clark CM, Fagan AM, Galasko DR, Holtzman DM, Jutel M, Kaye JA, Lemere CA, Leszek J, Li G, Peskind ER, Quinn JF, Yesavage JA, Ghiso JA, Wyss-Coray T. Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12145-50. Abstract

Dariusz Pytel nominates as Top AD Trend paper for 2009:

Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, 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, European Alzheimer's Disease Initiative Investigators, de Pancorbo MM, 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 JF, 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. Nat Genet. 2009 Oct;41(10):1094-9. Abstract

John Steele nominates as Top AD Trend paper for 2009:

Tampellini D, Rahman N, Gallo EF, Huang Z, Dumont M, Capetillo-Zarate E, Ma T, Zheng R, Lu B, Nanus DM, Lin MT, Gouras GK. Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci. 2009 Aug 5;29(31):9704-13. Abstract

Patricia Heyn nominates as Top AD Trend paper for 2009:

Rohe M, Synowitz M, Glass R, Paul SM, Nykjaer A, Willnow TE. Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression. J Neurosci. 2009 Dec 9;29(49):15472-8. Abstract

An Tanghe and Qinxi Guo nominate as Top AD Trend paper for 2009:

Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. Abstract

Sabah Ansar nominates as Top AD Trend paper for 2009:

Desino KE, Ansar S, Georg GI, Himes RH, Michaelis ML, Powell DR, Reiff EA, Telikepalli H, Audus KL. (3R,5S,7as)-(3,5-Bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol, a novel neuroprotective agent. J Med Chem. 2009 Dec 10;52(23):7537-43. Abstract

Terry Singeltary nominates as Top AD Trend papers for 2009:
Cisse M, Mucke L. Alzheimer's disease: A prion protein connection. Nature. 2009 Feb 26;457(7233):1090-1. Abstract

Aguzzi A. Cell biology: Beyond the prion principle. Nature. 2009 Jun 18;459(7249):924-5. Abstract

Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. Abstract

Tomasz Sobow nominates as Top AD Trend paper for 2009:

Abramov E, Dolev I, Fogel H, Ciccotosto GD, Ruff E, Slutsky I. Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci. 2009 Dec;12(12):1567-76. Abstract

Gjumrakch Aliev nominates as Top AD Trend papers for 2009:

Vancová O, Baciak L, Kašparová S, Kucharská J, Palacios HH, Horecký J, Aliev G. In vivo and in vitro assessment of brain bioenergetics in aging rats. J Cell Mol Med. 2009 Aug 10. Abstract

Aliev G, Palacios HH, Walrafen B, Lipsitt AE, Obrenovich ME, Morales L. Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease. Int J Biochem Cell Biol. 2009 Oct;41(10):1989-2004. Abstract

Shenk JC, Liu J, Fischbach K, Xu K, Puchowicz M, Obrenovich ME, Gasimov E, Alvarez LM, Ames BN, Lamanna JC, Aliev G. The effect of acetyl-L-carnitine and R-alpha-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer's disease. J Neurol Sci. 2009 Aug 15;283(1-2):199-206. Abstract

Obrenovich ME, Morales LA, Cobb CJ, Shenk JC, Méndez GM, Fischbach K, Smith MA, Qasimov EK, Perry G, Aliev G. Insights into cerebrovascular complications and Alzheimer disease through the selective loss of GRK2 regulation. J Cell Mol Med. 2009 May;13(5):853-65. Abstract

Aliev G, Liu J, Shenk JC, Fischbach K, Pacheco GJ, Chen SG, Obrenovich ME, Ward WF, Richardson AG, Smith MA, Gasimov E, Perry G, Ames BN. Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats. J Cell Mol Med. 2009 Feb;13(2):320-33. Abstract

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  1. FAILURE TO LAUNCH

    IMHO this nagging question is the largest trend in the AD field in 2009: Why don’t our enduring hypotheses about Alzheimer disease lead us to a complete understanding of the mechanism of the disease and generate curative therapies?
    Certainly, amyloidβ is part of the disease process (amyloid cascade hypothesis). And, some external factors such as Chlamydophila pneumoniae (pathogen hypothesis) in combination with variations in APOE and other genes (Alzgene) along with aging and epigenetic changes, all have a place on the disease path. However, the challenge remains to tie all of the genetic variability, epigenetic modifications, internal and external factors at the mechanistic, biochemical level with new, original hypotheses (pathogenic chromatin modification hypothesis) to reveal the complete disease path. This could become the foundation for novel research and underpin an eventual cure.

  2. Dear Alzforum Staff,

    Happy New Year!

    Thank you for this constructive move and the way you have put together elements that seem to be involved in AD. It is truly a great gift to us all!

    In my humble opinion, this is a thorough collection. Only a couple of minor notes: I'd add findings on the link to 1) ApoE and α7 (or, in general, the nicotinic system), and 2) ApoE and γ-secretase hypotheses.

    Wishing you a fruitful year and decade.

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References

News Citations

  1. Paper Alert-cum-SfN: Bapineuzumab Published, More AN1792 Presented
  2. Vienna: New Shoot Among Ashes of Drug Trials
  3. Dimebon: Bright Star or Black Hole?
  4. Vienna: New Genes, Anyone? ICAD Saves Best for Last
  5. ADNI: One-year Data Narrow Field of MRI, FDG-PET Approaches
  6. ADNI: Mission Creep From Alzheimer Disease to Healthy Senior?
  7. Vienna: In Genetics, Bigger Is Better—Data Sharing Nets Three New Hits
  8. Paper Alert: GWAS Hits Clusterin, CR1, PICALM Formally Published
  9. Cortical Hubs Found Capped With Amyloid
  10. Multi-Paper Alert: More Data That Brain Amyloid Is Bad for You
  11. Sleep Deprivation Taxes Neurons, Racks Up Brain Aβ?
  12. Eibsee: Channel Vanishes in Sharper Image
  13. Double Paper Alert—Keystone Presentations Now in Press
  14. New Spin on γ-Secretase—Tangled in Tetraspanin Web?
  15. Aβ Boosts Memory; Mint/X11 Proteins Boost Aβ?
  16. Spine Shrinkers: Aβ Oligomers Caught in the Act
  17. The Many Misdeeds of Aβ—Seizures and Axonal Transport Interference
  18. Neuronal Glutamate Fuels Aβ-induced LTD
  19. The Ups and Downs of Aβ: Synaptic Activity Yields Mixed Results
  20. What’s My Line?—Fishing for the True Role of Aβ
  21. Aβ the Bad Apple? Seeding and Propagating Amyloidosis
  22. Traveling Tau—A New Paradigm for Tau- and Other Proteinopathies?
  23. Keystone: Tau, Huntingtin—Do Prion-like Properties Play a Role in Disease?
  24. Research Brief: α-synuclein Spoils the Neural Neighborhood
  25. Research Brief: Sixth Case of Brain Damage in NFL Player
  26. Targeting Secretases Reduces Effects of Head Injury
  27. Brief: NFL Survey on Dementia Splashes Across Front Pages
  28. Prague: N-terminal APP Story Buzzes in the Hallways
  29. Chicago: AD and Epilepsy—Joined at the Synapse?
  30. Keystone: Partners in Crime—Do Aβ and Prion Protein Pummel Plasticity?
  31. NO Joke: Viagra Lessens Aβ, Cognitive Problems in AD Mice
  32. Yeast Screen Implicates PARK9 in Synuclein Toxicity
  33. BDNF the Next AD Gene Therapy?
  34. Big Haul? A G Protein-coupled Receptor Regulates Aβ Production

Paper Citations

  1. . Modulation of gamma-secretase specificity using small molecule allosteric inhibitors. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20228-33. PubMed.
  2. . gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci. 2009 Oct 14;29(41):13042-52. PubMed.
  3. . Amyloid beta mediates memory formation. Learn Mem. 2009 Apr;16(4):267-72. PubMed.
  4. . Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. PubMed.
  5. . Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation. Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15950-5. PubMed.
  6. . A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol. 2009 Jul;66(1):48-54. PubMed.
  7. . A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009 Dec 15;73(24):2061-70. PubMed.
  8. . Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1088-93. PubMed.
  9. . GAB2 as an Alzheimer disease susceptibility gene: follow-up of genomewide association results. Arch Neurol. 2009 Feb;66(2):250-4. PubMed.
  10. . Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12145-50. PubMed.
  11. . Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1094-9. PubMed.
  12. . Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci. 2009 Aug 5;29(31):9704-13. PubMed.
  13. . Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression. J Neurosci. 2009 Dec 9;29(49):15472-8. PubMed.
  14. . APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PubMed.
  15. . (3R,5S,7as)-(3,5-Bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol, a novel neuroprotective agent. J Med Chem. 2009 Dec 10;52(23):7537-43. PubMed.
  16. . Alzheimer's disease: A prion protein connection. Nature. 2009 Feb 26;457(7233):1090-1. PubMed.
  17. . Cell biology: Beyond the prion principle. Nature. 2009 Jun 18;459(7249):924-5. PubMed.
  18. . Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. PubMed.
  19. . Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci. 2009 Dec;12(12):1567-76. PubMed.
  20. . In vivo and in vitro assessment of brain bioenergetics in aging rats. J Cell Mol Med. 2010 Nov;14(11):2667-74. PubMed.
  21. . Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease. Int J Biochem Cell Biol. 2009 Oct;41(10):1989-2004. PubMed.
  22. . The effect of acetyl-L-carnitine and R-alpha-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer's disease. J Neurol Sci. 2009 Aug 15;283(1-2):199-206. PubMed.
  23. . Insights into cerebrovascular complications and Alzheimer disease through the selective loss of GRK2 regulation. J Cell Mol Med. 2009 May;13(5):853-65. PubMed.
  24. . Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats. J Cell Mol Med. 2009 Feb;13(2):320-33. PubMed.

Other Citations

  1. BOLD New Look—Aβ Linked to Default Network Dysfunction

Further Reading

No Available Further Reading