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.
Bapineuzumab Published, More AN1792 Presented
Vienna: New Shoot Among Ashes of Drug Trials
Dimebon: 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.”
Vienna: 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.
ADNI: One-year Data Narrow Field of MRI, FDG-PET Approaches (Part 1)
ADNI: 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.
Vienna: In Genetics, Bigger Is Better—Data Sharing Nets Three New Hits
Paper 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.
Cortical Hubs Found Capped With Amyloid (Buckner et al.)
BOLD New Look—Aβ Linked to Default Network Dysfunction
Multi-Paper Alert: More Data That Brain Amyloid Is Bad for You
Sleep 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.
Eibsee: Channel Vanishes in Sharper Image
Double Paper Alert—Keystone Presentations Now in Press
New Spin on γ-Secretase—Tangled in Tetraspanin Web?

Shelton 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

Mako 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:
Aβ Boosts Memory; Mint/X11 Proteins Boost Aβ?
Spine Shrinkers: Aβ Oligomers Caught in the Act (Koffie et al.)
The Many Misdeeds of Aβ—Seizures and Axonal Transport Interference
Neuronal Glutamate Fuels Aβ-induced LTD
The Ups and Downs of Aβ: Synaptic Activity Yields Mixed Results
What’s My Line?—Fishing for the True Role of Aβ (Abramov et al.)

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

Transmissible Proteinopathy Hypothesis Is Spreading
Aβ the Bad Apple? Seeding and Propagating Amyloidosis
Traveling Tau—A New Paradigm for Tau and Other Proteinopathies? (Clavaguera et al.)
Keystone: Tau, Huntingtin—Do Prion-like Properties Play a Role in Disease?
Research Brief: α-synuclein Spoils the Neural Neighborhood

Recognizing Sports Concussion as Dementia Risk Factor
Research Brief: Sixth Case of Brain Damage in NFL Player
Targeting Secretases Reduces Effects of Head Injury
NFL Survey on Dementia Splashes Across Front Pages

Stories to Watch in 2010
Keystone: Death Receptor Ligand—New Role for APP, New Model for AD?
Vienna: In Genetics, Bigger Is Better—Data Sharing Nets Three New Hits
Chicago: AD and Epilepsy—Joined at the Synapse?
Keystone: Partners in Crime—Do Aβ and Prion Protein Pummel Plasticity?
NO Joke: Viagra Lessens Aβ, Cognitive Problems in AD Mice
Yeast Screen Implicates PARK9 in Synuclein Toxicity
BDNF the Next AD Gene Therapy?
Big 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