Select publications support our development pipeline of innovative therapeutics that are designed to preserve and restore brain function for patients at risk of neurodegeneration.

Clinical Program: Human Studies

Bakker A, Albert MS, Krauss GL, Speck CL, Gallagher M (2015) Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. NeuroImage: Clinical 7: 688-698.
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Haberman, R.P., Branch, A. & Gallagher, M. (2017) Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer’s Disease. Neurotherapeutics. doi:10.1007/s13311-017-0541-z.
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Mohs R, Rosenzweig-Lipson S, Gallagher M, Albert M (2016) Phase 3 Clinical Trial in MCI due to AD Targeting Hippocampal Hyperactivity 9th International Conference on Clinical Trials for Alzheimer’s Disease, San Diego, CA.
CTAD Mohs Poster


Rosenblum M, Colantuoni E, Steingrimsson J, Bakker A, Gallagher M (2016) Improving Precision and Power by Adjusting for Prognostic Baseline Variables in Alzheimer’s Disease Clinical Trials 9th International Conference on Clinical Trials for Alzheimer’s Disease, San Diego, CA.
CTAD Colantuoni Poster


Rosenzweig-Lipson S, Mulcahy S, Payie K, Bullock S,  Melsopp E, James J,  Gallagher M (2015) Pharmacokinetic Profile of a Novel Low Dose Extended Release Formulation of AGB101 (Levetiracetam). 8th Clinical Trials on Alzheimer’s Disease, Barcelona, Spain.
CTAD poster 2015


Tran T, Speck C, Pisupati A, Gallagher M, Bakker A (2016) Increased hippocampal activation in ApoE-4 carriers and non-carriers with amnestic mild cognitive impairment. NeuroImage: Clinical 13:237-245.

  • Patients with aMCI show increased fMRI activation in DG/CA3 relative to controls.
  • Increased DG/CA3 activation is observed equally in ApoE-4 carriers and non-carriers.
  • Hippocampal dysfunction in aMCI is observed independent of ApoE-4 carrier status.

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Yassa MA, Stark SM, Bakker A, Albert MS, Gallagher M, Stark CE (2010) High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment. Neuroimage 51: 1242-1252.

Hippocampal hyperactivity using fMRI in studies of aging/aMCI were reported by several groups. This publication was the first using high resolution to localize the hyperactivity within specific circuits of the hippocampus.

The localization in MCI/humans was consistent with elevated activity discovered in Dr. Gallagher’s animal model (Wilson et al. ref).

This paper provided the background clinical research for the NIH grant awarded to assess low dose levetiracetam in patients with amnestic mild cognitive impairment (Dr. Gallagher, P.I.).
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Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, Yassa MA, Bassett SS, Shelton AL, Gallagher M (2012) Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron 74: 467-474.

First wave of levetiracetam study in aMCI patients demonstrated target engagement (lowered hippocampal overactivity) and functionally improved memory performance in the scanning task.
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Putcha D, Brickhouse M, O’Keefe K, Sullivan C, Rentz D, Marshall G, Dickerson B, Sperling R (2011) Hippocampal hyperactivation associated with cortical thinning in Alzheimer’s disease signature regions in non-demented elderly adults. The Journal of Neuroscience 31: 17680-17688.

In patients with aMCI, the degree of hippocampal overactivity predicts severity of cognitive impairment and extent of atrophy in cortical areas first affected by neurodegeneration in Alzheimer’s disease.
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Rhinn H, Fujita R, Qiang L, Cheng R, Lee JH, Abeliovich A (2013) Integrative genomics identifies APOE ε4 effectors in Alzheimer’s disease. Nature 500: 45-50.

A bioinformatics approach identified effector pathways for the risk associated with ApoE4 (mechanisms through which ApoE4 mediates pathological effects).

Sv2a (the target of levetiracetam) was among top candidates.

In human IPS neurons from ApoE4 carriers levetiracetam blocked the effects on BACE processing of amyloid to increase beta amyloid (see Fig. 4 and supplementary data).
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Berchtold NC, Sabbagh MN, Beach TG, Kim RC, Cribbs DH, Cotman CW (2014) Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer’s disease. Neurobiology of Aging 35: 1961-1972.

Microarrays on brain tissue from well-characterized autopsied brains show a clustering of expression profiles in aMCI patients for synaptic function/plasticity molecules in the hippocampus consistent with aberrant overactivity.

Paper highlights the study of levetiracetam in aMCI patients as a rational therapeutic approach.
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Preclinical Program: Animal Models

Koh MT, Haberman RP, Foti S, McCown TJ, Gallagher M (2010) Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology 35: 1016-1025.

In well-characterized aged rats with memory impairment, first report of therapeutic window using low dose levetiracetam to target hippocampal hyperactivity discovered in this model (ref Wilson et al. 2003;2005; 2006). (see fig. 5 for levetiracetam data).
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Busche MA, Chen X, Henning HA, Reichwald J, Staufenbield M, Sakmann B, Konnerth A (2012) Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences USA 109: 8740-8745.

Soluble amyloid (in the absence of amyloid plaques) causes hippocampal hyperactivity.

Important implications for amyloid therapies because most antibodies in clinical trials targeting amyloid target amyloid plaques NOT soluble amyloid.
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Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L (2012) Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proceedings of the National Academy of Sciences USA 109: E2 895–E2 903.

Low dose levetiracetam rescues molecular, synaptic, physiological, and memory impairment in an ‘amyloid’ mouse model of Alzheimer’s.

Drug exposure with low doses is consistent with clinical PK in AgeneBio’s study of aMCI patients and in AI rat model, both referenced in this pub (ref 39, 64).

Other anti-epileptics are ineffective in the J20 model.
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Suberbielle E, Sanchez PE, Kravitz AV, Wang X, Ho K, Eilertson K, Devidze N, Kreitzer AC, Mucke L (2013) Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nature Neuroscience 16: 613-621.

Significant neuronal injury (DNA double-stand breaks) in an amyloid mouse model is prevented by low dose levetiracetam (see fig. 6).
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Discovery GABA Program

Gill KM, Lodge DJ, Cook JM, Aras S, Grace AA (2011) A novel a5GABAAR-Positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of Schizophrenia. Neuropsychopharmacology 36: 1903-1911.

Animal model used for schizophrenia shows a beneficial response to GABA A alph5 positive allosteric modulator. Other recent papers citing this target for autism.
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Koh MT, Rosenzweig-Lipson S, Gallagher M (2013) Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. Neuropharmacology 64: 145-152.

Publication by AgeneBio demonstrating benefit of GABA A alpha 5 positive allosteric modulators in memory-impaired aged rats.
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