About

Michela Gallagher is the Krieger-Eisenhower Professor of Psychology & Neuroscience at Johns Hopkins University. Her research program is broadly based in the area of systems neuroscience, utilizing animal models such as rats and mice, as well as studies in humans. A special emphasis of her work is neurocognitive aging. She studies the neurobiological basis for the differing outcomes observed at older ages, including cognitive impairment and well-preserved cognitive function, sometimes referred to as 'successful aging.' Gallagher leads a diverse team of researchers investigating these neurobiological mechanisms across species and directs studies aimed at testing treatments in animals and conducting clinical trials in humans to improve memory function in older adults suffering from memory problems, such as patients with mild cognitive impairment at risk for Alzheimer’s disease. Her basic research has been supported for over 20 years by the National Institute on Aging, and her clinical research in humans is currently supported by a Grand Opportunity Award under the American Recovery and Reinvestment Act of 2009. Additionally, she heads the Neurogenetics and Behavior Center at Johns Hopkins University, an innovative resource dedicated to studying mice with targeted genetic manipulations at high levels of cognitive and affective function.

Research topics

• Neuroscience
• Psychology
• Biology
• Internal medicine
• Medicine

Selected publications

• Circadian Changes in CA1 LTP Are Driven by Shifts in Excitation–Inhibition Balance and Reverse Direction after Puberty in Mice

  Journal of Neuroscience · 2026-03-03 · 2 citations

  articleOpen access

  Long-term potentiation (LTP), the best-characterized form of Hebbian synaptic plasticity, is well known to be under strong circadian regulation. In mice and rats, both nocturnal species, most studies indicate that LTP in the hippocampal CA1 region is more robust when induced during the dark phase. Our examination of the underlying mechanisms at the CA3→CA1 synapse in mice of all sexes indicates that the capacity to support LTP does not differ between the light and dark phases of the 24 h day. Instead, the magnitude of theta burst stimulation-induced LTP (TBS-LTP) correlates with daily fluctuations in the ratio of synaptic excitation to inhibition (E/I ratio): both the E/I ratio and TBS-LTP are higher during the dark phase. On the other hand, LTD induced with low-frequency stimulation did not change across the circadian cycle. Consistent with a causal relationship between the E/I ratio and TBS-LTP, blockade of inhibition abolishes the light-dark difference in TBS-LTP induction. Likewise, pairing-induced LTP, which is not constrained by inhibitory recruitment, does not differ between cycles. Supporting this, in the APP/PS1 model of AD neither the E/I ratio nor TBS-LTP varies across the light-dark cycle, despite preserved circadian regulation of locomotor activity. Finally, we made the intriguing observation that these daily oscillations reverse direction after puberty in WT mice, shifting from being larger in the dark cycle of 2-month-old mice to being larger in the light cycle in 8-month-old mice. This developmental switch may reflect an age-dependent reorganization of circadian control over hippocampal plasticity.

  PublisherOA PDFDOI

• Altered NPTX2 dynamics associated with impaired cognitive aging

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-17 · 1 citations

  preprintOpen access

  Abstract Changes in synaptic integrity and neural activity homeostasis are hallmarks of brain aging and are closely tied to cognitive outcomes. Yet, defining their relationship across the continuum from normal aging to neurodegenerative disease has proven challenging. Recent research investigating the dynamic changes of neuronal pentraxin 2 (NPTX2, or Narp, neuronal activity-related pentraxin) in cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) subjects supports its promise as a prognostic marker of disease progression, possibly as an expression of synaptic damage related to cognitive impairment. However, studies in human subjects are unable to clearly differentiate age-related and disease-related processes. Here we took advantage of a well-characterized rat model that displays substantial individual differences in hippocampal memory during aging, uncontaminated by slowly progressive, spontaneous neurodegenerative disease. Through this approach, we aimed to interrogate the underlying neural substrates that mediate aging as a uniquely permissive condition and the primary risk for neurodegeneration. We found that successful cognitive aging is associated with an elevation of NPTX2 levels above that found in young or cognitively impaired subjects. Pharmacological engagement of neural activity was sufficient to increase NPTX2 levels in all subjects, but cognitively-impaired aged subjects failed to recruit NPTX2 in response to a hippocampus-dependent memory task. Together the findings demonstrate that changes in NPTX2 are coupled to differential cognitive outcomes of aging, and that successful neurocognitive aging is associated with adaptive upregulation of NPTX2, not simply the persistence of youthful synaptic dynamics. Significance Statement Although aging is the most prominent risk factor for Alzheimer Disease (AD), the age-dependent processes that disrupt neurophysiological homeostasis leading to neurodegenerative disease remain poorly defined. Alterations in NPTX2, a synaptic protein biomarker for AD, may elucidate aging processes underlying pathological trajectories. We examined NPTX2 in an aging context and identified circuit specific alterations of NPTX2 that are coupled with distinct memory outcomes in aging in the absence of potential confounds of neurodegenerative disease. Greater NPTX2, associated with successful cognitive aging, may reflect coordinated molecular and circuit-level adaptations that sustain memory-relevant hippocampal activity. Development of targets and interventions that promote neuroadaptive network homeostasis, bending the trajectory of aging away from neurodegeneration, are a potentially valuable alternative to current therapeutic strategies.

  PublisherOA PDFDOI

• NPTX2 transfection improves synaptic E/I balance and performance in learning impaired aged rats

  Progress in Neurobiology · 2025-03-07 · 3 citations

  articleCorresponding
  PublisherDOI

• Parallel circadian-like oscillations in LTP and excitation inhibition balance in mouse CA1 reverse direction after puberty

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-15 · 1 citations

  preprintOpen access

  Long-term potentiation (LTP), the best-characterized form of Hebbian synaptic plasticity, is well known to be under strong circadian regulation. In mice and rats, both nocturnal species, most studies indicate that LTP in the hippocampal CA1 region is more robust when induced during the dark phase. Our examination of the underlying mechanisms at the CA3 to CA1 synapse provides evidence that the capacity to express LTP does not differ between the light and dark cycles of the 24-hour day. Instead, the magnitude of theta-burst stimulation-induced LTP (TBS-LTP) correlates with daily fluctuations in the ratio of synaptic excitation to inhibition (E/I ratio): both the E/I ratio and TBS-LTP are higher during the dark phase. Consistent with a causal relationship, blockade of inhibition abolishes the light-dark difference in TBS-LTP induction, likewise, pairing-induced LTP, which is less constrained by inhibitory recruitment, does not differ between cycles. Supporting this model, using the APP/PS1 model of AD we observed that neither the E/I ratio nor TBS-LTP change during the light cycle. Finally, we made the intriguing observation that these daily oscillations reverse direction after puberty in WT mice, shifting from being larger in the dark cycle of 2-month-old mice to being larger in the light cycle in 8-month-old mice. This developmental switch may reflect an age-dependent reorganization of circadian control over hippocampal plasticity.

  PublisherOA PDFDOI

• The HOPE4MCI study: A randomized double‐blind assessment of AGB101 for the treatment of MCI due to AD

  Alzheimer s & Dementia Translational Research & Clinical Interventions · 2024-01-01 · 27 citations

  articleOpen accessSenior authorCorresponding

  INTRODUCTION: In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD. METHODS: = 81), an extended-release formulation of low dose (220 mg) levetiracetam. The primary endpoint was the change in Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB) comparing follow up at 18 months to baseline. The goal of the primary efficacy analysis was to estimate the difference between the AGB101 and placebo arms in the mean change of the primary endpoint. RESULTS: The mean change in CDR-SB was estimated to be 1.12 (95% confidence interval [CI]: 0.66, 1.69) for the AGB101 arm and 1.22 (95% CI: 0.75, 1.78) for the placebo arm. The estimated difference between arms is -0.10 (95% CI: -0.85, 0.58), which was not statistically significant. In a prespecified analysis, the difference was -0.45 (95% CI: -1.43, 0.53) for ApoE-4 noncarriers and -0.10 (95% CI: -0.92, 0.72) for apolipoprotein E (ApoE)-4 carriers. DISCUSSION: The possibility that ApoE-4 carriers and noncarriers will respond differently to therapeutic intervention is consistent with recently reported findings from biologics and the present results show further testing of AGB101 in patients with MCI due to AD who are noncarriers of the ApoeE-4 allele is warranted. Conclusions from the HOPE4MCI study are limited primarily due to the small sample size and results can only be regarded as a guide to future research.

  PublisherOA PDFDOI

• Positive Allosteric Modulation of GABAA α5 Receptors Improves Memory performance of rats with Conditions of Hippocampal Hyperactivity

  Neurotherapeutics · 2024-07-01

  articleOpen accessSenior author
  PublisherOA PDFDOI

• The HOPE4MCI study: AGB101 treatment reduces entorhinal cortex atrophy in patients with amnestic mild cognitive impairment due to Alzheimer’s Disease who are ApoE‐4 non‐carriers

  Alzheimer s & Dementia · 2024-12-01

  articleOpen access

  Abstract Background Hippocampal hyperactivity is a hallmark of prodromal Alzheimer’s disease (AD) that predicts progression in patients with amnestic mild cognitive impairment (aMCI). AGB101 is an extended‐release formulation of levetiracetam in the dose range previously demonstrated to normalize hippocampal activity and improve cognitive performance in aMCI. The HOPE4MCI clinical trial used a 78‐week protocol to assess progression in amyloid‐positive patients with MCI due to AD. Mohs et al. (2024) reported the clinical/cognitive results showing that ApoE‐4 non‐carriers had a more favorable treatment effect of AGB101 over the 78‐week duration of the study. Here we report effects of AGB101 on biomarkers of AD in those patients. Methods Forty‐four participants who completed the 78‐week protocol were ApoE‐4 non‐carriers. Structural MRI scans obtained in the study at baseline and after 78 weeks were analyzed using the Automated Segmentation of Hippocampal Subfields (ASHS) software providing volume measures of key structures of the medial temporal lobe relevant to AD progression. Blood samples collected at 78 weeks in the study were also analyzed for plasma biomarkers in those participants. Results Treatment with AGB101 significantly reduced atrophy in the left entorhinal cortex (p < 0.05) compared to placebo. Reduced atrophy in the entorhinal cortex was significantly correlated with the change in CDR‐SB score (r = ‐0.511) over 78 weeks, as well as with biomarkers of neurodegeneration neurofilament light (NfL; r = ‐0.382) and glial fibrillary acidic protein (GFAP; r = ‐0.398) collected at completion of the protocol. Conclusion As reported in Mohs et al. (2024), progression on the primary clinical/cognitive endpoint of the Clincial Dementia Rating Scale Sum of Boxes score (CDR‐SB) occurred over the 78‐week protocol in the HOPE4MCI study and non‐carriers of ApoE4 treated with AGB101 showed a substantially more favorable effect than carriers. Here we report that treatment with AGB101, in those participants significantly reduced atrophy of the entorhinal cortex. That reduction in atrophy was significantly coupled with the change in CDR‐SB and with plasma biomarkers of disease. These exploratory analyses would be consistent with a reduction in neurodegeneration in the non‐carriers of ApoE4 treated with AGB101 prior to a clinical diagnosis of dementia.

  PublisherOA PDFDOI
• RETRACTED

  Retraction Note: A specific amyloid-β protein assembly in the brain impairs memory

  Nature · 2024-06-24 · 14 citations

  retraction
  PublisherOA PDFDOI

• Investigating protein structural changes associated with cognitive decline in a rodent model of aging using limited proteolysis mass spectrometry

  Biophysical Journal · 2024-02-01

  articleOpen access
  PublisherOA PDFDOI

• The HOPE4MCI study: AGB101 treatment reduces entorhinal cortex atrophy in patients with amnestic mild cognitive impairment due to Alzheimer's Disease who are ApoE‐4 non‐carriers

  Alzheimer s & Dementia · 2024-12-01

  articleOpen access

  Abstract Background Hippocampal hyperactivity is a hallmark of prodromal Alzheimer’s disease (AD) that predicts progression in patients with amnestic mild cognitive impairment (aMCI). AGB101 is an extended‐release formulation of levetiracetam in the dose range previously demonstrated to normalize hippocampal activity and improve cognitive performance in aMCI. The HOPE4MCI clinical trial used a 78‐week protocol to assess progression in amyloid‐positive patients with MCI due to AD. Mohs et al. (2024) reported the clinical/cognitive results showing that ApoE‐4 non‐carriers had a more favorable treatment effect of AGB101 over the 78‐week duration of the study. Here we report effects of AGB101 on biomarkers of AD in those patients. Methods Forty‐four participants who completed the 78‐week protocol were ApoE‐4 non‐carriers. Structural MRI scans obtained in the study at baseline and after 78 weeks were analyzed using the Automated Segmentation of Hippocampal Subfields (ASHS) software providing volume measures of key structures of the medial temporal lobe relevant to AD progression. Blood samples collected at 78 weeks in the study were also analyzed for plasma biomarkers in those participants. Results Treatment with AGB101 significantly reduced atrophy in the left entorhinal cortex (p < 0.05) compared to placebo. Reduced atrophy in the entorhinal cortex was significantly correlated with the change in CDR‐SB score (r = ‐0.511) over 78 weeks, as well as with biomarkers of neurodegeneration neurofilament light (NfL; r = ‐0.382) and glial fibrillary acidic protein (GFAP; r = ‐0.398) collected at completion of the protocol. Conclusion As reported in Mohs et al. (2024), progression on the primary clinical/cognitive endpoint of the Clincial Dementia Rating Scale Sum of Boxes score (CDR‐SB) occurred over the 78‐week protocol in the HOPE4MCI study and non‐carriers of ApoE4 treated with AGB101 showed a substantially more favorable effect than carriers. Here we report that treatment with AGB101, in those participants significantly reduced atrophy of the entorhinal cortex. That reduction in atrophy was significantly coupled with the change in CDR‐SB and with plasma biomarkers of disease. These exploratory analyses would be consistent with a reduction in neurodegeneration in the non‐carriers of ApoE4 treated with AGB101 prior to a clinical diagnosis of dementia.

  PublisherOA PDFDOI

Recent grants

• PHASE II/III trial for Slowing Progression in Mild Cognitive Impairment

  NIH · $7.6M · 2015–2023

• GABA-A alpha-5 agonists for the treatment of amnestic Mild Cognitive Impairment

  NIH · $2.3M · 2012–2016

• NIH Grant K02MH000406

  NIH · $386k · 1992

• PROJECT 1-Neural encoding based on lateral and medial entorhinal information processing streams in behaviorally-characterized aged rats

  NIH · $72.5M · 1997–2027

• NIH Grant R01MH039180

  NIH · $342k · 1991

Frequent coauthors

• Peter C. Holland

  Johns Hopkins University

  63 shared

• Arnold B. Bakker

  University of Johannesburg

  32 shared

• James Knierim

  Johns Hopkins University

  31 shared

• Ming Teng Koh

  Johns Hopkins University

  25 shared

• Jung‐Soo Han

  Shandong Agricultural University

  23 shared

• Peter R. Rapp

  National Institute on Aging

  22 shared

• Rebecca P. Haberman

  Hinge Health

  21 shared

• Caroline L. Speck

  Johns Hopkins University

  21 shared

Awards & honors

• Grand Opportunity Award, a stimulus-funded research grant un…