The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non‐carriers with mild cognitive impairment due to Alzheimer's disease
Abstract Introduction 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 norma...
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Wiley
2024-10-01
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| Series: | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
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| Online Access: | https://doi.org/10.1002/trc2.70004 |
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| author | Arnold Bakker Nisha Rani Richard Mohs Michela Gallagher |
| author_facet | Arnold Bakker Nisha Rani Richard Mohs Michela Gallagher |
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| description | Abstract Introduction 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 study was a 78‐week trial to assess the progression of MCI due to AD. As reported in Mohs et al., the decline in the Clinical Dementia Rating Sum of Boxes score (CDR‐SB) was reduced by 40% in apolipoprotein E (APOE) ε4 non‐carriers over the 78‐week duration of the study with a negligible effect in carriers. Here we report an exploratory analysis of the effects of AGB101 on neuroimaging and biomarker measures in the 44 APOE ε4 non‐carriers who completed the 78‐week protocol. Methods Structural magnetic resonance imaging scans obtained at baseline and after 78 weeks were analyzed using the Automated Segmentation of Hippocampal Subfields 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 analyzed for plasma biomarkers. Results Treatment with AGB101 significantly reduced atrophy of the left entorhinal cortex (ERC) compared to placebo. This reduction in atrophy was correlated with less decline in the CDR‐SB score over 78 weeks and with lower neurofilament light chain (NfL), a marker of neurodegeneration. Discussion The HOPE4MCI study showed that APOE ε4 non‐carriers treated with AGB101 demonstrated a substantially more favorable treatment effect compared to carriers. Here we report that treatment with AGB101 in non‐carriers of APOE ε4 significantly reduced atrophy of the left ERC over 78 weeks. That reduction in atrophy was closely coupled with the change in CDR‐SB and with plasma NfL indicative of neurodegeneration in the brain. These exploratory analyses are consistent with a reduction in neurodegeneration in APOE ε4 non‐carriers treated with AGB101 before a clinical diagnosis of dementia. Highlights AGB101 slows entorhinal cortex (ERC) atrophy in apolipoprotein E (APOE) ε4 non‐carriers with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Slowing ERC atrophy by AGB101 is associated with less Clinical Dementia Rating Sum of Boxes decline. Slowing ERC atrophy by AGB101 is associated with lower neurofilament light chain. AGB101 treatment reduces neurodegeneration in APOE ε4 non‐carriers with MCI due to AD. |
| format | Article |
| id | doaj-art-28fac5d5773f462590d65b3d203ee3dc |
| institution | DOAJ |
| issn | 2352-8737 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Wiley |
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| series | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
| spelling | doaj-art-28fac5d5773f462590d65b3d203ee3dc2025-08-20T02:43:28ZengWileyAlzheimer’s & Dementia: Translational Research & Clinical Interventions2352-87372024-10-01104n/an/a10.1002/trc2.70004The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non‐carriers with mild cognitive impairment due to Alzheimer's diseaseArnold Bakker0Nisha Rani1Richard Mohs2Michela Gallagher3Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore Maryland USADepartment of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore Maryland USAAgeneBio, Inc. Baltimore Maryland USADepartment of Psychological and Brain Sciences Johns Hopkins University Baltimore Maryland USAAbstract Introduction 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 study was a 78‐week trial to assess the progression of MCI due to AD. As reported in Mohs et al., the decline in the Clinical Dementia Rating Sum of Boxes score (CDR‐SB) was reduced by 40% in apolipoprotein E (APOE) ε4 non‐carriers over the 78‐week duration of the study with a negligible effect in carriers. Here we report an exploratory analysis of the effects of AGB101 on neuroimaging and biomarker measures in the 44 APOE ε4 non‐carriers who completed the 78‐week protocol. Methods Structural magnetic resonance imaging scans obtained at baseline and after 78 weeks were analyzed using the Automated Segmentation of Hippocampal Subfields 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 analyzed for plasma biomarkers. Results Treatment with AGB101 significantly reduced atrophy of the left entorhinal cortex (ERC) compared to placebo. This reduction in atrophy was correlated with less decline in the CDR‐SB score over 78 weeks and with lower neurofilament light chain (NfL), a marker of neurodegeneration. Discussion The HOPE4MCI study showed that APOE ε4 non‐carriers treated with AGB101 demonstrated a substantially more favorable treatment effect compared to carriers. Here we report that treatment with AGB101 in non‐carriers of APOE ε4 significantly reduced atrophy of the left ERC over 78 weeks. That reduction in atrophy was closely coupled with the change in CDR‐SB and with plasma NfL indicative of neurodegeneration in the brain. These exploratory analyses are consistent with a reduction in neurodegeneration in APOE ε4 non‐carriers treated with AGB101 before a clinical diagnosis of dementia. Highlights AGB101 slows entorhinal cortex (ERC) atrophy in apolipoprotein E (APOE) ε4 non‐carriers with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Slowing ERC atrophy by AGB101 is associated with less Clinical Dementia Rating Sum of Boxes decline. Slowing ERC atrophy by AGB101 is associated with lower neurofilament light chain. AGB101 treatment reduces neurodegeneration in APOE ε4 non‐carriers with MCI due to AD.https://doi.org/10.1002/trc2.70004AGB101Alzheimer's diseaseclinical trialentorhinal cortex atrophylevetiracetammild cognitive impairment |
| spellingShingle | Arnold Bakker Nisha Rani Richard Mohs Michela Gallagher The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non‐carriers with mild cognitive impairment due to Alzheimer's disease Alzheimer’s & Dementia: Translational Research & Clinical Interventions AGB101 Alzheimer's disease clinical trial entorhinal cortex atrophy levetiracetam mild cognitive impairment |
| title | The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non‐carriers with mild cognitive impairment due to Alzheimer's disease |
| title_full | The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non‐carriers with mild cognitive impairment due to Alzheimer's disease |
| title_fullStr | The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non‐carriers with mild cognitive impairment due to Alzheimer's disease |
| title_full_unstemmed | The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non‐carriers with mild cognitive impairment due to Alzheimer's disease |
| title_short | The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non‐carriers with mild cognitive impairment due to Alzheimer's disease |
| title_sort | hope4mci study agb101 treatment slows progression of entorhinal cortex atrophy in apoe ε4 non carriers with mild cognitive impairment due to alzheimer s disease |
| topic | AGB101 Alzheimer's disease clinical trial entorhinal cortex atrophy levetiracetam mild cognitive impairment |
| url | https://doi.org/10.1002/trc2.70004 |
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