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  • 1.
    Hemmingsson, Eva-Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Hjelmare, Ellen
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Weidung, Bodil
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Department of Public Health and Caring Sciences, Geriatric Medicine, Uppsala University, Uppsala, Sweden.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Antiviral treatment associated with reduced risk of clinical Alzheimer's disease: A nested case-control study2021In: Alzheimer’s & Dementia: Translational Research & Clinical Interventions, E-ISSN 2352-8737, Vol. 7, no 1, article id e12187Article in journal (Refereed)
    Abstract [en]

    Introduction: In this nested case-control study, we investigated if antiviral treatment given prior to onset of Alzheimer's disease (AD) could influence incident AD.

    Methods: From a large population-based cohort study in northern Sweden, 262 individuals that later developed AD were compared to a non-AD matched control group with respect to prescriptions of herpes antiviral treatment. All included subjects were herpes simplex virus 1 (HSV1) carriers and the matching criteria were age, sex, apolipoprotein E genotype (ε4 allele carriership), and study sample start year.

    Results: Among those who developed AD, 6 prescriptions of antivirals were found, compared to 20 among matched controls. Adjusted for length of follow-up, a conditional logistic regression indicated a difference in the risk for AD development between groups (odds ratio for AD with an antiviral prescription 0.287, P = .018).

    Discussion: Antiviral treatment might possibly reduce the risk for later development of HSV1-associated AD.

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  • 2.
    Lopatko Lindman, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Hemmingsson, Eva-Stina
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Weidung, Bodil
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Department of Public Health and Caring Sciences, Geriatric Medicine, Uppsala University, Uppsala, Sweden.
    Brännström, Jon
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Herpesvirus infections, antiviral treatment, and the risk ofdementia: a registry-based cohort study in Sweden2021In: Alzheimer’s & Dementia: Translational Research & Clinical Interventions, E-ISSN 2352-8737, Vol. 7, no 1, article id e12119Article in journal (Refereed)
    Abstract [en]

    Introduction: Herpesviruses, including Herpes simplex virus type 1 (HSV1) and varicella zoster‐virus (VZV), have been implicated in Alzheimer's disease (AD) development. Likewise, antiviral treatment has been suggested to protect against dementia development in herpes‐infected individuals.

    Methods: The study enrolled 265,172 subjects aged ≥ 50 years, with diagnoses of VZV or HSV, or prescribed antiviral drugs between 31 December 2005 and 31 December 2017. Controls were matched in a 1:1 ratio by sex and birth year.

    Results: Antiviral treatment was associated with decreased risk of dementia (adjusted hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.86 to 0.92), while herpes infection without antiviral drugs increased the risk of dementia (adjusted HR 1.50, 95% CI 1.29 to 1.74).

    Discussion: Antiviral treatment was associated with a reduced long‐term risk of dementia among individuals with overt signs of herpes infection. This is consistent with earlier findings indicating that herpesviruses are involved in the pathogenesis of AD.

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  • 3.
    Lopatko Lindman, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Weidung, Bodil
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Department of Public Health and Caring Sciences, Geriatric Medicine, Uppsala University, Uppsala, Sweden.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Kok, Eloise
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    A genetic signature including apolipoprotein Eε4 potentiates the risk of herpes simplex-associated Alzheimer's disease2019In: Alzheimer’s & Dementia: Translational Research & Clinical Interventions, E-ISSN 2352-8737, Vol. 5, p. 697-704Article in journal (Refereed)
    Abstract [en]

    Introduction: Herpes simplex virus type 1 (HSV1) in combination with genetic susceptibility has previously been implicated in Alzheimer's disease (AD) pathogenesis.

    Methods: Plasma from 360 AD cases, obtained on average 9.6 years before diagnosis, and their age- and sex-matched controls, were analyzed for anti-HSV1 immunoglobulin (Ig) G with enzyme-linked immunosorbent assays (ELISAs). APOE genotype and nine other selected risk genes for AD were extracted from a genome-wide association study analysis by deCODE genetics, Reykjavik, Iceland.

    Results: The interaction between APOEε4 heterozygosity (APOEε24 or ε3/ε4) and anti-HSV1 IgG carriage increased the risk of AD (OR 4.55, P = .02). A genetic risk score based on the nine AD risk genes also interacted with anti-HSV1 IgG for the risk of developing AD (OR 2.35, P = .01).

    Discussion: The present findings suggest that the APOEε4 allele and other AD genetic risk factors might potentiate the risk of HSV1-associated AD.

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  • 4.
    Weidung, Bodil
    et al.
    Section of Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Hemmingsson, Eva-Stina
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom; UK Dementia Research Institute at UCL, London, United Kingdom.
    Ingelsson, Martin
    Section of Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; Krembil Brain Institute, University Health Network, Toronto, Canada; Department of Medicine and Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Wallenberg Centre for Molecular Medicin, Umeå, Sweden.
    VALZ-Pilot: High-dose valacyclovir treatment in patients with early-stage Alzheimer's disease2022In: Alzheimer’s & Dementia: Translational Research & Clinical Interventions, E-ISSN 2352-8737, Vol. 8, no 1, article id e12264Article in journal (Refereed)
    Abstract [en]

    Introduction: Herpes simplex virus (HSV) may be involved in Alzheimer's disease (AD) pathophysiology. The antiviral valacyclovir inhibits HSV replication.

    Methods: This phase-II pilot trial involved valacyclovir administration (thrice daily, 500 mg week 1, 1000 mg weeks 2–4) to persons aged ≥ 65 years with early-stage AD, anti-HSV immunoglobulin G, and apolipoprotein E ε4. Intervention safety, tolerability, feasibility, and effects on Mini-Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarkers were evaluated.

    Results: Thirty-two of 33 subjects completed the trial on full dosage. Eighteen percent experienced likely intervention-related mild, temporary adverse events. CSF acyclovir concentrations were mean 5.29 ± 2.31 μmol/L. CSF total tau and neurofilament light concentrations were unchanged; MMSE score and CSF soluble triggering receptor expressed on myeloid cells 2 concentrations increased (P = .02 and .03).

    Discussion: Four weeks of high-dose valacyclovir treatment was safe, tolerable, and feasible in early-stage AD. Our findings may guide future trial design.

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