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Principal Investigator: Brion S Maher
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $928,646
Funding agency: National Institute on Aging
Alzheimer’s disease is a major threat to public health. Because Alzheimer’s disease has no cure, it is critical to
identify its modifiable risk factors that can be targeted to reduce its burden. Although initial evidence suggests
its plausibility, relatively little attention has been paid to the role of common infections in Alzheimer’s disease
etiology. We propose to investigate the association of infection with common pathogens—Herpes Simplex
Virus Types 1 and 2, Cytomegalovirus, Epstein-Barr Virus, Toxoplasma gondii—measured four times over ~25
years, and SARS-CoV-2 (the virus that causes COVID-19), with: (a) cognitive decline, and adjudicated mild
cognitive impairment (MCI) and dementia diagnoses; (b) plasma biomarkers of Alzheimer’s disease; and (c)
markers of physiological aging (telomere shortening, cyclin-dependent kinase inhibitor p16INK4a, plasma-derived
senescence-associated secretory phenotypes, and epigenetic clocks). We will also explore sex, Alzheimer’s
disease risk genes, and stress-related exposures (mental disorders and their symptoms, stressful life events,
and poor sleep) as moderators that amplify the risk of adverse infection-induced cognitive, brain health, and
physiological aging outcomes. Inclusion of viral specific CD8 T-cell differentiation in combination with antibody
levels measured serially in the same individuals will allow us to distinguish between long-term infections and
reactivation and to evaluate the influence of the course of both infection and immune response to infection, on
our outcomes. Senescence-associated secretory phenotypes will point to novel senescent pathways by which
infections affect brain health. We will accomplish this using existing data and collecting new data from
participants in the Baltimore Epidemiological Catchment Area (ECA) Study Follow-up, which has been
assessed five times for >35 years (mean age = 70 years, range 58-100). Blood specimens have been collected
three times over ~25 years in the ECA, and we will collect an additional blood draw to obtain infection status at
four time points, providing a rare opportunity to quantify timing of exposure and reactivation of latent infections
in relation to cognitive and functional decline and Alzheimer’s disease biomarkers and potential pathways. The
MPIs of the proposed study are currently completing Wave 5 of data collection in the ECA, including measures
of cognitive and functional decline, adjudicated MCI and dementia diagnoses, cellular aging and genome-wide
genetic and epigenetics assays. Our preliminary data in the ECA link common pathogens of interest with lower
cognitive performance and suggest effect modification by apolipoprotein E genotype. Our team consists of
experts in cognitive aging and Alzheimer’s disease, neurovirology, neuropsychology, Alzheimer’s disease
biomarkers, genetics and epigenetics, and the biology of aging. Results will clarify the extent to which
common infections increase the risk for Alzheimer’s disease and related dementias, and because this work is
performed in a longitudinal cohort, it will elucidate mechanisms, identify moderators and candidate pathways
which precede decline, thus informing future preventive, and perhaps therapeutic, efforts.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AD dementia><AD pathology><AD prevention><AD related dementia><ADRD><Active Follow-up><Affect><Age><Aging><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer disease prevention><Alzheimer prevention><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's and related dementias><Alzheimer's biomarker><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease biological marker><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease pathology><Alzheimer's disease related dementia><Alzheimer's disease risk><Alzheimer's pathology><Alzheimers Dementia><Alzheimer’s biological marker><Alzheimer’s disease biomarker><Amentia><American><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Antibodies><Anxiety Disorders><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Area><Assay><Attention><Aβ><Baltimore><Bioassay><Biological><Biological Aging><Biological Assay><Biology of Aging><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Sample><Blood specimen><Brain><Brain Nervous System><Burkitt Herpesvirus><Burkitt Lymphoma Virus><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CDK Inhibitor Protein><CDK4I><CDKI Protein><CDKN2><CDKN2 Genes><CDKN2A><CDKN2A gene><CMM2><CMV><COVID-19><COVID-19 infection><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><CV-19><Catchment Area><Causality><Cell Aging><Cell Senescence><Cellular Aging><Cellular Senescence><Chronic><CoV-2><CoV2><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive aging><Cognitive decline><Cognitive function abnormal><Communicable Diseases><Coronavirus Infectious Disease 2019><Cyclin Kinase Inhibitor><Cyclin-Dependent Kinase Inhibitor><Cyclin-Dependent Kinase Inhibitor 2A Gene><Cytomegalovirus><Data><Data Collection><Dementia><Depressive Syndromes><Depressive disorder><Development><Diagnosis><Diagnostic><Disease><Disorder><Disturbance in cognition><EB virus><EBV><Encephalon><Epidemiological data><Epidemiology><Epidemiology data><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epstein Barr Virus><Etiology><Exhibits><Future><Generalized Growth><Genetic><Genetic Risk><Genotype><GrimAge clock><Growth><HCMV><HHV-2><HHV-4><HHV2><HHV4><HSV><HSV-1><HSV-2><HSV1><HSV2><Hannum clock><Health><Health Care Systems><Healthcare Systems><Herpes Simplex Type 1><Herpes Simplex Virus><Herpes Simplex Virus 1><Herpes Simplex Virus 2><Herpes Simplex Virus Type 1><Herpes Simplex Virus Type 2><Herpes labialis Virus><Herpesvirus 1><Herpesvirus 2 (alpha), Human><Herpesvirus progenitalis><Horvath clock><Human><Human (alpha) herpes virus 2><Human Herpesvirus 2><Human Herpesvirus 4><Human herpes simplex virus type 2><INK4><INK4A><Immune response><Immunological response><Impaired cognition><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Infectious Mononucleosis Virus><Inflammation><Interview><Length><Life><Life Style><Lifestyle><Light><Link><Long-term cohort><Longitudinal cohort><Longterm cohort><MT-bound tau><MTS1><MTS1 Genes><Measures><Mental disorders><Mental health disorders><Methylation><Mind><Modern Man><Modification><Nerve Degeneration><Neuron Degeneration><Neuropsychologies><Neuropsychology><Neurovirology><Older Population><Outcome><Participant><Pathway interactions><Performance><Persons><PhenoAge clocks><Photoradiation><Physiologic><Physiological><Plasma><Plasma Serum><Prevalence><Prevention><Preventive><Primary Senile Degenerative Dementia><Psychiatric Disease><Psychiatric Disorder><Public Health><Replicative Senescence><Reporting><Research><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Risk-associated variant><Role><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CO-V2><SARS-COVID-2><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Salivary Gland Viruses><Sampling><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Simplexvirus><Stress><Stressful Event><Structure><Subgroup><Symptoms><T cell differentiation><T cell response><T gondii><T. gondii><T8 Cells><T8 Lymphocytes><TP16><TSG9A><Telomere Shortening><Testing><Therapeutic><Time><Tissue Growth><Toxoplasma gondii><Viral><Virus><Woman><Work><Wrist><Wuhan coronavirus><a beta peptide><abeta><abeta deposition><accelerated aging><accelerated biological age><accelerated biological aging><actigraph><actigraphy><active followup><adjudication><adjudicative process and procedure><age acceleration><ages><alzheimer risk><amyloid beta><amyloid beta deposition><amyloid β deposition><amyloid-b protein><aβ deposition><beta amyloid fibril><biologic><biological process of age><blood-based biomarker><blood-based marker><brain health><causation><cognitive assessment><cognitive dysfunction><cognitive loss><cognitive performance><cognitive testing><cohort><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><cytomegalovirus group><decline in function><decline in functional status><dementia risk><developmental><disease causation><epidemiologic><epidemiologic data><epidemiological><epigenetic age clocks><epigenetic clock><epigenetic molecular clocks><epigenetically><follow up><follow-up><followed up><followup><functional decline><functional status decline><genome scale><genome-wide><genomewide><genomic data><genomic data-set><genomic dataset><hCoV19><herpes simplex i><herpes simplex ii><herpes simplex-1><host response><human alphaherpesvirus 2><hyper-phosphorylated tau><hyperphosphorylated tau><immune system response><immunoresponse><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><interest><latency/reactivation><latent infection><malleable risk><mental illness><methylation clock><microbial><microtubule bound tau><microtubule-bound tau><mild cognitive disorder><mild cognitive impairment><modifiable risk><mouse model><murine model><nCoV2><neural degeneration><neural inflammation><neurodegeneration><neurodegenerative><neurofilament><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal degeneration><neuropsychologic><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><older adult><older adulthood><older groups><older individuals><older person><ontogeny><p14ARF><p16 Genes><p16INK4 Genes><p16INK4A Genes><p16INK4a><pathogen><pathway><poor sleep><primary degenerative dementia><psychiatric illness><psychological disorder><reactivation from latency><risk allele><risk factor for dementia><risk for dementia><risk gene><risk genotype><risk loci><risk locus><risk variant><senescence><senescence associated secretome><senescence associated secretory phenotype><senescent><senile dementia of the Alzheimer type><seropositive><sex><social role><soluble amyloid precursor protein><stressful experience><stressful life event><stressful life experience><stressor><tau><tau Proteins><tau factor><telomere><telomere attrition><traumatic event><τ Proteins>