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  1. Article ; Online: Analysis of the longitudinal stability of human plasma miRNAs and implications for disease biomarkers.

    Sandau, Ursula S / Wiedrick, Jack T / McFarland, Trevor J / Galasko, Douglas R / Fanning, Zoe / Quinn, Joseph F / Saugstad, Julie A

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 2148

    Abstract: There is great interest in developing clinical biomarker assays that can aid in non-invasive diagnosis and/or monitoring of human diseases, such as cancer, cardiovascular disease, and neurological diseases. Yet little is known about the longitudinal ... ...

    Abstract There is great interest in developing clinical biomarker assays that can aid in non-invasive diagnosis and/or monitoring of human diseases, such as cancer, cardiovascular disease, and neurological diseases. Yet little is known about the longitudinal stability of miRNAs in human plasma. Here we assessed the intraindividual longitudinal stability of miRNAs in plasma from healthy human adults, and the impact of common factors (e.g., hemolysis, age) that may confound miRNA data. We collected blood by venipuncture biweekly over a 3-month period from 22 research participants who had fasted overnight, isolated total RNA, then performed miRNA qPCR. Filtering and normalization of the qPCR data revealed amplification of 134 miRNAs, 74 of which had high test-retest reliability and low percentage level drift, meaning they were stable in an individual over the 3-month time period. We also determined that, of nuisance factors, hemolysis and tobacco use have the greatest impact on miRNA levels and variance. These findings support that many miRNAs show intraindividual longitudinal stability in plasma from healthy human adults, including some reported as candidate biomarkers for Alzheimer's disease.
    MeSH term(s) Adult ; Humans ; MicroRNAs/genetics ; Hemolysis ; Reproducibility of Results ; Plasma ; Biomarkers
    Chemical Substances MicroRNAs ; Biomarkers
    Language English
    Publishing date 2024-01-25
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-024-52681-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A Blood Test for Alzheimer's Disease: It's about Time or Not Ready for Prime Time?

    Galasko, Douglas R / Grill, Joshua D / Lingler, Jennifer H / Heidebrink, Judith L

    Journal of Alzheimer's disease : JAD

    2022  Volume 90, Issue 3, Page(s) 963–966

    Abstract: A blood test for Alzheimer's disease is now available for clinical use in persons with cognitive impairment. This is an extraordinary milestone, though the amyloid-based PrecivityAD™ test is not without limitations. Pre and post-test counseling are ... ...

    Abstract A blood test for Alzheimer's disease is now available for clinical use in persons with cognitive impairment. This is an extraordinary milestone, though the amyloid-based PrecivityAD™ test is not without limitations. Pre and post-test counseling are essential. Phosphorylated tau blood tests are likely to follow soon. When used in conjunction with an appropriate clinical evaluation, blood tests provide the opportunity for an early, accurate, and accessible diagnosis of Alzheimer's disease. Standalone use, however, carries a significant risk of misinterpretation and is strongly discouraged. Now is the time to develop appropriate use criteria to guide the use of these promising assays.
    MeSH term(s) Humans ; Alzheimer Disease/diagnosis ; Amyloid beta-Peptides ; Biomarkers ; Cognitive Dysfunction/diagnosis ; Hematologic Tests ; tau Proteins
    Chemical Substances Amyloid beta-Peptides ; Biomarkers ; tau Proteins
    Language English
    Publishing date 2022-02-10
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-215490
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: APOE differentially moderates cerebrospinal fluid and plasma phosphorylated tau181 associations with multi-domain cognition.

    Weigand, Alexandra J / Ortiz, Gema / Walker, Kayla S / Galasko, Douglas R / Bondi, Mark W / Thomas, Kelsey R

    Neurobiology of aging

    2023  Volume 125, Page(s) 1–8

    Abstract: Biofluid markers of phosphorylated tau181 (p-tau181) are increasingly popular for the detection of early Alzheimer's pathologic changes. However, the differential dynamics of cerebrospinal fluid (CSF) and plasma p-tau181 remain under investigation. We ... ...

    Abstract Biofluid markers of phosphorylated tau181 (p-tau181) are increasingly popular for the detection of early Alzheimer's pathologic changes. However, the differential dynamics of cerebrospinal fluid (CSF) and plasma p-tau181 remain under investigation. We studied 727 participants from the Alzheimer's Disease Neuroimaging Initiative with plasma and CSF p-tau181 data, apolipoprotein (APOE) ε4 carrier status, amyloid positron emission tomography (PET) imaging, and neuropsychological data. Higher levels of plasma and CSF p-tau181 were observed among APOE ε4 carriers. CSF and plasma p-tau181 were significantly associated with memory, and this effect was greater in APOE ε4 carriers. However, whereas CSF p-tau181 was not significantly associated with language or attention/executive function among ε4 carriers or non-carriers, APOE ε4 status moderated the association of plasma p-tau181 with both language and attention/executive function. These findings lend support to the notion that p-tau181 biofluid markers are useful in measuring AD pathologic changes but also suggest that CSF and plasma p-tau181 have unique properties and dynamics that should be considered when using these markers in research and clinical practice.
    MeSH term(s) Humans ; Alzheimer Disease/diagnosis ; Amyloid beta-Peptides/cerebrospinal fluid ; Apolipoprotein E4/genetics ; Apolipoprotein E4/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Cognition ; tau Proteins/cerebrospinal fluid
    Chemical Substances Amyloid beta-Peptides ; Apolipoprotein E4 ; Biomarkers ; tau Proteins ; ApoE protein, human
    Language English
    Publishing date 2023-01-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 604505-4
    ISSN 1558-1497 ; 0197-4580
    ISSN (online) 1558-1497
    ISSN 0197-4580
    DOI 10.1016/j.neurobiolaging.2022.10.016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Alzheimer disease: CSF biomarkers for Alzheimer disease - approaching consensus.

    Galasko, Douglas R / Shaw, Leslie M

    Nature reviews. Neurology

    2017  Volume 13, Issue 3, Page(s) 131–132

    MeSH term(s) Alzheimer Disease ; Amyloid beta-Peptides ; Biomarkers ; Consensus ; Dementia ; Humans
    Chemical Substances Amyloid beta-Peptides ; Biomarkers
    Language English
    Publishing date 2017-02-03
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 2491514-2
    ISSN 1759-4766 ; 1759-4758
    ISSN (online) 1759-4766
    ISSN 1759-4758
    DOI 10.1038/nrneurol.2017.11
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  5. Article: Differential Effects of APOE Genotype on MicroRNA Cargo of Cerebrospinal Fluid Extracellular Vesicles in Females With Alzheimer's Disease Compared to Males.

    Sandau, Ursula S / McFarland, Trevor J / Smith, Sierra J / Galasko, Douglas R / Quinn, Joseph F / Saugstad, Julie A

    Frontiers in cell and developmental biology

    2022  Volume 10, Page(s) 864022

    Abstract: Multiple biological factors, including age, sex, and genetics, influence Alzheimer's disease (AD) risk. Of the 6.2 million Americans living with Alzheimer's dementia in 2021, 3.8 million are women and 2.4 million are men. The strongest genetic risk ... ...

    Abstract Multiple biological factors, including age, sex, and genetics, influence Alzheimer's disease (AD) risk. Of the 6.2 million Americans living with Alzheimer's dementia in 2021, 3.8 million are women and 2.4 million are men. The strongest genetic risk factor for sporadic AD is apolipoprotein E-e4 (APOE-e4). Female APOE-e4 carriers develop AD more frequently than age-matched males and have more brain atrophy and memory loss. Consequently, biomarkers that are sensitive to biological risk factors may improve AD diagnostics and may provide insight into underlying mechanistic changes that could drive disease progression. Here, we have assessed the effects of sex and APOE-e4 on the miRNA cargo of cerebrospinal fluid (CSF) extracellular vesicles (EVs) in AD. We used ultrafiltration (UF) combined with size exclusion chromatography (SEC) to enrich CSF EVs (e.g., Flotillin+). CSF EVs were isolated from female and male AD or controls (CTLs) that were either APOE-e3,4 or -e3,3 positive (n = 7/group, 56 total). MiRNA expression levels were quantified using a custom TaqMan™ array that assayed 190 miRNAs previously found in CSF, including 25 miRNAs that we previously validated as candidate AD biomarkers. We identified changes in the EV miRNA cargo that were affected by both AD and sex. In total, four miRNAs (miR-16-5p, -331-3p, -409-3p, and -454-3p) were significantly increased in AD vs. CTL, independent of sex and APOE-e4 status. Pathway analysis of the predicted gene targets of these four miRNAs with identified pathways was highly relevant to neurodegeneration (e.g., senescence and autophagy). There were also three miRNAs (miR-146b-5p, -150-5p, and -342-3p) that were significantly increased in females vs. males, independent of disease state and APOE-e4 status. We then performed a statistical analysis to assess the effect of APOE genotype in AD within each sex and found that APOE-e4 status affects different subsets of CSF EV miRNAs in females vs. males. Together, this study demonstrates the complexity of the biological factors associated with AD risk and the impact on EV miRNAs, which may contribute to AD pathophysiology.
    Language English
    Publishing date 2022-04-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2022.864022
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Limitations of the human iPSC-derived neuron model for early-onset Alzheimer's disease.

    Valdes, Phoebe / Henry, Kenneth W / Fitzgerald, Michael Q / Muralidharan, Koushik / Caldwell, Andrew B / Ramachandran, Srinivasan / Goldstein, Lawrence S B / Mobley, William C / Galasko, Douglas R / Subramaniam, Shankar

    Molecular brain

    2023  Volume 16, Issue 1, Page(s) 75

    Abstract: Non-familial Alzheimer's disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer's disease (EOAD) and constitutes ~ 5-6% of all AD cases (Mendez et al. in Continuum 25:34-51, 2019). While EOAD exhibits the same ... ...

    Abstract Non-familial Alzheimer's disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer's disease (EOAD) and constitutes ~ 5-6% of all AD cases (Mendez et al. in Continuum 25:34-51, 2019). While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline (Sirkis et al. in Mol Psychiatry 27:2674-88, 2022; Caldwell et al. in Mol Brain 15:83, 2022) as observed in the more prevalent late-onset AD (LOAD), EOAD patients tend to have more severe cognitive deficits, including visuospatial, language, and executive dysfunction (Sirkis et al. in Mol Psychiatry 27:2674-88, 2022). Patient-derived induced pluripotent stem cells (iPSCs) have been used to model and study penetrative, familial AD (FAD) mutations in APP, PSEN1, and PSEN2 (Valdes et al. in Research Square 1-30, 2022; Caldwell et al. in Sci Adv 6:1-16, 2020) but have been seldom used for sporadic forms of AD that display more heterogeneous disease mechanisms. In this study, we sought to characterize iPSC-derived neurons from EOAD patients via RNA sequencing. A modest difference in expression profiles between EOAD patients and non-demented control (NDC) subjects resulted in a limited number of differentially expressed genes (DEGs). Based on this analysis, we provide evidence that iPSC-derived neuron model systems, likely due to the loss of EOAD-associated epigenetic signatures arising from iPSC reprogramming, may not be ideal models for studying sporadic AD.
    MeSH term(s) Humans ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Induced Pluripotent Stem Cells/pathology ; Mutation/genetics ; Neurons/pathology
    Language English
    Publishing date 2023-11-03
    Publishing country England
    Document type Journal Article
    ZDB-ID 2436057-0
    ISSN 1756-6606 ; 1756-6606
    ISSN (online) 1756-6606
    ISSN 1756-6606
    DOI 10.1186/s13041-023-01063-5
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  7. Article ; Online: Antioxidants for Alzheimer disease-reply.

    Galasko, Douglas R / Aisen, Paul

    JAMA neurology

    2013  Volume 70, Issue 2, Page(s) 270–271

    MeSH term(s) Alzheimer Disease/drug therapy ; Antioxidants/therapeutic use ; Humans
    Chemical Substances Antioxidants
    Language English
    Publishing date 2013-02-12
    Publishing country United States
    Document type Letter ; Comment
    ZDB-ID 2702023-X
    ISSN 2168-6157 ; 2168-6149
    ISSN (online) 2168-6157
    ISSN 2168-6149
    DOI 10.1001/jamaneurol.2013.935
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  8. Article: Objective subtle cognitive decline and plasma phosphorylated tau181: Early markers of Alzheimer's disease-related declines.

    Thomas, Kelsey R / Bangen, Katherine J / Edmonds, Emily C / Weigand, Alexandra J / Walker, Kayla S / Bondi, Mark W / Galasko, Douglas R

    Alzheimer's & dementia (Amsterdam, Netherlands)

    2021  Volume 13, Issue 1, Page(s) e12238

    Abstract: Introduction: Objectively-defined subtle cognitive decline (Obj-SCD) and plasma phosphorylated-tau181 (p-tau181) are promising early Alzheimer's disease (AD) markers. However, associations between Obj-SCD and p-tau181, and their combined prognostic ... ...

    Abstract Introduction: Objectively-defined subtle cognitive decline (Obj-SCD) and plasma phosphorylated-tau181 (p-tau181) are promising early Alzheimer's disease (AD) markers. However, associations between Obj-SCD and p-tau181, and their combined prognostic potential, are unknown.
    Methods: Baseline and 4-year longitudinal p-tau181 changes were compared across cognitively unimpaired (CU;
    Results: CU and Obj-SCD has lower baseline p-tau181 than MCI and did not differ from one another. Longitudinally, Obj-SCD had the steepest p-tau181 increase. Obj-SCD/p-tau181-positive participants had the fastest rates of amyloid accumulation, cognitive decline, and functional decline.
    Conclusions: Despite assumptions that cognitive changes invariably follow biomarker changes, early neuropsychological difficulties may emerge before/concurrently with plasma p-tau181 changes. Combining Obj-SCD and p-tau181, two potentially accessible early markers, was associated with the faster declines in AD-related outcomes.
    Language English
    Publishing date 2021-10-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2832898-X
    ISSN 2352-8729
    ISSN 2352-8729
    DOI 10.1002/dad2.12238
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  9. Article ; Online: Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer's disease.

    Caldwell, Andrew B / Liu, Qing / Zhang, Can / Schroth, Gary P / Galasko, Douglas R / Rynearson, Kevin D / Tanzi, Rudolph E / Yuan, Shauna H / Wagner, Steven L / Subramaniam, Shankar

    Alzheimer's & dementia : the journal of the Alzheimer's Association

    2022  Volume 18, Issue 11, Page(s) 2117–2130

    Abstract: While amyloid-β (Aβ) plaques are considered a hallmark of Alzheimer's disease, clinical trials focused on targeting gamma secretase, an enzyme involved in aberrant Aβ peptide production, have not led to amelioration of AD symptoms or synaptic ... ...

    Abstract While amyloid-β (Aβ) plaques are considered a hallmark of Alzheimer's disease, clinical trials focused on targeting gamma secretase, an enzyme involved in aberrant Aβ peptide production, have not led to amelioration of AD symptoms or synaptic dysregulation. Screening strategies based on mechanistic, multi-omics approaches that go beyond pathological readouts can aid in the evaluation of therapeutics. Using early-onset Alzheimer's (EOFAD) disease patient lineage PSEN1
    MeSH term(s) Humans ; Alzheimer Disease/drug therapy ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Amyloid beta-Peptides/metabolism ; Plaque, Amyloid/pathology ; Induced Pluripotent Stem Cells/metabolism
    Chemical Substances Amyloid Precursor Protein Secretases (EC 3.4.-) ; Amyloid beta-Protein Precursor ; Amyloid beta-Peptides
    Language English
    Publishing date 2022-01-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2211627-8
    ISSN 1552-5279 ; 1552-5260
    ISSN (online) 1552-5279
    ISSN 1552-5260
    DOI 10.1002/alz.12553
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  10. Article: The neuroinflammatory marker sTNFR2 relates to worse cognition and tau in women across the Alzheimer's disease spectrum.

    Bernier, Rachel A / Banks, Sarah J / Panizzon, Matthew S / Andrews, Murray J / Jacobs, Emily G / Galasko, Douglas R / Shepherd, Alyx L / Akassoglou, Katerina / Sundermann, Erin E

    Alzheimer's & dementia (Amsterdam, Netherlands)

    2022  Volume 14, Issue 1, Page(s) e12284

    Abstract: Introduction: Despite women showing greater Alzheimer's disease (AD) prevalence, tau burden, and immune/neuroinflammatory response, whether neuroinflammation impacts cognition differently in women versus men and the biological basis of this impact ... ...

    Abstract Introduction: Despite women showing greater Alzheimer's disease (AD) prevalence, tau burden, and immune/neuroinflammatory response, whether neuroinflammation impacts cognition differently in women versus men and the biological basis of this impact remain unknown. We examined sex differences in how cerebrospinal fluid (CSF) neuroinflammation relates to cognition across the aging-mild cognitive impairment (MCI)-AD continuum and the mediating role of phosphorylated tau (p-tau) versus other AD biomarkers.
    Methods: Participants included 284 individuals from the Alzheimer's Disease Neuroimaging Initiative study. CSF neuroinflammatory markers included interleukin-6, tumor necrosis factor α, soluble tumor necrosis factor receptor 2 (sTNFR2), and chitinase-3-like protein 1. AD biomarkers were CSF p-tau
    Results: We found a sex-by-sTNFR2 interaction on Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes. Higher levels of sTNFR2 related to poorer cognition in women only. Among biomarkers, only p-tau
    Discussion: Women may be more susceptible than men to the adverse effects of sTNFR2 on cognition with a potential etiological link with tau to these effects.
    Language English
    Publishing date 2022-04-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2832898-X
    ISSN 2352-8729
    ISSN 2352-8729
    DOI 10.1002/dad2.12284
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