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  • 1
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    Online Resource
    A Multimodal Genomic Analysis Framework Identifies Transposable Element (TE) Activation in Alzheimer's Disease
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S3 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S3 ( 2022-12)
    Abstract: Transposable elements (TEs), known colloquially as “jumping genes” or “viral elements”, constitute approximately 45% of the human genome. Recent evidences showed that TEs are activated in AD by age‐associated epigenetic alterations or retroviral infection; yet, mechanisms of AD‐risk TE activation remain elusive. Method We investigated TE activation underlying AD pathobiology and therapeutic discovery using three large RNA‐sequencing datasets from the AD knowledge portal: (1) 284 AD patients and 150 healthy controls from Mount Sinai Brain Bank (MSBB), (2) 161 AD patients and 195 healthy controls from Mayo Clinic (Mayo), and (3) 106 AD patients and 44 healthy controls from Religious Orders Study or the Rush Memory and Aging Project (ROSMAP). We developed a multi‐modal genomic analysis framework that leverages TE differential expression, genome‐wide association study (GWAS), and X‐quantitative trait loci (X‐QTLs). Result We identified 6, 13, and 4 differentially expressed TEs (i.e., L1MC4, HERVK22‐int, and HERV1_LTRa) across MSBB, Mayo, and ROSMAP cohorts, respectively, at the family level. We further identified 442, 857, and 806 differentially expressed TEs (i.e., L1ME2) at locus levels across MSBB, Mayo, and ROSMAP cohorts, including 18, 5, and 2 locus‐based TEs in Mayo cohorts that specifically activated in neurons, microglia, and endothelial cells, respectively. Using integrative analysis of differentially expressed TEs with AD GWAS loci, and X‐QTLs, we identified the likely AD‐risk genes (including CEACAM19, CR1, and TOMM40, and cg04406254) involved in TE activation of AD. Using a drug repurposing approach, we showed that valacyclovir (an approved antiviral drug) was significantly associated with reduced incidence of AD in two large patient databases: (a) Hazard ratio (HR) = 0.55 (p 〈 0.001) in MarketScan with 7.32 individuals; and (b) HR = 0.72 (p 〈 0.001) in Optum with 5.62 million older individuals ( 〉 65 years old). In addition, valacyclovir alters LINE‐1 expression in AD patient‐induced pluripotent stem cells (iPSC)‐derived neurons, supporting mechanistically potential beneficial effect of suppressing TE activation in AD. Conclusion This study characterized the genome regulatory control of AD‐risk TE activation and established the likely causal relationship between TE activation and AD pathobiology. The TE‐targeted therapeutic approaches (i.e., valacyclovir) will require randomized controlled trials.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S3
    DOI: 10.1002/alz.066866
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 2
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    PDE5 inhibitor drugs for use in dementia
    Wiley ; 2023
    In:  Alzheimer's & Dementia: Translational Research & Clinical Interventions Vol. 9, No. 3 ( 2023-07)
    Details
    In: Alzheimer's & Dementia: Translational Research & Clinical Interventions, Wiley, Vol. 9, No. 3 ( 2023-07)
    Abstract: Alzheimer's disease and related dementias (ADRD) remain a major health‐care challenge with few licensed medications. Repurposing existing drugs may afford prevention and treatment. Phosphodiesterase‐5 (PDE5) is widely expressed in vascular myocytes, neurons, and glia. Potent, selective, Food and Drug Administration–approved PDE5 inhibitors are already in clinical use (sildenafil, vardenafil, tadalafil) as vasodilators in erectile dysfunction and pulmonary arterial hypertension. Animal data indicate cognitive benefits of PDE5 inhibitors. In humans, real‐world patient data suggest that sildenafil and vardenafil are associated with reduced dementia risk. While a recent clinical trial of acute tadalafil on cerebral blood flow was neutral, there may be chronic actions of PDE5 inhibition on cerebrovascular or synaptic function. We provide a perspective on the potential utility of PDE5 inhibitors for ADRD. We conclude that further prospective clinical trials with PDE5 inhibitors are warranted. The choice of drug will depend on brain penetration, tolerability in older people, half‐life, and off‐target effects. HIGHLIGHTS Potent phosphodiesterase‐5 (PDE5) inhibitors are in clinical use as vasodilators. In animals PDE5 inhibitors enhance synaptic function and cognitive ability. In humans the PDE5 inhibitor sildenafil is associated with reduced risk of Alzheimer's disease. Licensed PDE5 inhibitors have potential for repurposing in dementia. Prospective clinical trials of PDE5 inhibitors are warranted.
    Type of Medium: Online Resource
    ISSN: 2352-8737 , 2352-8737
    URL: Issue
    URL: Article
    DOI: 10.1002/trc2.v9.3
    DOI: 10.1002/trc2.12412
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2832891-7
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  • 3
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    Metabolic endophenotype associated with right ventricular glucose uptake in pulmonary hypertension
    Wiley ; 2021
    In:  Pulmonary Circulation Vol. 11, No. 4 ( 2021-10), p. 1-12
    Details
    In: Pulmonary Circulation, Wiley, Vol. 11, No. 4 ( 2021-10), p. 1-12
    Abstract: Alterations in metabolism and bioenergetics are hypothesized in the mechanisms leading to pulmonary vascular remodeling and heart failure in pulmonary hypertension (PH). To test this, we performed metabolomic analyses on 30 PH individuals and 12 controls. Furthermore, using 2‐[18F]fluoro‐2‐deoxy‐D‐glucose positron emission tomography, we dichotomized PH patients into metabolic phenotypes of high and low right ventricle (RV) glucose uptake and followed them longitudinally. In support of metabolic alterations in PH and its progression, the high RV glucose group had higher RV systolic pressure (p  〈  0.001), worse RV function as measured by RV fractional area change and peak global longitudinal strain (both p  〈  0.05) and may be associated with poorer outcomes (33% death or transplantation in the high glucose RV uptake group compared to 7% in the low RV glucose uptake group at five years follow‐up, log‐ranked p = 0.07). Pathway enrichment analysis identified key metabolic pathways including fructose catabolism, arginine‐nitric oxide metabolism, tricarboxylic acid cycle, and ketones metabolism. Integrative human protein‐protein interactome network analysis of metabolomic and transcriptomic data identified key pathobiological pathways: arginine biosynthesis, tricarboxylic acid cycle, purine metabolism, hypoxia‐inducible factor 1, and apelin signaling. These findings identify a PH metabolomic endophenotype, and for the first time link this to disease severity and outcomes.
    Type of Medium: Online Resource
    ISSN: 2045-8940 , 2045-8940
    URL: Article
    DOI: 10.1177/20458940211054325
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2638089-4
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  • 4
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    Identifying miRNAs in multiple sclerosis gray matter lesions that correlate with atrophy measures
    Wiley ; 2021
    In:  Annals of Clinical and Translational Neurology Vol. 8, No. 6 ( 2021-06), p. 1279-1291
    Details
    In: Annals of Clinical and Translational Neurology, Wiley, Vol. 8, No. 6 ( 2021-06), p. 1279-1291
    Abstract: Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Though MS was initially considered to be a white matter demyelinating disease, myelin loss in cortical gray matter has been reported in all disease stages. We previously identified microRNAs (miRNAs) in white matter lesions (WMLs) that are detected in serum from MS patients. However, miRNA expression profiles in gray matter lesions (GMLs) from progressive MS brains are understudied. Methods We used a combination of global miRNAs and gene expression profiling of GMLs and independent validation using real‐time quantitative polymerase chain reaction (RT‐qPCR), immuno‐in situ hybridization, and immunohistochemistry. Results Compared to matched myelinated gray matter (GM) regions, we identified 82 miRNAs in GMLs, of which 10 were significantly upregulated and 17 were significantly downregulated. Among these 82 miRNAs, 13 were also detected in serum and importantly were associated with brain atrophy in MS patients. The predicted target mRNAs of these miRNAs belonged to pathways associated with axonal guidance, TGF‐β signaling, and FOXO signaling. Further, using state‐of‐the‐art human protein–protein interactome network analysis, we mapped the four key GM atrophy‐associated miRNAs (hsa‐miR‐149*, hsa‐miR‐20a, hsa‐miR‐29c, and hsa‐miR‐25) to their target mRNAs that were also changed in GMLs. Interpretation Our study identifies miRNAs altered in GMLs in progressive MS brains that correlate with atrophy measures. As these miRNAs were also detected in sera of MS patients, these could act as markers of GML demyelination in MS.
    Type of Medium: Online Resource
    ISSN: 2328-9503 , 2328-9503
    URL: Issue
    URL: Article
    DOI: 10.1002/acn3.v8.6
    DOI: 10.1002/acn3.51365
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2740696-9
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  • 5
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    Pioglitazone reduces the incidence of Alzheimer’s disease: From genetics to population‐based validation
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S3 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S3 ( 2021-12)
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S3
    DOI: 10.1002/alz.051950
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2201940-6
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  • 6
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    Population‐based Discovery and Ethnically Mixed Mendelian Randomization Validation Identifies Telmisartan as a Candidate Drug for Alzheimer’s Disease in African Americans
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S10 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S10 ( 2022-12)
    Abstract: Elevated incidences of Alzheimer’s disease (AD) and disease progression may be associated with African American (AA)‐specific disease comorbidities, such as hypertension, diabetes, and chronic kidney disease. Treatments and management of these comorbidities — such as antihypertensive angiotensin‐II receptor blockers (ARBs) — may reduce risk of AD in AA people, while conferring additional beneficial effects on renal function and diabetes control. Method We conducted a race‐specific pharmacoepidemiologic study to investigate the association between telmisartan (an ARB having PPAR‐gamma (PPARG) agonistic properties and beneficial anti‐diabetic effects) use and AD using Cox analysis, Kaplan‐Meier analysis, and propensity score‐matched log‐rank test. We further conducted ethnically mixed Mendelian randomization analysis to identify likely causal relationships between telmisartan use and AD in AA people. All models were adjusted for age, sex, underlying health, and comorbidities. Result In Cox analyses of ARB users in insurance claim data, telmisartan use was significantly associated with reduced risks of AD in AA people (Hazard ratio [HR] = 0.77, P‐value = 0.002), but was not associated with AD reduction in non‐Hispanic White Americans (HR = 0.97, P‐value = 0.411). Compared to lisinopril (an angiotensin‐converting‐enzyme inhibitor) use, telmisartan use was associated with stronger reduced risk of AD in AA people (HR = 0.68, P‐value 〈 0.001). In all sensitivity and secondary analyses, telmisartan use was associated with stronger protective effects (including AD and dementia) in AA people. Using ethnically mixed Mendelian randomization analysis from large genome‐wide association studies (over 2 million individuals) across AD, hypertension, and diabetes, we demonstrated that telmisartan has greater beneficial effect on AD in AA people compared to European populations. Conclusion We identified that telmisartan is a candidate drug for potential prevention and treatment of AD in AA people, but not in non‐Hispanic White Americans. Our findings indicate that early comorbidity management (hypertension, diabetes, and kidney dysfunction) by telmisartan will significantly reduce AD incidence for aged individuals, in particular for aged AA people. The association between telmisartan use and decreased incidence of AD in AAs will require a randomized controlled trial with an ethnically diverse population to establish causality and explore therapeutic outcomes.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S10
    DOI: 10.1002/alz.066634
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 7
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    Inhibition of histone deacetylases sensitizes EGF receptor‐TK inhibitor‐resistant non‐small‐cell lung cancer cells to erlotinib in vitro and in vivo
    Wiley ; 2017
    In:  British Journal of Pharmacology Vol. 174, No. 20 ( 2017-10), p. 3608-3622
    Details
    In: British Journal of Pharmacology, Wiley, Vol. 174, No. 20 ( 2017-10), p. 3608-3622
    Abstract: Intrinsic and/or acquired resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) commonly occurs in patients with non‐small‐cell lung cancer (NSCLC). Here, we developed a combined therapy of histone deacetylase inhibition by a novel HDAC inhibitor, YF454A, with erlotinib to overcome EGFR‐TKI resistance in NSCLC. Experimental Approach The sensitization of the effects of erlotinib by YF454A was examined in a panel of EGFR‐TKI‐resistant NSCLC cell lines in vitro and two different erlotinib‐resistant NSCLC xenograft mouse models in vivo . Western blotting and Affymetrix GeneChip expression analysis were further performed to determine the underlying mechanisms for the effects of the combination of erlotinib and YF454A. Key Results YF454A and erlotinib showed a strong synergy in the suppression of cell growth by blocking the cell cycle and triggering cell apoptosis in EGFR‐TKI‐resistant NSCLC cells. The combined treatment led to a significant decrease in tumour growth and tumour weight compared with single agents alone. Mechanistically, this combination therapy dramatically down‐regulated the expression of several crucial EGFR‐TKI resistance‐related receptor tyrosine kinases, such as Her2, c‐Met, IGF1R and AXL, at both the transcriptional and protein levels and consequently blocked the activation of downstream molecules Akt and ERK. Transcriptomic profiling analysis further revealed that YF454A and erlotinib synergistically suppressed the cell cycle pathway and decreased the transcription of cell‐cycle related genes, such as MSH6 and MCM7 . Conclusion and Implications Our preclinical study of YF454A provides a rationale for combining erlotinib with a histone deacetylase inhibitor to treat NSCLC with EGFR‐TKI resistance.
    Type of Medium: Online Resource
    ISSN: 0007-1188 , 1476-5381
    URL: Issue
    URL: Article
    DOI: 10.1111/bph.v174.20
    DOI: 10.1111/bph.13961
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2029728-2
    SSG: 15,3
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  • 8
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    Aging‐related cell type‐specific pathophysiologic immune responses that exacerbate disease severity in aged COVID‐19 patients
    Wiley ; 2022
    In:  Aging Cell Vol. 21, No. 2 ( 2022-02)
    Details
    In: Aging Cell, Wiley, Vol. 21, No. 2 ( 2022-02)
    Abstract: Coronavirus disease 2019 (COVID‐19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID‐19 incidence and severity as a function of age. Our analysis leveraged age‐specific COVID‐19 mortality and laboratory testing from a large COVID‐19 registry, along with epidemiological data of ~3.4 million individuals, large‐scale deep immune cell profiling data, and single‐cell RNA‐sequencing data from aged COVID‐19 patients across diverse populations. We found that decreased lymphocyte count and elevated inflammatory markers (C‐reactive protein, D‐dimer, and neutrophil–lymphocyte ratio) are significantly associated with age‐specific COVID‐19 severities. We identified the reduced abundance of naïve CD8 T cells with decreased expression of antiviral defense genes (i.e., IFITM3 and TRIM22 ) in aged severe COVID‐19 patients. Older individuals with severe COVID‐19 displayed type I and II interferon deficiencies, which is correlated with SARS‐CoV‐2 viral load. Elevated expression of SARS‐CoV‐2 entry factors and reduced expression of antiviral defense genes ( LY6E and IFNAR1 ) in the secretory cells are associated with critical COVID‐19 in aged individuals. Mechanistically, we identified strong TGF‐beta‐mediated immune–epithelial cell interactions (i.e., secretory‐non‐resident macrophages) in aged individuals with critical COVID‐19. Taken together, our findings point to immuno‐inflammatory factors that could be targeted therapeutically to reduce morbidity and mortality in aged COVID‐19 patients.
    Type of Medium: Online Resource
    ISSN: 1474-9718 , 1474-9726
    URL: Issue
    URL: Article
    DOI: 10.1111/acel.v21.2
    DOI: 10.1111/acel.13544
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2099130-7
    SSG: 12
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  • 9
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    Altered gene expression in excitatory neurons is associated with Alzheimer's disease and its higher incidence in women
    Wiley ; 2023
    In:  Alzheimer's & Dementia: Translational Research & Clinical Interventions Vol. 9, No. 1 ( 2023-01)
    Details
    In: Alzheimer's & Dementia: Translational Research & Clinical Interventions, Wiley, Vol. 9, No. 1 ( 2023-01)
    Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder involving interactions between different cell types in the brain. Previous single‐cell and bulk expression Alzheimer's studies have reported conflicting findings about the key cell types and cellular pathways whose expression is primarily altered in this disease. We re‐analyzed these data in a uniform, coherent manner aiming to resolve and extend past findings. Our analysis sheds light on the observation that females have higher AD incidence than males. Methods We re‐analyzed three single‐cell transcriptomics datasets. We used the software Model‐based Analysis of Single‐cell Transcriptomics (MAST) to seek differentially expressed genes comparing AD cases to matched controls for both sexes together and each sex separately. We used the GOrilla software to search for enriched pathways among the differentially expressed genes. Motivated by the male/female difference in incidence, we studied genes on the X‐chromosome, focusing on genes in the pseudoautosomal region (PAR) and on genes that are heterogeneous across individuals or tissues for X‐inactivation. We validated findings by analyzing bulk AD datasets from the cortex in the Gene Expression Omnibus. Results Our results resolve a contradiction in the literature, showing that by comparing AD patients to unaffected controls, excitatory neurons have more differentially expressed genes than do other cell types. Synaptic transmission and related pathways are altered in a sex‐specific analysis of excitatory neurons. PAR genes and X‐chromosome heterogeneous genes, including, for example, BEX1 and ELK1 , may contribute to the difference in sex incidence of Alzheimer's disease. GRIN1 , stood out as an overexpressed autosomal gene in cases versus controls in all three single‐cell datasets and as a functional candidate gene contributing to pathways upregulated in cases. Discussion Taken together, these results point to a potential linkage between two longstanding questions concerning AD pathogenesis, involving which cell type is the most important and why females have a higher incidence than males. Highlights By reanalyzing three, published, single‐cell RNAseq datasets, we resolved a contradiction in the literature and showed that when comparing AD patients to unaffected controls, excitatory neurons have more differentially expressed genes than do other cell types. Further analysis of the published single‐cell datasets showed that synaptic transmission and related pathways are altered in a sex‐specific analysis of excitatory neurons. Combining analysis of single‐cell datasets and publicly available bulk transcriptomics datasets revealed that X‐chromosome genes, such as BEX1 , ELK1 , and USP11 , whose X‐inactivation status is heterogeneous may contribute to the higher incidence in females of Alzheimer's disease.
    Type of Medium: Online Resource
    ISSN: 2352-8737 , 2352-8737
    URL: Issue
    URL: Article
    DOI: 10.1002/trc2.v9.1
    DOI: 10.1002/trc2.12373
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2832891-7
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  • 10
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    Population‐based discovery and Mendelian randomization analysis identify telmisartan as a candidate medicine for Alzheimer's disease in African Americans
    Wiley ; 2023
    In:  Alzheimer's & Dementia Vol. 19, No. 5 ( 2023-05), p. 1876-1887
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 19, No. 5 ( 2023-05), p. 1876-1887
    Abstract: African Americans (AAs) and European Americans (EAs) differ in Alzheimer's disease (AD) prevalence, risk factors, and symptomatic presentation and AAs are less likely to enroll in AD clinical trials. Methods We conducted race‐conscious pharmacoepidemiologic studies of 5.62 million older individuals (age ≥60) to investigate the association of telmisartan exposure and AD outcome using Cox analysis, Kaplan–Meier analysis, and log‐rank test. We performed Mendelian randomization (MR) analysis of large ethnically diverse genetic data to test likely causal relationships between telmisartan's target and AD. Results We identified that moderate/high telmisartan exposure was significantly associated with a reduced incidence of AD in the AAs compared to low/no telmisartan exposure (hazard ratio [HR] = 0.77, 95% CI: 0.65–0.91, p ‐value = 0.0022), but not in the non‐Hispanic EAs (HR = 0.97, 95% CI: 0.89–1.05, p ‐value = 0.4110). Sensitivity and sex‐/age‐stratified patient subgroup analyses identified that telmisartan's medication possession ratio (MPR) and average hypertension daily dosage were significantly associated with a stronger reduction in the incidence of both AD and dementia in AAs. Using MR analysis from large genome‐wide association studies (GWAS) (over 2 million individuals) across AD, hypertension, and diabetes, we further identified AA‐specific beneficial effects of telmisartan for AD. Discussion Randomized controlled trials with ethnically diverse patient cohorts are warranted to establish causality and therapeutic outcomes of telmisartan and AD. Highlights Telmisartan is associated with lower risk of Alzheimer's disease (AD) in African Americans (AAs). Telmisartan is the only angiotensin II receptor blockers having PPAR‐γ agonistic properties with beneficial anti‐diabetic and renal function effects, which mitigate AD risk in AAs. Mendelian randomization (MR) analysis demonstrates the specificity of telmisartan's protective mechanism to AAs.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v19.5
    DOI: 10.1002/alz.12819
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2201940-6
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