Alzheimer's Research & Therapy最新文献

{"title":"Herpes zoster and long-term risk of subjective cognitive decline.","authors":"Tian-Shin Yeh, Gary C Curhan, Barbara P Yawn, Walter C Willett, Sharon G Curhan","doi":"10.1186/s13195-024-01511-x","DOIUrl":"10.1186/s13195-024-01511-x","url":null,"abstract":"<p><strong>Background: </strong>Herpes zoster (HZ), commonly known as \"shingles,\" may contribute to cognitive decline through mechanisms such as neuroinflammation or direct neuronal injury. However, evidence on the longitudinal association between HZ and cognitive decline is conflicting and whether the risk differs by APOE ε4-carrier status has not been studied; prospective cohort studies on the association between HZ vaccination and cognitive decline are also lacking.</p><p><strong>Methods: </strong>We included 149,327 participants from three large cohorts-the Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS)-to prospectively examine the association between HZ and subsequent subjective cognitive decline (SCD). Poisson regression was used to estimate the multivariable-adjusted relative risk (MVRR) of a 3-unit increment in SCD score according to years since HZ compared with participants with no history of HZ.</p><p><strong>Results: </strong>Compared with individuals with no history of HZ, the MVRR (95% CI) of a 3-unit increment in SCD score was significantly and independently higher among individuals with a history of HZ, but the duration of time since HZ when the elevated risk of SCD was statistically significant differed among the cohorts. In NHS, HZ was associated with higher long-term risk of SCD; compared with individuals with no history of HZ, the MVRR (95% CI) of a 3-unit increment in SCD score was 1.14 (1.01, 1.32) for ≥ 13 years since HZ. In NHS II, HZ was associated with higher risk of SCD in both the short-term [MVRR 1.34 (1.18, 1.53) for 1-4 years] and long-term [MVRR 1.20 (1.08, 1.34) for ≥ 13 years since HZ]. In HPFS, an elevated risk of SCD was suggested across all time points. Among the subset of participants with information on APOE ε4, there was a suggestion that the association differed by APOE ε4 carrier status, but the results were not consistent between women and men. Among the subset of women with information on HZ vaccination, there was a suggestion that the long-term risk of SCD may be greater among women who were not vaccinated against HZ.</p><p><strong>Conclusions: </strong>Data from three large independent cohorts of women and men showed that HZ was associated with higher long-term risk of SCD, and the risk may differ by APOE ε4-carrier status.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"180"},"PeriodicalIF":7.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma lipidomics in early APP/PS1 female mouse model and its relationship with brain: Is it affected by the estrous cycle?","authors":"Laura Ferré-González, Ángel Balaguer, Marta Roca, Artemis Ftara, Ana Lloret, Consuelo Cháfer-Pericás","doi":"10.1186/s13195-024-01549-x","DOIUrl":"10.1186/s13195-024-01549-x","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the most prevalent dementia, showing higher incidence in women. Besides, lipids play an essential role in brain, and they could be dysregulated in neurodegeneration. Specifically, impaired plasma lipid levels could predict early AD diagnosis. This work aims to identify the main plasma lipids altered in early AD female mouse model and evaluate their relationship with brain lipidome. Also, the possible involvement of the estrous cycle in lipid metabolism has been evaluated.</p><p><strong>Methods: </strong>Plasma samples of wild-type (n = 10) and APP/PS1 (n = 10) female mice of 5 months of age were collected, processed, and analysed using a lipidomic mass spectrometry-based method. A statistical analysis involving univariate and multivariate approaches was performed to identify significant lipid differences related to AD between groups. Also, cytology tests were conducted to confirm estrous cycle phases.</p><p><strong>Results: </strong>Three hundred thirty lipids were detected in plasma, 18 of them showed significant differences between groups; specifically, some triacylglycerols, cholesteryl esters, lysophosphatidylcholines, phosphatidylcholines, and ether-linked phosphatidylcholines, increased in early AD; while other phosphatidylcholines, phosphatidylethanolamines, ceramides, and ether-linked phosphatidylethanolamines decreased in early AD. A multivariate approach was developed from some lipid variables, showing high diagnostic indexes (70% sensitivity, 90% specificity, 80% accuracy). From brain and plasma lipidome, some significant correlations were observed, mainly in the glycerophospholipid family. Also, some differences were found in both plasma and brain lipids, according to the estrous cycle phase.</p><p><strong>Conclusions: </strong>Therefore, lipid alterations can be identified in plasma at early AD stages in mice females, with a relationship with brain lipid metabolism for most of the lipid subfamilies, suggesting some lipids as potential AD biomarkers. In addition, the estrous cycle monitoring could be relevant in female studies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"183"},"PeriodicalIF":7.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"¹⁸F-FDG PET can effectively rule out conversion to dementia and the presence of CSF biomarker of neurodegeneration: a real-world data analysis.","authors":"Sébastien Heyer, Maïa Simon, Matthieu Doyen, Ali Mortada, Véronique Roch, Elodie Jeanbert, Nathalie Thilly, Catherine Malaplate, Anna Kearney-Schwartz, Thérèse Jonveaux, Aurélie Bannay, Antoine Verger","doi":"10.1186/s13195-024-01535-3","DOIUrl":"10.1186/s13195-024-01535-3","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Precisely defining the delay in onset of dementia is a particular challenge for early diagnosis. Brain [&lt;sup&gt;18&lt;/sup&gt;F] fluoro-2-deoxy-2-D-glucose (&lt;sup&gt;18&lt;/sup&gt;F-FDG) Positron Emission Tomography (PET) is a particularly interesting tool for the early diagnosis of neurodegenerative diseases, through the measurement of the cerebral glucose metabolic rate. There is currently a lack of longitudinal studies under real-life conditions, with sufficient patients, to accurately evaluate the predictive values of brain &lt;sup&gt;18&lt;/sup&gt;F-FDG PET scans. Here, we aimed to estimate the value of brain &lt;sup&gt;18&lt;/sup&gt;F-FDG PET for predicting the risk of dementia conversion and the risk of occurrence of a neurodegenerative pathology.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Longitudinal data for a cohort of patients with no diagnosis of dementia at the time of recruitment referred by a tertiary memory clinic for brain &lt;sup&gt;18&lt;/sup&gt;F-FDG PET were matched with (Prince M, Wimo A, Guerchet Maëlenn, Ali G-C, Wu Y-T et al. World Alzheimer Report 2015. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. [Research Report] Alzheimer's Disease International. 2015. 2015.) data from the French National Health Data System (NHDS), (Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-62.) data from the National Alzheimer Bank (NAB), and (Davis M, O`Connell T, Johnson S, Cline S, Merikle E, Martenyi F, et al. Estimating Alzheimer's Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia. CAR. 2018;15(8):777-88.) lumbar puncture (LP) biomarker data. The criteria for dementia conversion were the designation, within the three years after the brain &lt;sup&gt;18&lt;/sup&gt;F-FDG PET scan, of a long-term condition for dementia in the NHDS and a dementia stage of cognitive impairment in the NAB. The criterion for the identification of a neurodegenerative disease in the medical records was the determination of LP biomarker levels.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Among the 403 patients (69.9 ± 11.4 years old, 177 women) from the initial cohort with data matched with the NHDS data, 137 were matched with the NAB data, and 61 were matched with LP biomarker data. Within three years of the scan, a &lt;sup&gt;18&lt;/sup&gt;F-FDG PET had negative predictive values of 85% for dementia conversion (according to the NHDS and NAB datasets) and 95% for the presence of LP neurodegeneration biomarkers.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;A normal brain &lt;sup&gt;18&lt;/sup&gt;F-FDG PET scan can help rule out the risk of dementia conversion and the presence of cerebrospinal fluid (CSF) biomarker of neurodegeneration early with high certainty, allowing modifications to patient management regimens in the short term.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Trial registration: &lt;/strong&gt;Clinical Trials database (NCT04804722). March ","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"182"},"PeriodicalIF":7.9,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11320856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein intake and episodic memory: the moderating role of the apolipoprotein E ε4 status","authors":"Musung Keum, Boung Chul Lee, Young Min Choe, Guk-Hee Suh, Shin Gyeom Kim, Hyun Soo Kim, Jaeuk Hwang, Dahyun Yi, Jee Wook Kim","doi":"10.1186/s13195-024-01546-0","DOIUrl":"https://doi.org/10.1186/s13195-024-01546-0","url":null,"abstract":"This study investigated the correlation between protein intake and Alzheimer’s disease (AD)-related cognitive decline, particularly in episodic memory, among older adults without dementia. Furthermore, we assessed the moderating effect of apolipoprotein ε4 (APOE4) on this association and analyzed its influence on other cognitive functions beyond memory. The study involved 196 participants who underwent assessments for protein intake, cognitive performance, APOE4 genotyping, and nutritional biomarkers. Protein intake was categorized into low, medium, and high based on the consumption of dairy, legumes, eggs, meat, and fish. High protein intake was significantly associated with better episodic memory and overall cognition. Moreover, a significant interaction was found between high protein intake and APOE4, indicating that APOE4 moderates the association between high protein intake level and episodic memory. Sensitivity analysis confirmed these results among participants with stable food intake. Our study results demonstrated that high protein intake is associated with better episodic memory among older adults without dementia. Furthermore, the findings highlight the significant role of APOE4 status in moderating the relationship between protein consumption and episodic memory. These results suggest that dietary interventions focusing on protein intake could be beneficial for cognitive health, particularly in individuals with a genetic predisposition to AD.","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"125 1","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141942644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interrelationships of CSF sTREM2, AD pathology, minimal depressive symptoms, and cognition in non-demented adults.","authors":"Xue Liu, Guang-Xiang Yu, Mei Xue, Liang-Yu Huang, Yan Fu, Zuo-Teng Wang, Lan Tan, Ya-Nan Ou","doi":"10.1186/s13195-024-01550-4","DOIUrl":"10.1186/s13195-024-01550-4","url":null,"abstract":"<p><strong>Background: </strong>Microglial activation has been suggested to be involved in the pathogenesis of depression and Alzheimer's disease (AD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is a marker of microglial activation. The purpose of this study was to investigate the interrelationships of cerebrospinal fluid (CSF) sTREM2, AD pathology, as well as minimal depressive symptoms (MDSs), and cognition.</p><p><strong>Methods: </strong>A total of 545 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative cohort were included in our study. The average age of the total population was 72.6 years and the percentage of females was 42.6%. Linear regression models were conducted to investigate the linear relationships of MDSs with CSF sTREM2, AD pathology, cognition, and brain structure. Mediation models and structural equation models (SEM) were conducted to examine whether CSF sTREM2 mediated the relationships of MDSs with AD pathology and cognition.</p><p><strong>Results: </strong>Results revealed that individuals with MDSs had lower CSF sTREM2 levels than normal controls. Linear regression showed that MDSs were linearly associated with CSF sTREM2 (P_FDR = 0.012) and amyloid biomarkers (P_FDR < 0.05), as well as cognitive scores (P_FDR < 0.05) and hippocampal volume (P_FDR = 0.003). Mediation analyses revealed that CSF sTREM2 mediated the association between MDSs and amyloid pathology, with the mediating proportions ranging from 6.030 to 18.894%. However, SEM failed to reveal that MDS affected cognition through CSF amyloid pathology and CSF sTREM2.</p><p><strong>Conclusions: </strong>MDSs are associated with amyloid pathology and cognition. CSF sTREM2 may potentially be an intervenable target between depression and AD pathology.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"179"},"PeriodicalIF":7.9,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11316296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141911298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Cholinesterase inhibitors and memantine are associated with a reduced mortality in nursing home residents with dementia: a longitudinal observational study.","authors":"Charlotte Havreng-Théry, Bruno Oquendo, Victoria Zolnowski-Kolp, Pierre Krolak-Salmon, François Bertin-Hugault, Carmelo Lafuente-Lafuente, Joël Belmin","doi":"10.1186/s13195-024-01548-y","DOIUrl":"10.1186/s13195-024-01548-y","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"178"},"PeriodicalIF":7.9,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between treatment with sacubitril/valsartan and the risk of Alzheimer’s disease: a clinical update","authors":"Antoine Garnier-Crussard","doi":"10.1186/s13195-024-01547-z","DOIUrl":"https://doi.org/10.1186/s13195-024-01547-z","url":null,"abstract":"Since 2014, sacubitril/valsartan (Entresto®) is widely prescribed for heart failure. Despite neprilysin inhibition’s benefits in heart failure, concerns about potential amyloid-beta (Aβ) accumulation and Alzheimer’s disease (AD) risk have persisted. This narrative review, a decade post-approval, evaluates the risk of amyloid pathology and neurocognitive disorders in long-term sacubitril/valsartan use. Clinical trials, real-world studies, and pharmacovigilance data do not indicate an increased risk of cognitive decline. In patients treated with sacubitril/valsartan blood-based amyloid biomarkers show perturbations, while neuroimaging biomarkers reveal no significant increase in amyloid load. Despite a theoretical risk of amyloid accumulation and AD under treatment with sacubitril/valsartan, current clinical data appears reassuring, and there is no signal indicating an increased risk of cognitive decline, but a perturbation of amyloid blood-based biomarkers, which implies great caution when interpreting biomarkers in this context.","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"74 1","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding machine learning applications in dementia research and clinical practice: a review for biomedical scientists and clinicians.","authors":"Yihan Wang, Shu Liu, Alanna G Spiteri, Andrew Liem Hieu Huynh, Chenyin Chu, Colin L Masters, Benjamin Goudey, Yijun Pan, Liang Jin","doi":"10.1186/s13195-024-01540-6","DOIUrl":"10.1186/s13195-024-01540-6","url":null,"abstract":"<p><p>Several (inter)national longitudinal dementia observational datasets encompassing demographic information, neuroimaging, biomarkers, neuropsychological evaluations, and muti-omics data, have ushered in a new era of potential for integrating machine learning (ML) into dementia research and clinical practice. ML, with its proficiency in handling multi-modal and high-dimensional data, has emerged as an innovative technique to facilitate early diagnosis, differential diagnosis, and to predict onset and progression of mild cognitive impairment and dementia. In this review, we evaluate current and potential applications of ML, including its history in dementia research, how it compares to traditional statistics, the types of datasets it uses and the general workflow. Moreover, we identify the technical barriers and challenges of ML implementations in clinical practice. Overall, this review provides a comprehensive understanding of ML with non-technical explanations for broader accessibility to biomedical scientists and clinicians.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"175"},"PeriodicalIF":7.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Digital remote assessment of speech acoustics in cognitively unimpaired adults: feasibility, reliability and associations with amyloid pathology","authors":"Rosanne L. van den Berg, Casper de Boer, Marissa D. Zwan, Roos J. Jutten, Mariska van Liere, Marie-Christine A.B.J. van de Glind, Mark A. Dubbelman, Lisa Marie Schlüter, Argonde C. van Harten, Charlotte E. Teunissen, Elsmarieke van de Giessen, Frederik Barkhof, Lyduine E. Collij, Jessica Robin, William Simpson, John E Harrison, Wiesje M. van der Flier, Sietske A.M. Sikkes","doi":"10.1186/s13195-024-01543-3","DOIUrl":"https://doi.org/10.1186/s13195-024-01543-3","url":null,"abstract":"Digital speech assessment has potential relevance in the earliest, preclinical stages of Alzheimer’s disease (AD). We evaluated the feasibility, test-retest reliability, and association with AD-related amyloid-beta (Aβ) pathology of speech acoustics measured over multiple assessments in a remote setting. Fifty cognitively unimpaired adults (Age 68 ± 6.2 years, 58% female, 46% Aβ-positive) completed remote, tablet-based speech assessments (i.e., picture description, journal-prompt storytelling, verbal fluency tasks) for five days. The testing paradigm was repeated after 2–3 weeks. Acoustic speech features were automatically extracted from the voice recordings, and mean scores were calculated over the 5-day period. We assessed feasibility by adherence rates and usability ratings on the System Usability Scale (SUS) questionnaire. Test-retest reliability was examined with intraclass correlation coefficients (ICCs). We investigated the associations between acoustic features and Aβ-pathology, using linear regression models, adjusted for age, sex and education. The speech assessment was feasible, indicated by 91.6% adherence and usability scores of 86.0 ± 9.9. High reliability (ICC ≥ 0.75) was found across averaged speech samples. Aβ-positive individuals displayed a higher pause-to-word ratio in picture description (B = -0.05, p = 0.040) and journal-prompt storytelling (B = -0.07, p = 0.032) than Aβ-negative individuals, although this effect lost significance after correction for multiple testing. Our findings support the feasibility and reliability of multi-day remote assessment of speech acoustics in cognitively unimpaired individuals with and without Aβ-pathology, which lays the foundation for the use of speech biomarkers in the context of early AD.","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"48 1","pages":""},"PeriodicalIF":9.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141863789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing regional brain uptake of incretin receptor agonists after intranasal delivery in CD-1 mice and the APP/PS1 mouse model of Alzheimer's disease.","authors":"Noor Abdulhameed, Alice Babin, Kim Hansen, Riley Weaver, William A Banks, Konrad Talbot, Elizabeth M Rhea","doi":"10.1186/s13195-024-01537-1","DOIUrl":"10.1186/s13195-024-01537-1","url":null,"abstract":"<p><p>Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer's disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"173"},"PeriodicalIF":7.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}