Alzheimer's Research & Therapy最新文献

{"title":"CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer's disease patients.","authors":"Marlies Oosthoek, Everard G B Vijverberg, Elena R Blujdea, Sjors G J G In't Veld, Martín Pucheu Avilés, Sára E Zsadanyi, Yanaika S Hok-A-Hin, Allerdien Visser, Wiesje M van der Flier, Frederik Barkhof, Marta Del Campo, Martijn C Schut, Alexandre Bejanin, Daniel Alcolea, Charlotte E Teunissen, Lisa Vermunt","doi":"10.1186/s13195-025-01799-3","DOIUrl":"https://doi.org/10.1186/s13195-025-01799-3","url":null,"abstract":"<p><strong>Background: </strong>Amyloid-related imaging abnormalities (ARIA) are a common and potentially dangerous side effect in anti-amyloid therapies, creating a need for tools to assess ARIA risk. Several patient factors have been linked to ARIA; namely the presence of microbleeds (MBL⁺), APOE E4 carriership (APOE4⁺), and extremely low CSF Aβ42 concentrations (A^L). We hypothesize that studying the CSF proteome of Alzheimer's disease (AD) dementia patients from a high-risk group (MBL⁺APOE4⁺A^L) can inform on the biological underpinnings of ARIA risk and aid the progress of ARIA risk biomarkers.</p><p><strong>Methods: </strong>We utilized CSF proteomic data of AD (n = 156) and cognitively unimpaired individuals (CU n = 100) of the Amsterdam Dementia Cohort. The proteome of the defined high-risk (n = 13) was compared to low-risk AD group (n = 23), using age and sex corrected linear regressions followed by gene ontology analysis. For biomarker prioritization, we selected proteins that were abnormal in the high-risk group versus low-risk and CU patients. The biomarkers were validated in an independent cohort (high risk n = 14, low risk n = 9) analyzed using customized multiplex panels. Lastly, we assessed biomarker lead co-expression.</p><p><strong>Results: </strong>Ninety-four proteins differentiated in the high-risk group compared to low-risk (p < 0.05), none surviving FDR correction. These proteins were enriched for synapse-related proteins and axonogenesis. CHIT1 (vs. low-risk AD: FC = 1.0, p = 0.014, vs. CU: FC = 2.4, p < 0.001) and DDAH1 (vs. low-risk AD: FC=-0.31, p = 0.046, vs. CU: FC = 0.5, p < 0.001) were prioritized as biomarker. DDAH1 protein changes replicated in an independent cohort (FC=-0.37, p = 0.010), and CHIT1 replicated on a trend level (FC = 0.70, p = 0.104). DDAH1 levels had the highest co-expression with synaptic process, energy utilization and RNA-binding cell signaling related proteins (R > 0.8).</p><p><strong>Conclusions: </strong>The findings suggest that in the high risk group, there is a lack of upregulation in synapse and axonogenesis related proteins. High CSF CHIT1 and less increased CSF DDAH1 levels within AD relate to ARIA risk. From the literature, the link to ARIA risk for CHIT1 could be its contribution to innate immunity or vascular amyloid deposition, and for DDAH1 to blood-brain barrier integrity. Biomarker assays are available to assess the potential of CHIT1 and DDAH1 in trials and treatment studies in the clinical setting.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"169"},"PeriodicalIF":7.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688637","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":"Inhibition of FAM19A5 reverses synaptic loss and cognitive decline in mouse models of Alzheimer's disease.","authors":"Han-Byul Kim, Sangjin Yoo, Hoyun Kwak, Shi-Xun Ma, Ryunhee Kim, Minhyeok Lee, Nui Ha, Soonil Pyo, Soon-Gu Kwon, Eun-Ho Cho, Sang-Myeong Lee, Juwon Jang, Won Kyum Kim, Hae-Chul Park, Minkyung Baek, Yosub Park, Ji-Young Park, Jin-Woo Park, Sun Wook Hwang, Jong-Ik Hwang, Jae Young Seong","doi":"10.1186/s13195-025-01813-8","DOIUrl":"10.1186/s13195-025-01813-8","url":null,"abstract":"<p><strong>Background: </strong>FAM19A5 is a secretory protein primarily expressed in neurons. Although its role in synaptic function has been suggested, the precise molecular mechanisms underlying its effects at the synapse remain unclear. Given that synaptic loss is a critical hallmark of Alzheimer's disease (AD), elucidating the mechanisms involving FAM19A5 could provide valuable insights into reversing synaptic loss in AD.</p><p><strong>Methods: </strong>The binding partner of FAM19A5 was identified through co-immunoprecipitation experiments of mouse brain tissue. The effect of FAM19A5 on spine density in hippocampal neurons was evaluated using immunocytochemistry by overexpressing FAM19A5, treating neurons with FAM19A5 protein, and/or an anti-FAM19A5 antibody NS101. Target engagement of NS101 was determined by measuring FAM19A5 levels in mouse, rat, and human plasma at specific time points post NS101 injection using ELISA. Changes in spine density and dynamics in P301S tauopathy mice were assessed via Golgi staining and two-photon microscopy after NS101 administration. The synaptic strengthening of hippocampal neurons in APP/PS1 amyloidopathy mice after NS101 treatment was assessed by measuring miniature excitatory postsynaptic currents (mEPSCs) and field excitatory postsynaptic potentials (fEPSPs). Cognitive performance in AD mice after NS101 treatment was measured using the Y-maze and Morris water maze tests.</p><p><strong>Results: </strong>FAM19A5 binds to LRRC4B, a postsynaptic adhesion molecule, leading to reductions in spine density in mouse hippocampal neurons. Inhibiting FAM19A5 function with NS101 increased spine density. Intravenous administration of NS101 increased spine density in the prefrontal cortex of P301S mice, which initially showed reduced spine density compared to wild-type (WT) mice. NS101 normalized the spine elimination rate in P301S mice, restoring the net spine count to levels comparable to WT mice. NS101 treatment enhanced the frequency of mEPSCs and fEPSPs in the hippocampal synapses of APP/PS1 mice, leading to improved cognitive function. The increases in plasma FAM19A5 levels upon systemic NS101 administration suggest that the antibody effectively engages its target and facilitates the transport of FAM19A5 from the brain.</p><p><strong>Conclusions: </strong>This study demonstrated that inhibiting FAM19A5 function with an anti-FAM19A5 antibody restores synaptic integrity and enhances cognitive function in AD, suggesting a novel therapeutic strategy for AD.</p><p><strong>Trial registration: </strong>https://clinicaltrials.gov/study/NCT05143463 , Identifier: NCT05143463, Release date: 3 December 2021.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"168"},"PeriodicalIF":7.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681805","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":"A normative calculator for MoCA domain scores: proxy for Z-scores of conventional neuropsychological tests.","authors":"Tau Ming Liew","doi":"10.1186/s13195-025-01810-x","DOIUrl":"https://doi.org/10.1186/s13195-025-01810-x","url":null,"abstract":"<p><strong>Background: </strong>Test items in MoCA (Montreal Cognitive Assessment) can be used to generate 5 domain scores (i.e. Memory, Language, Attention, Executive and Visuospatial) which have been shown to approximate well-established neuropsychological tests. As neuropsychological tests are known to be affected by age, sex, education, and language of administration, this study derived a regression-based Z-score calculator for MoCA Domain Scores (MDS) that adjusts individual performance for these key confounders; with the intention of improving the clinical utility of MDS as a proxy for conventional neuropsychological tests.</p><p><strong>Methods: </strong>Participants ≥ 50 years were recruited from Alzheimer's Disease Centers across USA (n = 25,330), and completed MoCA and conventional neuropsychological tests. A subset with normal cognition and global Clinical Dementia Rating of 0 (n = 11,371) was used to derive the Z-score calculator for MDS; while the full sample (n = 25,330) verified the performance of MDS Z-scores in detecting domain-specific impairments (as defined by conventional neuropsychological tests), using areas under the receiver operating characteristic curve (AUC).</p><p><strong>Results: </strong>MDS varied significantly by age, sex, education, and language of administration even among participants with normal cognition. Based on age-, sex-, education-, and language-adjusted Z-scores, the respective AUCs were 91.2% for MoCA-Memory (95%CI 90.7-91.6), 83.6% for MoCA-Language (95%CI 83.0-84.3), 88.7% for MoCA-Attention (95%CI 88.0-89.4), 85.5% for MoCA-Executive (95%CI 84.8-86.1), and 81.0% for MoCA-Visuospatial (95%CI 80.2-81.8). At the commonly-used cut-off of Z-scores ≤ -1.50, all the MDS had specificities of ≥ 80%.</p><p><strong>Conclusions: </strong>MDS Z-scores can be easily computed using the newly-developed Excel-based calculator, and provide a viable alternative when conventional neuropsychological tests are needed but cannot be feasibly administered, such as in non-specialty clinics with large volume of patients at high-risk of cognitive impairment (e.g. primary-care, geriatric, and stroke-prevention clinics), and, with further validation and calibration, plausibly also in other resource-limited healthcare settings (e.g. in lower- and middle-income countries). They can complement neuropsychological tests as part of the systematic evaluation of cognitive impairment, and help reserve neuropsychological tests for patients most likely to benefit from further evaluation.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"167"},"PeriodicalIF":7.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688636","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":"Periodontitis-induced neuroinflammation triggers IFITM3-Aβ axis to cause alzheimer's disease-like pathology and cognitive decline.","authors":"Lingwenyao Kong, Juanjuan Li, Lu Gao, Yonggang Zhao, Weixian Chen, Xumeng Wang, Songlin Wang, Fu Wang","doi":"10.1186/s13195-025-01818-3","DOIUrl":"10.1186/s13195-025-01818-3","url":null,"abstract":"<p><strong>Background: </strong>Periodontitis is a risk factor linked to Alzheimer's disease (AD), and characterized by amyloid-beta (Aβ) pathology. Mounting evidence suggests a contributory role of periodontitis in the onset and progression of AD. Type I interferons are upregulated in Porphyromonas gingivalis (Pg)-induced periodontitis in murine models. Colonization of Pg has been identified in the brains of patients with AD. Recently, interferon-induced transmembrane protein 3 (IFITM3), an inflammation-induced innate immunity protein, was identified as a novel γ-secretase modulatory protein for Aβ production in AD. However, whether periodontitis triggers an increase in type I interferons in the brain, subsequently inducing AD-like pathology by eliciting the innate immune response of glial cells and activating the IFITM3-Aβ axis, remains unclear. Additionally, the question of whether colonization of Pg in brain induces innate immune in astrocytes and microglia remains unanswered.</p><p><strong>Methods: </strong>We assessed the impact of Pg-induced periodontitis on cognitive impairment in C57BL/6J and APP/PS1 mice using behavioral tests. The effects of Periodontitis/Pg on microglia and astrocytes were measured using quantitative reverse transcriptase PCR (qRT-PCR), western blotting, and histological staining.</p><p><strong>Results: </strong>Pg-induced periodontitis led to cognitive impairment in C57BL/6J mice and exacerbated a cognitive decline in APP/PS1 mice. Furthermore, Pg-induced periodontitis elevated the levels of interferon (IFN)-β, IFITM3, and Aβ deposition in the brains of both C57BL/6J and APP/PS1 mice. We also identified Pg DNA, glial activation, and the expression of inflammatory mediators in the brain of a Pg-induced periodontitis model. Additionally, our findings confirmed astrocytes as the primary responders to Pg-induced innate immunity and inflammation both in vitro and in vivo. Periodontitis also induces an increase in IFITM3 expression in periodontal tissue, salivary glands.</p><p><strong>Conclusions: </strong>We define a previously unidentified link between periodontitis and cognitive decline, and provide new evidence linking oral pathogenic bacteria-induced innate immunity and neuroinflammation to AD pathogenesis and cognitive decline, partly through increased blood-brain barrier (BBB) permeability, triggered neuroinflammation, and elevated IFITM3 in glial cells for Aβ deposition. Moreover, periodontitis exacerbates innate immunity and cognitive impairment in AD mice, underscoring the importance of preventive and therapeutic strategies for periodontal disease in AD patients.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"166"},"PeriodicalIF":7.9,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666847","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":"Functional-structural co-dependent brain mapping of metamemory in amnestic mild cognitive impairment.","authors":"Juan-Juan Lu, Jie Ma, Mou-Xiong Zheng, Jia-Jia Wu, Yun-Ting Xiang, Jing Jin, Qi-Hao Guo, Xu-Yun Hua, Jian-Guang Xu","doi":"10.1186/s13195-025-01816-5","DOIUrl":"10.1186/s13195-025-01816-5","url":null,"abstract":"<p><strong>Background: </strong>Metamemory, a measure of introspective awareness of memory performance, provides an internally-generated drive, profoundly impacting external memory activities. Given its role in regulating memory along internal-external axis, understanding metamemory and underlying neural mechanisms in amnestic mild cognitive impairment (aMCI) is crucial for memory improvement. The present study was aimed to explore metamemory alterations and structural and functional remodeling characteristics underlying metamemory, as well as key brain regions that potentially moderated its intrinsic associations with age, education, and first-order cognition in aMCI.</p><p><strong>Methods: </strong>Sixty-seven aMCI patients and fifty-two healthy controls underwent neuropsychological assessments and magnetic resonance imaging in this case-control study. Generalized linear models analyzed metamemory-related neuroimaging characteristics. Moderation analysis examined their roles in relationships with age, education, and first-order cognition.</p><p><strong>Results: </strong>Patients with aMCI exhibited lower estimation of performance in prediction (EOP-pre) (P < 0.001) and postdiction (EOP-post) (P = 0.002). Amplitude of low-frequency fluctuation (ALFF) of left parahippocampal gyrus (PHG.L) (P = 0.026) and mediodorsal medial magnocellular (ltMDm) (P = 0.001), along with group × ALFF interaction effects in right cuneus (P = 0.010) and inferior parietal gyrus (P = 0.011) affected metamemory. Functional connectivity between ltMDm and left anterior cingulate cortex-pregenual (ACCpre.L) alleviated the association between metamemory and recall (P = 0.030). PHG.L ALFF enhanced the association between education and metamemory (P = 0.043).</p><p><strong>Conclusions: </strong>Metamemory in aMCI was associated with parietotemporal and thalamic functional remodeling. Regions including ltMDm, ACCpre.L, and PHG.L influenced its intrinsic relationships with education/recall, providing new insights for aMCI interventions.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"164"},"PeriodicalIF":7.9,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666731","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":"Ante-mortem cognitive trajectories associated with Aβ and tau biomarker profiles in older adults with cerebrovascular disease: a longitudinal cohort study.","authors":"Emily Rosenich, Yen Ying Lim","doi":"10.1186/s13195-025-01776-w","DOIUrl":"10.1186/s13195-025-01776-w","url":null,"abstract":"<p><strong>Background: </strong>Beta-amyloid (Aβ) plaques and tau tangles are pathological hallmarks of Alzheimer's disease (AD); however, autopsy studies reveal that most older adults also present with cerebrovascular disease (CVD) markers. It remains unclear how Aβ and tau relate to cognition in the context of concurrent CVD. In initially cognitively unimpaired older adults with CVD, this study aimed to determine ante-mortem cognitive trajectories associated with elevated Aβ and/or tau at autopsy.</p><p><strong>Methods: </strong>Participants aged 65-95 classified as cognitively unimpaired at baseline from the National Alzheimer's Coordinating Center database, with ≥ 1 follow-up between 2005 and 2015, and available autopsy/APOE data were included in this cohort study (N = 863). All participants had at least one of six CVD markers at autopsy. Participants were classified into four groups (A - T-, A + T-, A - T+, A + T+) based on semiquantitative Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque staging and Braak staging. Linear mixed models assessed rate of change in Preclinical Alzheimer's Cognitive Composite scores, episodic memory, and executive function.</p><p><strong>Results: </strong>A + T + adults demonstrated significantly faster cognitive decline on all outcomes in the ~ 10 years preceding death compared to A - T- adults (d = 0.34-0.46). Similarly, when compared to A + T - adults, A + T + adults showed significantly faster decline on all outcomes (d = 0.19-0.37). At the last visit prior to death, a greater proportion of A + T + adults (36%) received a dementia diagnosis compared to A - T+ (15%; OR = 6.00), A + T- (14%; OR = 8.00) and A - T- adults (12%; OR = 6.86), p <.001. When analyses were restricted to exclude dementia diagnoses, significantly faster decline on all outcomes (p's < 0.001, d = 0.29-0.37) was similarly observed in A + T + adults compared to A - T- adults.</p><p><strong>Conclusions: </strong>In older adults with concurrent CVD, A + T + at autopsy was associated with greater cognitive decline over 10 years preceding death compared to A - T- older adults. Faster cognitive decline in A + T + in the context of low final visit dementia diagnoses may suggest that post-mortem A + T + is associated with a steep trajectory of cognitive decline ante-mortem, but that dementia progression is not inevitable.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"165"},"PeriodicalIF":7.9,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666730","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":"A novel biochemical analysis for ApoE4 quantification in plasma and discrimination of homozygous and heterozygous APOE ε4 carriers.","authors":"Andrés Rodríguez, Olga Calero, Sergio Veiga, Miriam Menacho-Román, Ignacio Arribas, Lluís Cano, Guillermo García-Ribas, Miguel Calero","doi":"10.1186/s13195-025-01811-w","DOIUrl":"10.1186/s13195-025-01811-w","url":null,"abstract":"<p><strong>Background: </strong>The APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is associated with increased risk of amyloid-related imaging abnormalities (ARIA) during anti-amyloid therapy. Accurate identification of ε4 carriers, particularly APOE ε4/ε4 individuals, is clinically relevant. This study outlines the development and validation of e4Quant, a novel turbidimetric assay for quantifying plasma ApoE4 as a non-genetic alternative to APOE genotyping.</p><p><strong>Methods: </strong>The e4Quant test utilizes a proprietary particle-enhanced immunoturbidimetry method, employing an isoform-specific anti-ApoE4 antibody on standard chemistry analyzers. Plasma samples from 160 individuals of known APOE genotype (35 APOE ε4/ε4 homozygotes, 115 APOE ε4 heterozygotes, and 10 APOE ε4 non-carriers) were analyzed for ApoE4 and total ApoE levels. The test's discriminatory performance was assessed by ROC analysis and two-threshold classification algorithms.</p><p><strong>Results: </strong>ApoE4 levels ascertained by the e4Quant test exhibited clear genotype-dependent stratification. ROC analysis indicated 100% sensitivity and specificity in distinguishing APOE ε4 carriers from non-carriers, and 88.6% sensitivity and 90.4% specificity for discriminating homozygous from heterozygous carriers. Normalizing ApoE4 to total ApoE improved classification (sensitivity 94.3%, specificity 93.9%). A combined ratio-plus-concentration approach further enhanced discrimination (sensitivity 91.4%, specificity 100%). Three ε4 homozygous samples with low ApoE4/total ApoE ratios were misclassified.</p><p><strong>Discussion: </strong>The e4Quant assay offers a rapid, cost-effective, and highly accurate biochemical alternative to APOE genotyping, suitable for clinical and research settings, particularly in assessing AD risk and optimizing anti-amyloid therapeutic strategies. One subgroup of APOE ε4/ε4 subjects had unexpectedly low ApoE4 levels, raising questions about potential biological heterogeneity and its impact on Alzheimer's disease biology.</p><p><strong>Conclusion: </strong>The e4Quant assay is a novel alternative for genotyping to determine APOE ε4 carrier status, while also providing quantitative measurements of ApoE4 levels. Its high diagnostic accuracy, ease of use in standard clinical laboratories, and potential utility for personalized medicine in AD treatment highlight its translational value. Further studies are warranted to investigate the clinical significance of APOE ε4 expression variability and its impact on disease progression and treatment response.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"163"},"PeriodicalIF":7.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648272","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":"Age-related differences in Rostral-Middle locus coeruleus microstructure: A critical role in cognitive decline revealed by magnetic resonance relaxometry.","authors":"Jonghyun Bae, Zhaoyuan Gong, Caio Mazucanti, Murat Bilgel, John P Laporte, Mary E Faulkner, Alex Guo, Christopher M Bergeron, Josephine M Egan, Susan M Resnick, Christopher E Ramsden, Mustapha Bouhrara","doi":"10.1186/s13195-025-01809-4","DOIUrl":"10.1186/s13195-025-01809-4","url":null,"abstract":"<p><strong>Background: </strong>The Locus Coeruleus (LC) is a critical brain region affected by neurodegenerative diseases and aging. Despite its importance, in-vivo investigations of age-related LC degeneration and association with cognitive decline have been limited.</p><p><strong>Method: </strong>We employed magnetic resonance relaxometry, namely the Bayesian Monte-Carlo analysis of multicomponent driven equilibrium single pulse observation of T₁ and T₂ (BMC-mcDESPOT) MRI method, to estimate microstructural integrity represented by longitudinal (R₁) and transverse (R₂) relaxation rates, as well as Myelin Water Fraction (MWF) in the LC of a diverse cohort of 120 cognitively unimpaired individuals aged 22 to 94 years. BMC-mcDESPOT offers high spatial resolution and is effective for mapping detailed microstructural changes within the LC. We examined age-related differences in LC microstructure, their associations with cognitive changes, and the spatial variation of these microstructural changes within the LC, exploring their distinctive contributions to cognitive decline.</p><p><strong>Results: </strong>LC-R₂ values declined significantly with age, particularly in the rostral-middle regions. LC-R₁ and LC-MWF values showed significant positive correlations with cross-sectional memory scores. Longitudinally, the rostra-middle LC-R₂ values showed an age-moderated effect, with lower values predicting steeper memory decline at advanced ages.</p><p><strong>Conclusions: </strong>Quantitative MR relaxometry reveals that LC microstructural integrity declines with age and is predictive of cognitive decline, particularly in memory. Our MR relaxometry biomarkers, especially in the rostral LC, serve as sensitive imaging biomarkers of early structural alterations and cognitive declines in aging.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"161"},"PeriodicalIF":7.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641534","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":"Cardiovascular risk factors are associated with lower posterior-medial network functional connectivity in older adults.","authors":"Léa Chauveau, Julie Gonneaud, Géraldine Poisnel, Brigitte Landeau, Antoine Garnier-Crussard, Anne-Lise Pitel, Daniel Roquet, Edelweiss Touron, Sacha Haudry, Florence Mezenge, Anne Chocat, Denis Vivien, Vincent de La Sayette, Gaël Chételat, Robin de Flores","doi":"10.1186/s13195-025-01808-5","DOIUrl":"10.1186/s13195-025-01808-5","url":null,"abstract":"<p><strong>Background: </strong>Cortico-hippocampal functional networks, specifically the anterior-temporal (AT) and posterior-medial (PM) systems, are crucial for memory and highly vulnerable to aging and Alzheimer's disease (AD). While modifiable cardiovascular risk factors may offer prevention opportunities to preserve brain aging, their effects on AT/PM functional connectivity remain unknown. This study aims to investigate these associations in older adults, considering major risk categories and exploring potential interactions with protective lifestyle habits and AD risk factors.</p><p><strong>Methods: </strong>One hundred thirty-one community-dwelling cognitively unimpaired adults aged 65 + were selected from the Age-Well trial, a French monocentric population-based study conducted from 2016 to 2020. Resting-state fMRI and cardiovascular risk assessments were performed at baseline and 18-month follow-up. Functional connectivity within the AT and PM networks was derived from seed-based analyses using the perirhinal and parahippocampal cortices as individual seeds, respectively. Generalized additive and linear mixed models assessed the effects of cardiovascular risk factors on AT/PM functional connectivity, including interactions with protective lifestyle habits and AD risk factors.</p><p><strong>Results: </strong>Baseline mean age was 69 (65-84) years, with 63.5% women. Higher abdominal fat (95% CI: -0.00118, -0.00005; F = 5.39; P =.02), higher LDL cholesterol (95% CI: -0.01642, -0.00345; F = 10.40; P =.001), longer smoking duration (95% CI: NA; F = 3.89; P =.03) and greater alcohol consumption (95% CI: -0.01134, -0.00045; F = 4.66; P =.02) were consistently associated with lower PM connectivity, collectively explaining 11.4% of the variance. However, only LDL cholesterol survived multiple comparisons, possibly reflecting a more direct involvement in cardiovascular mechanisms affecting functional connectivity. No association was found with AT connectivity. Exploratory analyses showed that these relationships were independent of cerebral Aβ-positivity or APOE-ε4 carrier status and were unaffected by physical activity and Mediterranean diet when considered separately.</p><p><strong>Discussion: </strong>This study highlights converging associations between higher cardiovascular risk factors and lower functional connectivity in cognitively unimpaired older adults, specifically affecting the PM-but not AT-network, and independent of AD risk. Targeting these specific modifiable factors may prevent age-related network alterations to promote cognitive health in aging.</p><p><strong>Trial registration information: </strong>The Age-Well trial was registered with ClinicalTrials.gov on November 25, 2016 (identifier: NCT02977819).</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"159"},"PeriodicalIF":7.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641535","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":"Combinatorial targeting of NMDARs and 5-HT₄Rs exerts beneficial effects in a mouse model of Alzheimer's disease.","authors":"Briana K Chen, Holly C Hunsberger, Alicia Whye, Louise C Matthews, Alyson Yook, Moshe J Willner, Ryan W Logan, Stefanie Johns, Eric Weisblum, Christine A Denny","doi":"10.1186/s13195-025-01804-9","DOIUrl":"10.1186/s13195-025-01804-9","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the leading cause of dementia. There are limited approved medications that delay cognitive decline or lessen neuropsychiatric symptoms. Numerous clinical trials for AD using a single drug administration have failed to meet therapeutic endpoints, which is most likely due to the complexity of AD. A multimodal therapeutic intervention is more likely to improve symptoms by targeting multiple targets implicated in AD. Here, we investigated if targeting both N-Methyl-D-aspartic acid receptors (NMDARs) and serotonin type 4 receptors (5-HT₄R) may have beneficial effects in a mouse model of AD, as they have separately been shown to improve cognition and/or mood.</p><p><strong>Methods: </strong>Male and female control (Ctrl) or APP/PS1 mice were administered single, intermittent, or chronic administration of 1) saline; 2) (R,S)-ketamine, an NMDAR antagonist; 3) prucalopride, a 5-HT₄R agonist; or 4) (R,S)-ketamine + prucalopride to simultaneously target co-morbid neuropsychiatric and cognitive deficits. Behavioral assays were then administered to measure cognition, perseverative behavior, hyponeophagia, and/or sleep. Brains were processed for glial fibrillary acidic protein (GFAP) immunohistochemistry.</p><p><strong>Results: </strong>Single and chronic administration of (R,S)-ketamine + prucalopride administration improved cognitive decline by increasing memory retrieval in a contextual fear conditioning (CFC) paradigm in APP/PS1 mice. Drug efficacy was less effective in females than in males and was age dependent. Hippocampal GFAP immunoreactivity was decreased by chronic (R,S)-ketamine + prucalopride treatment in females.</p><p><strong>Conclusions: </strong>Our results indicate that combined administration of (R,S)-ketamine + prucalopride is a novel multimodal therapeutic strategy to treat cognitive decline in AD. Future work will further characterize these interactions with the goal of clinical development.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"160"},"PeriodicalIF":7.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641551","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}