Alzheimer's Research & Therapy最新文献

{"title":"Molecular landscape of the overlap between Alzheimer's disease and somatic insulin-related diseases.","authors":"I Hyun Ruisch, Joanna Widomska, Ward De Witte, Nina R Mota, Giuseppe Fanelli, Veerle Van Gils, Willemijn J Jansen, Stephanie J B Vos, Abel Fóthi, Csaba Barta, Simone Berkel, Kazi A Alam, Aurora Martinez, Jan Haavik, Aet O'Leary, David Slattery, Mairéad Sullivan, Jeffrey Glennon, Jan K Buitelaar, Janita Bralten, Barbara Franke, Geert Poelmans","doi":"10.1186/s13195-024-01609-2","DOIUrl":"10.1186/s13195-024-01609-2","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards \"energy metabolism\" as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"239"},"PeriodicalIF":7.9,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492771","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":"Longitudinal evidence for a mutually reinforcing relationship between white matter hyperintensities and cortical thickness in cognitively unimpaired older adults.","authors":"Jose Bernal, Inga Menze, Renat Yakupov, Oliver Peters, Julian Hellmann-Regen, Silka Dawn Freiesleben, Josef Priller, Eike Jakob Spruth, Slawek Altenstein, Anja Schneider, Klaus Fliessbach, Jens Wiltfang, Björn H Schott, Frank Jessen, Ayda Rostamzadeh, Wenzel Glanz, Enise I Incesoy, Katharina Buerger, Daniel Janowitz, Michael Ewers, Robert Perneczky, Boris-Stephan Rauchmann, Stefan Teipel, Ingo Kilimann, Christoph Laske, Sebastian Sodenkamp, Annika Spottke, Anna Esser, Falk Lüsebrink, Peter Dechent, Stefan Hetzer, Klaus Scheffler, Stefanie Schreiber, Emrah Düzel, Gabriel Ziegler","doi":"10.1186/s13195-024-01606-5","DOIUrl":"10.1186/s13195-024-01606-5","url":null,"abstract":"<p><strong>Background: </strong>For over three decades, the concomitance of cortical neurodegeneration and white matter hyperintensities (WMH) has sparked discussions about their coupled temporal dynamics. Longitudinal studies supporting this hypothesis nonetheless remain scarce.</p><p><strong>Methods: </strong>We applied global and regional bivariate latent growth curve modelling to determine the extent to which WMH and cortical thickness were interrelated over a four-year period. For this purpose, we leveraged longitudinal MRI data from 451 cognitively unimpaired participants (DELCODE; median age 69.71 [IQR 65.51, 75.50] years; 52.32% female). Participants underwent MRI sessions annually over a four-year period (1815 sessions in total, with roughly four MRI sessions per participant). We adjusted all models for demographics and cardiovascular risk.</p><p><strong>Results: </strong>Our findings were three-fold. First, larger WMH volumes were linked to lower cortical thickness (σ = -0.165, SE = 0.047, Z = -3.515, P < 0.001). Second, individuals with higher WMH volumes experienced more rapid cortical thinning (σ = -0.226, SE = 0.093, Z = -2.443, P = 0.007), particularly in temporal, cingulate, and insular regions. Similarly, those with lower initial cortical thickness had faster WMH progression (σ = -0.141, SE = 0.060, Z = -2.336, P = 0.009), with this effect being most pronounced in temporal, cingulate, and insular cortices. Third, faster WMH progression was associated with accelerated cortical thinning (σ = -0.239, SE = 0.139, Z = -1.710, P = 0.044), particularly in frontal, occipital, and insular cortical regions.</p><p><strong>Conclusions: </strong>Our study suggests that cortical thinning and WMH progression could be mutually reinforcing rather than parallel, unrelated processes, which become entangled before cognitive deficits are detectable.</p><p><strong>Trial registration: </strong>German Clinical Trials Register (DRKS00007966, 04/05/2015).</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"240"},"PeriodicalIF":7.9,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492770","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":"Dissecting neural correlates of theory of mind and executive functions in behavioral variant frontotemporal dementia.","authors":"Christopher M Weise, Annerose Engel, Maryna Polyakova, Qiong Wu, Karsten Mueller, Sabine Herzig, Robert Jech, Janine Diehl-Schmid, Lina Riedl, Sarah Anderl-Straub, Johannes Kornhuber, Klaus Fassbender, Jens Wiltfang, Klaus Fliessbach, Johannes Prudlo, Matthis Synofzik, Adrian Danek, Markus Otto, Matthias L Schroeter","doi":"10.1186/s13195-024-01596-4","DOIUrl":"10.1186/s13195-024-01596-4","url":null,"abstract":"<p><p>Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"237"},"PeriodicalIF":7.9,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492868","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 of modifiable risk factors with progression to dementia in relation to amyloid and tau pathology.","authors":"Zsolt Huszár, Alina Solomon, Marie Anne Engh, Vanda Koszovácz, Tamás Terebessy, Zsolt Molnár, Péter Hegyi, András Horváth, Francesca Mangialasche, Miia Kivipelto, Gábor Csukly","doi":"10.1186/s13195-024-01602-9","DOIUrl":"10.1186/s13195-024-01602-9","url":null,"abstract":"<p><strong>Background: </strong>Dementia preventive interventions targeting multiple modifiable risk factors are a promising approach. However, the impact of modifiable risk factors in the presence of beta-amyloid or phosphorylated-tau (p-tau) pathology is unclear.</p><p><strong>Methods: </strong>The objective of the study was to examine the role of modifiable risk factors (vascular factors, depression, and smoking) in the progression to mild cognitive impairment (MCI) or dementia among 434 cognitively unimpaired (CU) and 611 individuals with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Vascular risk factors were summarized with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score, dichotomized into higher versus lower risk. Depression and smoking (yes/no) were categorised according to medical history or current symptoms. Analyses were stratified by beta-amyloid negative (A-) and positive (A +), p-tau negative (T-) and positive (T +), or beta-amyloid and p-tau negative (A-T-) and positive (A + T +) biomarker status. Cox proportional hazard models were adjusted for age, sex, education, baseline MMSE score, baseline hippocampal volume and ApoE4 carrier status.</p><p><strong>Results: </strong>Higher CAIDE score was associated with increased risk of progression to all-cause dementia in most MCI subgroups: adjusted hazard ratios (aHR) [95% CI] were 3.1 [1.43; 6.53] in the A- subgroup, 1.7 [1.20-2.27] in T + , 2.6 [1.06-6.59] in A-T-, and 1.6 [1.15-2.22] in the A + T + subgroup. Smoking (yes/no) was associated with increased dementia aHR in the A + MCI subgroup: 1.6 [1.07-2.34]. Depression increased dementia aHR in the T + MCI subgroup: 1.5 [1.06-2.02]. No significant associations were found in the CU biomarker subgroups.</p><p><strong>Conclusion: </strong>Addressing modifiable risk factors carries an important potential for reducing the risk of dementia even after the onset of Alzheimer's pathology. Knowledge of biomarker status can further optimize prevention strategies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"238"},"PeriodicalIF":7.9,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492865","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":"EEG biomarkers in Alzheimer's and prodromal Alzheimer's: a comprehensive analysis of spectral and connectivity features.","authors":"Chowtapalle Anuraag Chetty, Harsha Bhardwaj, G Pradeep Kumar, T Devanand, C S Aswin Sekhar, Tuba Aktürk, Ilayda Kiyi, Görsev Yener, Bahar Güntekin, Justin Joseph, Chinnakkaruppan Adaikkan","doi":"10.1186/s13195-024-01582-w","DOIUrl":"10.1186/s13195-024-01582-w","url":null,"abstract":"<p><strong>Background: </strong>Biomarkers of Alzheimer's disease (AD) and mild cognitive impairment (MCI, or prodromal AD) are highly significant for early diagnosis, clinical trials and treatment outcome evaluations. Electroencephalography (EEG), being noninvasive and easily accessible, has recently been the center of focus. However, a comprehensive understanding of EEG in dementia is still needed. A primary objective of this study is to investigate which of the many EEG characteristics could effectively differentiate between individuals with AD or prodromal AD and healthy individuals.</p><p><strong>Methods: </strong>We collected resting state EEG data from individuals with AD, prodromal AD, and normal cognition. Two distinct preprocessing pipelines were employed to study the reliability of the extracted measures across different datasets. We extracted 41 different EEG features. We have also developed a stand-alone software application package, Feature Analyzer, as a comprehensive toolbox for EEG analysis. This tool allows users to extract 41 EEG features spanning various domains, including complexity measures, wavelet features, spectral power ratios, and entropy measures. We performed statistical tests to investigate the differences in AD or prodromal AD from age-matched cognitively normal individuals based on the extracted EEG features, power spectral density (PSD), and EEG functional connectivity.</p><p><strong>Results: </strong>Spectral power ratio measures such as theta/alpha and theta/beta power ratios showed significant differences between cognitively normal and AD individuals. Theta power was higher in AD, suggesting a slowing of oscillations in AD; however, the functional connectivity of the theta band was decreased in AD individuals. In contrast, we observed increased gamma/alpha power ratio, gamma power, and gamma functional connectivity in prodromal AD. Entropy and complexity measures after correcting for multiple electrode comparisons did not show differences in AD or prodromal AD groups. We thus catalogued AD and prodromal AD-specific EEG features.</p><p><strong>Conclusions: </strong>Our findings reveal that the changes in power and connectivity in certain frequency bands of EEG differ in prodromal AD and AD. The spectral power, power ratios, and the functional connectivity of theta and gamma could be biomarkers for diagnosis of AD and prodromal AD, measure the treatment outcome, and possibly a target for brain stimulation.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"236"},"PeriodicalIF":7.9,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492769","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":"Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer's disease.","authors":"Hua Long, Adam Simmons, Arthur Mayorga, Brady Burgess, Tuan Nguyen, Balasubrahmanyam Budda, Anna Rychkova, Herve Rhinn, Ilaria Tassi, Michael Ward, Felix Yeh, Tina Schwabe, Robert Paul, Sara Kenkare-Mitra, Arnon Rosenthal","doi":"10.1186/s13195-024-01599-1","DOIUrl":"10.1186/s13195-024-01599-1","url":null,"abstract":"<p><strong>Background: </strong>Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer's disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy.</p><p><strong>Methods: </strong>Preclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers.</p><p><strong>Results: </strong>In cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks.</p><p><strong>Conclusions: </strong>These findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD.</p><p><strong>Trial registration: </strong>Clinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.</p><p><strong>Clinicaltrials: </strong>gov/study/NCT03635047 .</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"235"},"PeriodicalIF":7.9,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492772","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":"Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites.","authors":"Tong Tong, Congcong Zhu, John J Farrell, Zainab Khurshid, Eden R Martin, Margaret A Pericak-Vance, Li-San Wang, William S Bush, Gerard D Schellenberg, Jonathan L Haines, Wei Qiao Qiu, Kathryn L Lunetta, Lindsay A Farrer, Xiaoling Zhang","doi":"10.1186/s13195-024-01601-w","DOIUrl":"10.1186/s13195-024-01601-w","url":null,"abstract":"<p><strong>Background: </strong>Blood-derived mitochondrial DNA copy number (mtDNA-CN) is a proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA-CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA-CN and Alzheimer disease (AD) is unclear.</p><p><strong>Methods: </strong>We performed two-sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA-CN and AD to investigate the causal relationship between mtDNA-CN and AD. We estimated mtDNA-CN using whole-genome sequence data from blood and brain samples of 13,799 individuals from the Alzheimer's Disease Sequencing Project. Linear and Cox proportional hazards models adjusting for age, sex, and study phase were used to assess the association of mtDNA-CN with AD. The association of AD biomarkers and serum metabolites with mtDNA-CN in blood was evaluated in Alzheimer's Disease Neuroimaging Initiative using linear regression. We conducted a causal mediation analysis to test the natural indirect effects of mtDNA-CN change on AD risk through the significantly associated biomarkers and metabolites.</p><p><strong>Results: </strong>MR analysis suggested a causal relationship between decreased blood-derived mtDNA-CN and increased risk of AD (OR = 0.68; P = 0.013). Survival analysis showed that decreased mtDNA-CN was significantly associated with higher risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.002). We also identified significant associations of mtDNA-CN with brain FDG-PET (β = 0.103; P = 0.022), amyloid-PET (β = 0.117; P = 0.034), CSF amyloid-β (Aβ) 42/40 (β=-0.124; P = 0.017), CSF t-Tau (β = 0.128; P = 0.015), p-Tau (β = 0.140; P = 0.008), and plasma NFL (β=-0.124; P = 0.004) in females. Several lipid species, amino acids, biogenic amines in serum were also significantly associated with mtDNA-CN. Causal mediation analyses showed that about a third of the effect of mtDNA-CN on AD risk was mediated by plasma NFL (P = 0.009), and this effect was more significant in females (P < 0.005).</p><p><strong>Conclusions: </strong>Our study indicates that mtDNA-CN measured in blood is predictive of AD and is associated with AD biomarkers including plasma NFL particularly in females. Further, we illustrate that decreased mtDNA-CN possibly increases AD risk through dysregulation of mitochondrial lipid metabolism and inflammation.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"234"},"PeriodicalIF":7.9,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492867","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":"Blockade of brain alkaline phosphatase efficiently reduces amyloid-β plaque burden and associated cognitive impairment.","authors":"Lucia Soria-Tobar, Laura Román-Valero, Álvaro Sebastián-Serrano, Paloma Aivar, Beatriz Álvarez-Castelao, Miguel Díaz-Hernández","doi":"10.1186/s13195-024-01600-x","DOIUrl":"10.1186/s13195-024-01600-x","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the most prevalent neurodegenerative disease. Three new drugs for AD based on monoclonal antibodies against the amyloid-β peptide (Aβ) have recently been approved because they favor the reduction of the burden of senile plaque in the AD patient's brain. Nonetheless, both drugs have very limited applicability and benefits and show several side effects. These limitations invite us to find alternative strategies for treating patients with AD. Here, we explored whether tissue-nonspecific alkaline phosphatase (TNAP), an ectoenzyme upregulated in the brain of AD patients and whose inhibition has beneficial effects on tau-induced pathology, is also efficient in reducing senile plaque burden.</p><p><strong>Methods: </strong>To evaluate whether TNAP may reduce cerebral senile plaque loading and Aβ-related toxicity, we use both pharmacological and genetic approaches. We analyze postmortem samples from human AD patients, APP/PS1 mice (a mouse model that mimics amyloid pathology observed in AD patients) treated or not with TNAP inhibitors, and the newly generated transgenic mouse line, TNAP-deficient APP/PS1 mice.</p><p><strong>Results: </strong>For the first time, we describe that genetic or pharmacological blockade of TNAP effectively reduces senile plaque burden by promoting its clearance, which leads to amelioration of cognitive impairment caused by Aβ-induced toxicity. These beneficial effects of TNAP inhibition occur concomitantly with higher microglial recruitment toward the senile plaque and increased microglial phagocytic capacity of Aβ by a mechanism involving metalloprotease-depending osteopontin processing. In addition, we also found that TNAP blockade favors LRP1-mediated transport of Aβ through the BBB.</p><p><strong>Conclusions: </strong>Here, we have shown that TNAP inhibition effectively reduces brain senile plaque burden and associated behavioral defects. Furthermore, given that we had previously reported that TNAP blockade also ameliorates Tau-induced neurotoxicity and increases lifespan of P301S tauopathy mouse model, we can state that TNAP blockade may be a novel and efficient therapy for treating patients with AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"233"},"PeriodicalIF":7.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492866","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":"Amyloid deposition and its association with depressive symptoms and cognitive functions in late-life depression: a longitudinal study using amyloid-β PET images and neuropsychological measurements.","authors":"Kiwon Kim, Yoo Jin Jang, Jeong-Hyeon Shin, Mi Jin Park, Hyun Soo Kim, Joon-Kyung Seong, Hong Jin Jeon","doi":"10.1186/s13195-024-01562-0","DOIUrl":"10.1186/s13195-024-01562-0","url":null,"abstract":"<p><strong>Background: </strong>Although depression is linked to an increased risk of dementia, the association between late-onset depression (LOD) and amyloid burden remains unclear. This study aimed to determine amyloid deposition in patients with LOD compared to healthy controls (HC) using amyloid-beta (Aβ) positron emission tomography (PET) images and neuropsychological assessments.</p><p><strong>Methods: </strong>Forty patients first diagnosed with major depressive disorder after the age of 60 (LOD) and twenty-one healthy volunteers (HC) were enrolled. Depression and anxiety were evaluated using the 17-item Hamilton Depression Scale, Hamilton Anxiety Rating Scale, and Clinical Global Impression Scale. Cognitive function was assessed using the Korean versions of the Mini-Mental Status Examination, Montreal Cognitive Assessment, and Seoul Neuropsychological Screening Battery at baseline and 3-month follow-up. ¹⁸F-florbetapir PET images were co-registered with T1-weighted magnetic resonance images.</p><p><strong>Results: </strong>There was no significant difference in Aβ deposition between LOD and HC groups. No significant correlation between Aβ burden and depressive symptom severity was found in LOD patients. Higher somatic anxiety was correlated with lower Aβ burden in multiple brain regions, including the left inferior frontal lobe (p = 0.009), right anterior cingulate (p = 0.003), and right superior frontal lobe (p = 0.009). Despite cognitive recovery in areas such as attention (Digit Span Forward, p = 0.026), memory (Auditory Verbal Learning Test Recall Total, p = 0.010; Rey Complex Figure Test Delayed Recall, p = 0.039), and frontal executive function (Contrasting Program, p = 0.033) after three months of antidepressant treatment, cognitive improvement showed no association with amyloid deposition.</p><p><strong>Conclusions: </strong>These findings suggest distinct mechanisms may underlie amyloid deposition in neurodegenerative changes associated with depression. While amyloid burden in specific brain regions negatively correlated with somatic anxiety, it showed no significant correlation with the severity of depression or overall cognitive function.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"232"},"PeriodicalIF":7.9,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11490031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455919","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":"The impact of tau-PET in a selected memory clinic cohort: rationale and design of the TAP-TAU study.","authors":"Marie R Vermeiren, Joost Somsen, Gert Luurtsema, Fransje E Reesink, Nicolaas A Verwey, Liesbeth Hempenius, Nelleke Tolboom, Geert Jan Biessels, J Matthijs Biesbroek, Meike W Vernooij, Sophie E M Veldhuijzen van Zanten, Harro Seelaar, Emma M Coomans, Charlotte E Teunissen, Afina W Lemstra, Argonde C van Harten, Leonie N C Visser, Wiesje M van der Flier, Elsmarieke van de Giessen, Rik Ossenkoppele","doi":"10.1186/s13195-024-01588-4","DOIUrl":"10.1186/s13195-024-01588-4","url":null,"abstract":"<p><strong>Background: </strong>Tau-PET is a diagnostic tool with high sensitivity and specificity for discriminating Alzheimer's disease (AD) dementia from other neurodegenerative disorders in well-controlled research environments. The role of tau-PET in real-world clinical practice, however, remains to be established. The aim of the TAP-TAU study is therefore to investigate the impact of tau-PET in clinical practice.</p><p><strong>Methods: </strong>TAP-TAU is a prospective, longitudinal multi-center study in 300 patients (≥ 50 years old) with mild cognitive impairment or mild dementia across five Dutch memory clinics. Patients are eligible if diagnostic certainty is < 85% after routine dementia screening and if the differential diagnosis includes AD. More specifically, we will include patients who (i) are suspected of having mixed pathology (e.g., AD and vascular pathology), (ii) have an atypical clinical presentation, and/or (iii) show conflicting or inconclusive outcomes on other tests (e.g., magnetic resonance imaging or cerebrospinal fluid). Participants will undergo a [¹⁸F]flortaucipir tau-PET scan, blood-based biomarker sampling, and fill out questionnaires on patient reported outcomes and experiences. The primary outcomes are change (pre- versus post- tau-PET) in diagnosis, diagnostic certainty, patient management and patient anxiety and uncertainty. Secondary outcome measures are head-to-head comparisons between tau-PET and less invasive and lower cost diagnostic tools such as novel blood-based biomarkers and artificial intelligence-based classifiers.</p><p><strong>Results: </strong>TAP-TAU has been approved by the Medical Ethics Committee of the Amsterdam UMC. The first participant is expected to be included in October 2024.</p><p><strong>Conclusions: </strong>In TAP-TAU, we will investigate the added clinical value of tau-PET in a real-world clinical setting, including memory clinic patients with diagnostic uncertainty after routine work-up. Findings of our study may contribute to recommendations regarding which patients would benefit most from assessment with tau-PET. This study is timely in the dawning era of disease modifying treatments as an accurate etiological diagnosis becomes increasingly important.</p><p><strong>Trial registration: </strong>This trial is registered and authorized on December 21st, 2023 in EU Clinical Trials with registration number 2023-505430-10-00.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"230"},"PeriodicalIF":7.9,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11490118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455930","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}