Abnormal aggregation and accumulation of tau is a hallmark of tauopathy including Alzheimer’s disease. Effective targeting of tau for therapeutic purposes requires a clear understanding of its epitope landscape with identification of a key pathogenic tau species. Despite numerous proposed and tested tau epitopes, ranging from the N-terminus to the microtubule-binding region and C-terminus, the most effective target remains elusive.
Method
We compared the impact of tau aggregation and seeding using various peptides representing epitopes of anti-tau antibodies in clinical trials or fragments of the MTBR found in the cerebrospinal fluid of tauopathies. We also evaluated the effects of several tau antibodies on the inhibition of tau aggregation and seeding using recombinant tau protein or AD brain extracts.
Result
Peptide containing acetylated lysine-280 was most potent on tau seeding measured by tau-FRET and on inducing tau aggregation evaluated by thioflavin T compared to other peptides. Further, inhibition of tau aggregation and seeding was most prominent in anti-acetylated lysine-280 antibody-treated cells.
Conclusion
Our results demonstrate that acetylated lysine-280 is the most potent inducer of tau aggregation and seeding. These findings offer valuable insights into the design of tau-targeted therapeutics and highlight acetylated lysine-280 as a promising target for the treatment of tauopathies.
{"title":"A comparison of tau aggregation and seeding competency of anti-tau antibodies under clinical trials and their target epitopes itself","authors":"Min-Seok Kim, Ha-Lim Song, Seung-Yong Yoon","doi":"10.1002/alz.088690","DOIUrl":"https://doi.org/10.1002/alz.088690","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Abnormal aggregation and accumulation of tau is a hallmark of tauopathy including Alzheimer’s disease. Effective targeting of tau for therapeutic purposes requires a clear understanding of its epitope landscape with identification of a key pathogenic tau species. Despite numerous proposed and tested tau epitopes, ranging from the N-terminus to the microtubule-binding region and C-terminus, the most effective target remains elusive.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>We compared the impact of tau aggregation and seeding using various peptides representing epitopes of anti-tau antibodies in clinical trials or fragments of the MTBR found in the cerebrospinal fluid of tauopathies. We also evaluated the effects of several tau antibodies on the inhibition of tau aggregation and seeding using recombinant tau protein or AD brain extracts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>Peptide containing acetylated lysine-280 was most potent on tau seeding measured by tau-FRET and on inducing tau aggregation evaluated by thioflavin T compared to other peptides. Further, inhibition of tau aggregation and seeding was most prominent in anti-acetylated lysine-280 antibody-treated cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results demonstrate that acetylated lysine-280 is the most potent inducer of tau aggregation and seeding. These findings offer valuable insights into the design of tau-targeted therapeutics and highlight acetylated lysine-280 as a promising target for the treatment of tauopathies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"20 S6","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.088690","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248969","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}
Pycnanthus angolensis (Welw) Warb., Myristicaceae, is used extensively in ethnomedicine. Numerous health benefits have being ascribed to the use of different parts of P. angolensis including its role in cognition enhancement and inflammation. Hence, this study was undertaken to investigate the stem bark of the plant for memory enhancing activity in mice.
Method
The plant material was grinded into powder and extracted by maceration with 80% methanol at room temperature for 48h. This was subsequently fractionated using N-hexane, Dchloromethane (DCM), and Ethyl acetate. The Dichloromethane (DCM) fraction-the most potent fraction- (25, 50, and 100 mg/kg) was evaluated for memory enhancing activity using the Y maze, Morris Water Maze (MWM) and the Elevated plus maze (EPM), on the D-galactose plus scopolamine and ketamine induced amnesia model. The antioxidant markers and acetylcholinesterase inhibiting effect of DCM were also evaluated
Result
The results obtained from the behavioural studies indicate that the DCM fraction significantly (p<0.05) increased the alternation behaviour of the mice in the Y maze, decreased the escape latency in the MWM paradigm and decreased the transfer latency (TL) in the EPM. Biochemically, DCM increased Glutathione (GSH), and superoxide dismutase (SOD), but decreased Malondialdehyde (MDA) and acetylcholinesterase (AChE) activity in the brain.
Conclusion
The study therefore suggested that the DCM may possess significant memory enhancing activity, which may be due to the reverser of the activity of scopolamine, thereby, enhancing cholinergic transmission. The attenuation of the effect of ketamine by the DCM may possibly result from an increase in NMDA receptor activity.
{"title":"Evaluation of the Memory Enhancing Activity of Dichloromethane Fraction of the Methanol Extract of Pycnanthus angolensis Stem Bark on Experimental Models of Memory Impairment","authors":"Patrici Eziafa Chinwuba, Bakre Adewale Ganiyu","doi":"10.1002/alz.088192","DOIUrl":"https://doi.org/10.1002/alz.088192","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p><i>Pycnanthus angolensis</i> (Welw) Warb., Myristicaceae, is used extensively in ethnomedicine. Numerous health benefits have being ascribed to the use of different parts of <i>P. angolensis</i> including its role in cognition enhancement and inflammation. Hence, this study was undertaken to investigate the stem bark of the plant for memory enhancing activity in mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>The plant material was grinded into powder and extracted by maceration with 80% methanol at room temperature for 48h. This was subsequently fractionated using N-hexane, Dchloromethane (DCM), and Ethyl acetate. The Dichloromethane (DCM) fraction-the most potent fraction- (25, 50, and 100 mg/kg) was evaluated for memory enhancing activity using the Y maze, Morris Water Maze (MWM) and the Elevated plus maze (EPM), on the D-galactose plus scopolamine and ketamine induced amnesia model. The antioxidant markers and acetylcholinesterase inhibiting effect of DCM were also evaluated</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>The results obtained from the behavioural studies indicate that the DCM fraction significantly (p<0.05) increased the alternation behaviour of the mice in the Y maze, decreased the escape latency in the MWM paradigm and decreased the transfer latency (TL) in the EPM. Biochemically, DCM increased Glutathione (GSH), and superoxide dismutase (SOD), but decreased Malondialdehyde (MDA) and acetylcholinesterase (AChE) activity in the brain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The study therefore suggested that the DCM may possess significant memory enhancing activity, which may be due to the reverser of the activity of scopolamine, thereby, enhancing cholinergic transmission. The attenuation of the effect of ketamine by the DCM may possibly result from an increase in NMDA receptor activity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"20 S6","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.088192","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143249002","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}
Gordon An, Tammie L.S. Benzinger, Aristeidis Sotiras, Brian A. Gordon
<div> <section> <h3> Background</h3> <p>Alzheimer’s Disease can present with heterogenous neurodegenerative patterns. In order to optimize clinical trials and personalized medicine, the identification and characterization of diverse pathological brain patterns associated with AD have become paramount. Optimal approaches to identify such heterogeneity are unknown. The present study employed two distinct clustering approaches, namely HYDRA and CHIMERA, to delineate the spatial pattern of brain atrophy attributable to AD. Methods were applied to MRI scans from the Open Access Series of Imaging Studies (OASIS-4) project.</p> </section> <section> <h3> Methods</h3> <p>HYDRA uses a convex polytope formed by multiple linear hyperplanes that correspond to various pathological patterns, capturing disease subtypes. CHIMERA assesses the pathological transition by transforming NC distribution to separate transformations matching the disease distribution. While both identify spatial patterns, the distinction lies in HYDRA’s discriminative analysis of disease subtypes and CHIMERA’s generative nature on disease progression through distribution matching.</p> </section> <section> <h3> Results</h3> <p>Both approaches identified two patterns, or subtypes (Figure 1) with similar CDR results (Figure 2). All subtypes demonstrate marked atrophy within the medial temporal areas, notably the hippocampus. Disparities are evident when assessing subtypes: Subtype-2 across both methods shows pronounced variations in regions such as superior frontal, middle temporal, parietal cortex, and precuneus, areas paramount in AD pathology. Conversely, HYDRA’s Subtype-1 highlights subtle differences in temporal cortex relative to its Subtype-2. CHIMERA’s Subtype-1, while mirroring its Subtype-2 pattern, is less intensified, suggesting an earlier AD stage. Collectively, these patterns concur with recognized AD neuropathological trajectories, pinpointing regions initially impacted in progression. In addition, an in-depth exploration of subsequent analysis including a longitudinal data evaluation to observe the progression of these patterns over time is slated for later investigation.</p> </section> <section> <h3> Conclusion</h3> <p>Our findings demonstrate data-driven approaches to derive clinically meaningful patterns of neurodegeneration. A parallel evaluation of both approaches accentuates the robustness of clustering techniques, revealing consistent and overlapping insights into the intricate pathological landscapes of AD. This convergence in findings bolsters confidence in the reliabil
{"title":"Unraveling Alzheimer’s Disease Heterogeneity: A Comparative Analysis Using HYDRA and CHIMERA","authors":"Gordon An, Tammie L.S. Benzinger, Aristeidis Sotiras, Brian A. Gordon","doi":"10.1002/alz.094135","DOIUrl":"https://doi.org/10.1002/alz.094135","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alzheimer’s Disease can present with heterogenous neurodegenerative patterns. In order to optimize clinical trials and personalized medicine, the identification and characterization of diverse pathological brain patterns associated with AD have become paramount. Optimal approaches to identify such heterogeneity are unknown. The present study employed two distinct clustering approaches, namely HYDRA and CHIMERA, to delineate the spatial pattern of brain atrophy attributable to AD. Methods were applied to MRI scans from the Open Access Series of Imaging Studies (OASIS-4) project.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>HYDRA uses a convex polytope formed by multiple linear hyperplanes that correspond to various pathological patterns, capturing disease subtypes. CHIMERA assesses the pathological transition by transforming NC distribution to separate transformations matching the disease distribution. While both identify spatial patterns, the distinction lies in HYDRA’s discriminative analysis of disease subtypes and CHIMERA’s generative nature on disease progression through distribution matching.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Both approaches identified two patterns, or subtypes (Figure 1) with similar CDR results (Figure 2). All subtypes demonstrate marked atrophy within the medial temporal areas, notably the hippocampus. Disparities are evident when assessing subtypes: Subtype-2 across both methods shows pronounced variations in regions such as superior frontal, middle temporal, parietal cortex, and precuneus, areas paramount in AD pathology. Conversely, HYDRA’s Subtype-1 highlights subtle differences in temporal cortex relative to its Subtype-2. CHIMERA’s Subtype-1, while mirroring its Subtype-2 pattern, is less intensified, suggesting an earlier AD stage. Collectively, these patterns concur with recognized AD neuropathological trajectories, pinpointing regions initially impacted in progression. In addition, an in-depth exploration of subsequent analysis including a longitudinal data evaluation to observe the progression of these patterns over time is slated for later investigation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings demonstrate data-driven approaches to derive clinically meaningful patterns of neurodegeneration. A parallel evaluation of both approaches accentuates the robustness of clustering techniques, revealing consistent and overlapping insights into the intricate pathological landscapes of AD. This convergence in findings bolsters confidence in the reliabil","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"20 S9","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.094135","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143249016","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}
Adam C. Raikes, Francesca Vitali, Gerson D Hernandez, Fei Yin
<div> <section> <h3> Background</h3> <p>Age, female sex and the APOEe4 allele are among the top risk factors for developing late-onset Alzheimer’s disease (LOAD). Precision medicine for AD drug development necessitates targeting specific biological pathways driving AD pathology. We previously identified LOAD-associated transcriptomic signatures specific to both sex and APOE genotype. Here we extend these analyses to examine the association between these signatures and imaging-derived phenotypes (IDPs).</p> </section> <section> <h3> Method</h3> <p>Brain RNA-Seq datasets from ROSMAP (syn8456637) were obtained from the RNA-Seq Harmonization Study on AMP-AD, including 369 frontal cortex samples from APOEe3/e3 and APOEe3/e4 individuals. Differentially expressed genes (DEGs, p-value<0.01) between LOAD and cognitively normal controls were identified for each sex-genotype. IDPs were generated from 1155 individuals in ROSMAP, with 62 overlapping the RNA-Seq Harmonization Study. T1-weighted MRIs were processed using Fastsurfer (v.2.0.4), and cortical thickness (CT) and subcortical volumes (SV) were computed. After multi-site harmonization and covariate adjustment, effect sizes (Cohen’s d) for controls vs. AD were computed for each sex-genotype pairing. Correlations between these effect sizes and median regional DEG expression from the Allen Human Brain Atlas were examined.</p> </section> <section> <h3> Result</h3> <p>Controls showed anticipated CT and SV patterns, though male APOEe4s exhibited greater CT in more regions. Higher median expression of up (female APOEe3/e3, male APOEe4) and down (female APOEe3/e3, male APOEe3/e3, male APOEe4) regulated DEGs correlated with less CT in AD patients (r=0.21-0.41, p < 0.046). In APOEe4 carriers, higher median up (male, female) and down (female) DEG expression correlated with greater SV in AD patients (r=0.48-0.57, p < 0.043). Greater median downregulated DEG expression in APOEe3/e3s correlated with smaller SV (r=0.56, p=0.021). Higher median APOE expression was correlated with less CT in AD patients across sex-genotype pairings (r=0.38-0.86, p < 0.002), lower SV (females, all genotypes), and greater SV (male APOEe3/e3). No associations between median DEG expression and CT were observed in female APOEe4 carriers.</p> </section> <section> <h3> Conclusion</h3> <p>Our analyses reveal novel sex and APOE genotype-specific transcriptomic signatures associations with imaging-derived features in LOAD. Our findings transcriptome signature specific CT and SV profiles that may inform therapeutic targets. The present analyses provide support the identification and use of risk-factor specific biomarke
{"title":"Associations Between Sex- and APOE-Specific Transcriptomic Signatures in Alzheimer's Disease and Imaging-Derived Phenotypes: An AZ-ADRC-Research Education Scholars Team Science Project","authors":"Adam C. Raikes, Francesca Vitali, Gerson D Hernandez, Fei Yin","doi":"10.1002/alz.094079","DOIUrl":"https://doi.org/10.1002/alz.094079","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Age, female sex and the APOEe4 allele are among the top risk factors for developing late-onset Alzheimer’s disease (LOAD). Precision medicine for AD drug development necessitates targeting specific biological pathways driving AD pathology. We previously identified LOAD-associated transcriptomic signatures specific to both sex and APOE genotype. Here we extend these analyses to examine the association between these signatures and imaging-derived phenotypes (IDPs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>Brain RNA-Seq datasets from ROSMAP (syn8456637) were obtained from the RNA-Seq Harmonization Study on AMP-AD, including 369 frontal cortex samples from APOEe3/e3 and APOEe3/e4 individuals. Differentially expressed genes (DEGs, p-value<0.01) between LOAD and cognitively normal controls were identified for each sex-genotype. IDPs were generated from 1155 individuals in ROSMAP, with 62 overlapping the RNA-Seq Harmonization Study. T1-weighted MRIs were processed using Fastsurfer (v.2.0.4), and cortical thickness (CT) and subcortical volumes (SV) were computed. After multi-site harmonization and covariate adjustment, effect sizes (Cohen’s d) for controls vs. AD were computed for each sex-genotype pairing. Correlations between these effect sizes and median regional DEG expression from the Allen Human Brain Atlas were examined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>Controls showed anticipated CT and SV patterns, though male APOEe4s exhibited greater CT in more regions. Higher median expression of up (female APOEe3/e3, male APOEe4) and down (female APOEe3/e3, male APOEe3/e3, male APOEe4) regulated DEGs correlated with less CT in AD patients (r=0.21-0.41, p < 0.046). In APOEe4 carriers, higher median up (male, female) and down (female) DEG expression correlated with greater SV in AD patients (r=0.48-0.57, p < 0.043). Greater median downregulated DEG expression in APOEe3/e3s correlated with smaller SV (r=0.56, p=0.021). Higher median APOE expression was correlated with less CT in AD patients across sex-genotype pairings (r=0.38-0.86, p < 0.002), lower SV (females, all genotypes), and greater SV (male APOEe3/e3). No associations between median DEG expression and CT were observed in female APOEe4 carriers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our analyses reveal novel sex and APOE genotype-specific transcriptomic signatures associations with imaging-derived features in LOAD. Our findings transcriptome signature specific CT and SV profiles that may inform therapeutic targets. The present analyses provide support the identification and use of risk-factor specific biomarke","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"20 S9","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.094079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143249027","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}
<div> <section> <h3> Background</h3> <p>Recruiting large numbers of study participants for Alzheimer’s Disease (AD) drug trials remains a significant challenge in need of more effective approaches. Advertising can be an effective way to reach large numbers of prospective participants, but can suffer from low attendance rates. This study examined the relationship between the initial behaviors of prospective AD trial participants who did not attend their first scheduled appointment and their overall likelihood of eventually attending an in-person consultation.</p> </section> <section> <h3> Method</h3> <p>In 2023, 4,043 potential participants were identified through online advertising and scheduled for 5,561 appointments for an in-person pre-screen at a commercial research site. Only 45.0% attended their first scheduled appointment. In lieu of attending their first scheduled appointment, 32.3% (n = 1,307) called in to the clinic to modify (i.e. cancel or reschedule) their first scheduled appointment and the remaining 22.7% (n = 915) simply did not attend their first scheduled appointment. Recruiters attempted to reschedule the latter group for another appointment.</p> </section> <section> <h3> Result</h3> <p>Of the 4,043 potential participants who were ever scheduled for an in-person pre-screen, 55.8% of these participants eventually attended an appointment, whether during the first or subsequently scheduled appointments.</p> <p>Of the 1,307 potential participants who called in to modify their first scheduled appointment, 506 of these potential participants were scheduled for a subsequent appointment, with 57.3% of these persons eventually attending. This deviation from the 55.8% overall attendance rate is not statistically significant (p = 0.50).</p> <p>However, of the 915 potential participants who simply did not attend their first scheduled appointment, 352 were scheduled for a subsequent appointment. Of these 352, only 43.5% eventually attended an appointment. This deviation from both the overall attendance rate and the attendance rate for those who modified their first appointment were highly significant (p < 1e-4 for both).</p> </section> <section> <h3> Conclusion</h3> <p>Potential AD trial participants who modify their first appointment are adequately engaged in the process, and so not attending their first appointment does not adversely affect their chances of attending a pre-screen. In contrast, potential participants who simply do not show up are much less likely to ever attend any appointment (almost 25% relative, >13% absolute).</p> </section> </
{"title":"Initial evaluation rate invariance for Alzheimer’s Disease drug trials after first appointment modification","authors":"Ralph Lee, Yu-Jay Huoh, Brenda Martinez, Elly Lee","doi":"10.1002/alz.092240","DOIUrl":"https://doi.org/10.1002/alz.092240","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Recruiting large numbers of study participants for Alzheimer’s Disease (AD) drug trials remains a significant challenge in need of more effective approaches. Advertising can be an effective way to reach large numbers of prospective participants, but can suffer from low attendance rates. This study examined the relationship between the initial behaviors of prospective AD trial participants who did not attend their first scheduled appointment and their overall likelihood of eventually attending an in-person consultation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>In 2023, 4,043 potential participants were identified through online advertising and scheduled for 5,561 appointments for an in-person pre-screen at a commercial research site. Only 45.0% attended their first scheduled appointment. In lieu of attending their first scheduled appointment, 32.3% (n = 1,307) called in to the clinic to modify (i.e. cancel or reschedule) their first scheduled appointment and the remaining 22.7% (n = 915) simply did not attend their first scheduled appointment. Recruiters attempted to reschedule the latter group for another appointment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>Of the 4,043 potential participants who were ever scheduled for an in-person pre-screen, 55.8% of these participants eventually attended an appointment, whether during the first or subsequently scheduled appointments.</p>\u0000 \u0000 <p>Of the 1,307 potential participants who called in to modify their first scheduled appointment, 506 of these potential participants were scheduled for a subsequent appointment, with 57.3% of these persons eventually attending. This deviation from the 55.8% overall attendance rate is not statistically significant (p = 0.50).</p>\u0000 \u0000 <p>However, of the 915 potential participants who simply did not attend their first scheduled appointment, 352 were scheduled for a subsequent appointment. Of these 352, only 43.5% eventually attended an appointment. This deviation from both the overall attendance rate and the attendance rate for those who modified their first appointment were highly significant (p < 1e-4 for both).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Potential AD trial participants who modify their first appointment are adequately engaged in the process, and so not attending their first appointment does not adversely affect their chances of attending a pre-screen. In contrast, potential participants who simply do not show up are much less likely to ever attend any appointment (almost 25% relative, >13% absolute).</p>\u0000 </section>\u0000 </","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"20 S6","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.092240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143249076","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}
Lin Lin, Sarah Minucci, Sarah DiBartolo, Joshuaine Grant, Kumar Kandadi Muralidharan, Matthew Hutchison, Jessica Collins, Amanda Edwards, Heike Hering, Thierry Bussière, Danielle Graham, Fei Hua, John Roberts
Background
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of tau aggregates. Research in animal models has generated hypotheses on the underlying mechanisms of the interaction between Aβ and tau pathology. In support of this interaction, results from clinical trials have shown that treatment with anti-Aβ monoclonal antibodies (mAbs) affects tau pathology. Meanwhile, preliminary results from a phase 1b study showed that BIIB080, a tau-targeting antisense oligonucleotide (ASO), reduced tau biomarkers in early AD patients. Building upon our previous work of a quantitative systems pharmacology (QSP) model for anti-Aβ mAbs, we have developed a more comprehensive model incorporating the interplay between Aβ and tau pathways and therapies targeting Aβ and tau.
Method
A QSP model was developed that accounts for changes in Aβ and tau biomarkers in the progression of AD. It includes the production, aggregation, and inter-compartment transport of both Aβ and tau species, as well as changes in phospho-tau species and spreading of aggregated tau pathology. The model captures the interaction between Aβ and tau pathology by Aβ plaque-dependent tau hyperphosphorylation that drives NFT formation in Braak region I/II and tau pathology spreading to Braak regions III/IV and V/VI. Furthermore, the model incorporates mechanisms of action for anti-Aβ mAbs, including aducanumab, lecanemab, donanemab and gantenerumab, and the tau-targeting ASO, BIIB080. The model was calibrated using Aβ and tau biomarker data (Aβ42/Aβ40, t-tau and p-tau181 in CSF and plasma, amyloid and tau PET) from natural history studies as well as pharmacokinetic (PK) data and biomarker response data from the clinical trials with these therapies.
Result
Model simulations were in good agreement to the available clinical data. The calibrated model was able to match observed drug PK and Aβ and tau biomarker data, including amyloid re-accumulation after depletion. In addition, the model was able to reasonably capture the effects of anti-Aβ mAbs on tau pathology.
Conclusion
A QSP model was developed to integrate therapies targeting Aβ and tau pathologies in AD. The model can be utilized to explore dosing regimens to support the development of combination therapy.
{"title":"Quantitative Systems Pharmacology Model for Therapies Targeting Aβ and Tau Pathologies in Alzheimer’s Disease","authors":"Lin Lin, Sarah Minucci, Sarah DiBartolo, Joshuaine Grant, Kumar Kandadi Muralidharan, Matthew Hutchison, Jessica Collins, Amanda Edwards, Heike Hering, Thierry Bussière, Danielle Graham, Fei Hua, John Roberts","doi":"10.1002/alz.089337","DOIUrl":"https://doi.org/10.1002/alz.089337","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of tau aggregates. Research in animal models has generated hypotheses on the underlying mechanisms of the interaction between Aβ and tau pathology. In support of this interaction, results from clinical trials have shown that treatment with anti-Aβ monoclonal antibodies (mAbs) affects tau pathology. Meanwhile, preliminary results from a phase 1b study showed that BIIB080, a tau-targeting antisense oligonucleotide (ASO), reduced tau biomarkers in early AD patients. Building upon our previous work of a quantitative systems pharmacology (QSP) model for anti-Aβ mAbs, we have developed a more comprehensive model incorporating the interplay between Aβ and tau pathways and therapies targeting Aβ and tau.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>A QSP model was developed that accounts for changes in Aβ and tau biomarkers in the progression of AD. It includes the production, aggregation, and inter-compartment transport of both Aβ and tau species, as well as changes in phospho-tau species and spreading of aggregated tau pathology. The model captures the interaction between Aβ and tau pathology by Aβ plaque-dependent tau hyperphosphorylation that drives NFT formation in Braak region I/II and tau pathology spreading to Braak regions III/IV and V/VI. Furthermore, the model incorporates mechanisms of action for anti-Aβ mAbs, including aducanumab, lecanemab, donanemab and gantenerumab, and the tau-targeting ASO, BIIB080. The model was calibrated using Aβ and tau biomarker data (Aβ42/Aβ40, t-tau and p-tau181 in CSF and plasma, amyloid and tau PET) from natural history studies as well as pharmacokinetic (PK) data and biomarker response data from the clinical trials with these therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>Model simulations were in good agreement to the available clinical data. The calibrated model was able to match observed drug PK and Aβ and tau biomarker data, including amyloid re-accumulation after depletion. In addition, the model was able to reasonably capture the effects of anti-Aβ mAbs on tau pathology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>A QSP model was developed to integrate therapies targeting Aβ and tau pathologies in AD. The model can be utilized to explore dosing regimens to support the development of combination therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"20 S6","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.089337","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143249077","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}
<div> <section> <h3> Background</h3> <p>Alzheimer’s disease (AD) agitation is a distressing neuropsychiatric symptom characterized by excessive motor activity, verbal aggression, or physical aggression. Agitation is one of the causes of caregiver distress, increased morbidity and mortality, and early institutionalization in patients with AD. Current medications used for the management of agitation have modest efficacy and have substantial side effects. Therefore, there remains an urgent clinical priority for effective and safe treatments for agitation in AD.</p> <p>Serotonin-6 (5-HT<sub>6</sub>) receptors are widely expressed in the brain regions including the cortex, dorsal hippocampus, and striatum; brain areas centrally involved in mood and behavior. Blockade of 5-HT<sub>6</sub> receptors may have a potential therapeutic utility in managing agitation. Masupirdine is a potent and selective 5-HT<sub>6</sub> receptor antagonist and is being developed as a potential treatment for agitation associated with AD.</p> </section> <section> <h3> Method</h3> <p>Masupirdine was evaluated in animal models of aggressive behaviors like resident-intruder task and dominant-submissive assay. The cognitive and motor performances were assessed using the alternating lever cyclic ration schedule.</p> <p>Subgroup analyses of a Phase-2, 26-week proof-of-concept clinical study (NCT02580305) based on the neuropsychiatric inventory scale were carried out.</p> <p>A Phase-3, double-blind, randomized, placebo-controlled, global study is in progress to explore the efficacy, safety, tolerability, and pharmacokinetics of masupirdine in patients with agitation in dementia of the Alzheimer’s type (NCT05397639 and EudraCT 2021-003405-22).</p> </section> <section> <h3> Result</h3> <p>Oral administration of masupirdine significantly (p<0.05) attenuated aggressive behaviors in the resident-intruder task and dominant-submissive assay. In the alternating lever cyclic ration schedule, no changes were observed in the cognitive and motor performances after treatment with Masupirdine (p>0.05).</p> <p>Potential beneficial effects in reducing agitation/aggression symptoms were observed in the post hoc analyses of the Phase-2 study of masupirdine in AD patients.</p> <p>Updates from the ongoing Phase-3 study (NCT05397639 and EudraCT 2021-003405-22) will be presented in the poster.</p> </section> <section> <h3> Conclusion</h3> <p>Outcomes from animal models of aggression and subgroup analysis of the Phase-2 study suggest that masupirdine may allevia
{"title":"Masupirdine (SUVN-502): Phase-3 Study for the Potential Treatment of Agitation in Patients with Dementia of the Alzheimer’s Type, an Update","authors":"Ramakrishna Nirogi, Renny Abraham, Jyothsna Ravula, Satish Jetta, Vijay Benade, Anil Shinde, Mohammed Abdul Rasheed, Rajesh Kumar Badange, Vinod Kumar Goyal, Veera Raghava Chowdary Palacharla, Ramkumar Subramanian, Pradeep Jayarajan","doi":"10.1002/alz.087894","DOIUrl":"https://doi.org/10.1002/alz.087894","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alzheimer’s disease (AD) agitation is a distressing neuropsychiatric symptom characterized by excessive motor activity, verbal aggression, or physical aggression. Agitation is one of the causes of caregiver distress, increased morbidity and mortality, and early institutionalization in patients with AD. Current medications used for the management of agitation have modest efficacy and have substantial side effects. Therefore, there remains an urgent clinical priority for effective and safe treatments for agitation in AD.</p>\u0000 \u0000 <p>Serotonin-6 (5-HT<sub>6</sub>) receptors are widely expressed in the brain regions including the cortex, dorsal hippocampus, and striatum; brain areas centrally involved in mood and behavior. Blockade of 5-HT<sub>6</sub> receptors may have a potential therapeutic utility in managing agitation. Masupirdine is a potent and selective 5-HT<sub>6</sub> receptor antagonist and is being developed as a potential treatment for agitation associated with AD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>Masupirdine was evaluated in animal models of aggressive behaviors like resident-intruder task and dominant-submissive assay. The cognitive and motor performances were assessed using the alternating lever cyclic ration schedule.</p>\u0000 \u0000 <p>Subgroup analyses of a Phase-2, 26-week proof-of-concept clinical study (NCT02580305) based on the neuropsychiatric inventory scale were carried out.</p>\u0000 \u0000 <p>A Phase-3, double-blind, randomized, placebo-controlled, global study is in progress to explore the efficacy, safety, tolerability, and pharmacokinetics of masupirdine in patients with agitation in dementia of the Alzheimer’s type (NCT05397639 and EudraCT 2021-003405-22).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>Oral administration of masupirdine significantly (p<0.05) attenuated aggressive behaviors in the resident-intruder task and dominant-submissive assay. In the alternating lever cyclic ration schedule, no changes were observed in the cognitive and motor performances after treatment with Masupirdine (p>0.05).</p>\u0000 \u0000 <p>Potential beneficial effects in reducing agitation/aggression symptoms were observed in the post hoc analyses of the Phase-2 study of masupirdine in AD patients.</p>\u0000 \u0000 <p>Updates from the ongoing Phase-3 study (NCT05397639 and EudraCT 2021-003405-22) will be presented in the poster.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Outcomes from animal models of aggression and subgroup analysis of the Phase-2 study suggest that masupirdine may allevia","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"20 S6","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.087894","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143249078","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}
Roxane Dilcher, Charles B Malpas, Terence J O'Brien, Lucy Vivash
Background
Identifying biomarkers for primary tau pathologies like Progressive Supranuclear Palsy (PSP) is crucial for diagnosis and treatment development. The novel positron emission tomography (PET) radiotracer 18F-PI-2620 shows promise in detecting tau protein in PSP and this study investigates its correlation with clinical markers.
Methods
We conducted a cross-sectional analysis on 20 patients with clinically diagnosed probable PSP (Richardson’s Syndrome), who underwent T1-weighted MRI, lumbar puncture, blood testing, and 0-60 min dynamic 18F-PI-2620 PET scanning. Binding potential (BD) and Standardized uptake value ratios (SUVr) were generated for regions of interest. Clinical assessments included the Digit Span Memory task, Hayling, Stroop, Trail Making Test, NIH toolbox subtasks, the BRIEF-A, and the PSP-RS. Voxel-wise and region-based multiple regression analyses were employed to examine relationship between PET metrics and clinical markers using FSL, SPM, and R software.
Results
Preliminary results revealed a significant negative correlation between basal ganglia tau uptake and the Digit Span Reverse task or the BRIEF-A (voxel-wise, SUVr: p<0.01; BD: p<0.05). Region-based analyses (SUVr) showed basal ganglia tau uptake significantly correlated with impairments in the Digit Span Forward and Reverse task (p<0.01), working memory subtask of the NIH (p<0.05), and the BRIEF-A (‘Never’-scores, p<0.05). Significant interaction effects (p<0.05) showed that these associations were predominantly localized in the basal ganglia as compared to frontal or occipital regions. Additionally, basal ganglia atrophy was negatively associated with tau uptake (SUVr) in the basal ganglia and brainstem. Ongoing analysis explores associations with CSF/blood biomarkers (GFAP/NfL/tau).
Conclusions
Our findings highlight the potential of 18F-PI-2620 as an in-vivo tau biomarker in PSP diagnosis, demonstrating significant links between tau uptake in the basal ganglia, brain atrophy, executive dysfunction, and disease severity. These insights could drive the development of new biomarkers, advancing future clinical trial prospects.
{"title":"Tau-PET imaging in Progressive Supranuclear Palsy and relationship with biomarkers and clinical markers","authors":"Roxane Dilcher, Charles B Malpas, Terence J O'Brien, Lucy Vivash","doi":"10.1002/alz.093950","DOIUrl":"https://doi.org/10.1002/alz.093950","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Identifying biomarkers for primary tau pathologies like Progressive Supranuclear Palsy (PSP) is crucial for diagnosis and treatment development. The novel positron emission tomography (PET) radiotracer 18F-PI-2620 shows promise in detecting tau protein in PSP and this study investigates its correlation with clinical markers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a cross-sectional analysis on 20 patients with clinically diagnosed probable PSP (Richardson’s Syndrome), who underwent T1-weighted MRI, lumbar puncture, blood testing, and 0-60 min dynamic 18F-PI-2620 PET scanning. Binding potential (BD) and Standardized uptake value ratios (SUVr) were generated for regions of interest. Clinical assessments included the Digit Span Memory task, Hayling, Stroop, Trail Making Test, NIH toolbox subtasks, the BRIEF-A, and the PSP-RS. Voxel-wise and region-based multiple regression analyses were employed to examine relationship between PET metrics and clinical markers using FSL, SPM, and R software.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Preliminary results revealed a significant negative correlation between basal ganglia tau uptake and the Digit Span Reverse task or the BRIEF-A (voxel-wise, SUVr: p<0.01; BD: p<0.05). Region-based analyses (SUVr) showed basal ganglia tau uptake significantly correlated with impairments in the Digit Span Forward and Reverse task (p<0.01), working memory subtask of the NIH (p<0.05), and the BRIEF-A (‘Never’-scores, p<0.05). Significant interaction effects (p<0.05) showed that these associations were predominantly localized in the basal ganglia as compared to frontal or occipital regions. Additionally, basal ganglia atrophy was negatively associated with tau uptake (SUVr) in the basal ganglia and brainstem. Ongoing analysis explores associations with CSF/blood biomarkers (GFAP/NfL/tau).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings highlight the potential of 18F-PI-2620 as an in-vivo tau biomarker in PSP diagnosis, demonstrating significant links between tau uptake in the basal ganglia, brain atrophy, executive dysfunction, and disease severity. These insights could drive the development of new biomarkers, advancing future clinical trial prospects.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"20 S9","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.093950","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143249083","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}
A. Zarina Kraal, Hugh V. McFarlane, Jeffrey D. Pyne, Indira C. Turney, Patrick J. Lao, Jessica Mazen, Adam M. Brickman, Jennifer J. Manly
Background
High glycemic levels, indexed by hemoglobin A1c (HbA1c), heighten risk for Alzheimer’s Disease and Related Dementias (ADRD). Previous studies suggest that high HbA1c and low socioeconomic status (SES) may be associated with MRI markers of ADRD risk, including lower cortical thickness and greater white matter hyperintensities (WMH). The weathering hypothesis suggests that the stress of low SES accelerates and exacerbates physiological deterioration, leading to worsening health outcomes. However, the role of SES as a potential moderator of the associations between HbA1c and MRI markers of ADRD is underdeveloped. We hypothesized that higher HbA1c and lower SES are associated with MRI markers of ADRD risk, and the association between HbA1c and MRI markers is stronger among individuals with low SES.
Method
Participants were middle-aged adults in the Offspring Study of Racial and Ethnic Disparities in Alzheimer’s Disease (N = 616; age = 54.5±10.6; 68.6% Latinx, 21.2% Non-Latinx Black, 7.2% Non-Latinx White; 65.6% women). HbA1c level was determined from blood assays. MRI markers included cortical thickness of AD signature regions and log-transformed WMH. Confirmatory factor analysis estimated SES from self-reported income and education. Structural equation models quantified main and interaction effects of HbA1c and SES on MRI markers, adjusting for age, sex, and prediabetes/type 2 diabetes.
Result
There were no main or interaction effects of HbA1c and SES on either MRI marker, independent of covariates. However, examination of moderation by each SES indicator showed that higher HbA1c was associated with lower cortical thickness among participants with high income (unstandardized estimate = -0.0214, SE = 0.0107, 95%CI[-0.0424, -0.0003]). Effect estimates were similar in analyses restricted to individuals with prediabetes and type 2 diabetes (n = 250; age = 58.1±9.0; 72.8% Latinx, 23.6% Non-Latinx Black, 3.7% Non-Latinx White; 68.8% women).
Conclusion
HbA1c-related effects on markers of ADRD risk in middle-age may occur via neurodegenerative processes. Associations involving cerebrovascular pathways warrant further investigation. Examination of other indicators of SES (e.g., occupation, wealth, debts) and region-specific WMH may help clarify the role of SES in modifying the link between glycemic level and brain health.
{"title":"Does socioeconomic status modify the association between glycemic level and MRI markers of ADRD risk in middle-aged adults?","authors":"A. Zarina Kraal, Hugh V. McFarlane, Jeffrey D. Pyne, Indira C. Turney, Patrick J. Lao, Jessica Mazen, Adam M. Brickman, Jennifer J. Manly","doi":"10.1002/alz.094021","DOIUrl":"https://doi.org/10.1002/alz.094021","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>High glycemic levels, indexed by hemoglobin A1c (HbA1c), heighten risk for Alzheimer’s Disease and Related Dementias (ADRD). Previous studies suggest that high HbA1c and low socioeconomic status (SES) may be associated with MRI markers of ADRD risk, including lower cortical thickness and greater white matter hyperintensities (WMH). The weathering hypothesis suggests that the stress of low SES accelerates and exacerbates physiological deterioration, leading to worsening health outcomes. However, the role of SES as a potential moderator of the associations between HbA1c and MRI markers of ADRD is underdeveloped. We hypothesized that higher HbA1c and lower SES are associated with MRI markers of ADRD risk, and the association between HbA1c and MRI markers is stronger among individuals with low SES.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>Participants were middle-aged adults in the Offspring Study of Racial and Ethnic Disparities in Alzheimer’s Disease (N = 616; age = 54.5±10.6; 68.6% Latinx, 21.2% Non-Latinx Black, 7.2% Non-Latinx White; 65.6% women). HbA1c level was determined from blood assays. MRI markers included cortical thickness of AD signature regions and log-transformed WMH. Confirmatory factor analysis estimated SES from self-reported income and education. Structural equation models quantified main and interaction effects of HbA1c and SES on MRI markers, adjusting for age, sex, and prediabetes/type 2 diabetes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>There were no main or interaction effects of HbA1c and SES on either MRI marker, independent of covariates. However, examination of moderation by each SES indicator showed that higher HbA1c was associated with lower cortical thickness among participants with high income (unstandardized estimate = -0.0214, SE = 0.0107, 95%CI[-0.0424, -0.0003]). Effect estimates were similar in analyses restricted to individuals with prediabetes and type 2 diabetes (n = 250; age = 58.1±9.0; 72.8% Latinx, 23.6% Non-Latinx Black, 3.7% Non-Latinx White; 68.8% women).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>HbA1c-related effects on markers of ADRD risk in middle-age may occur via neurodegenerative processes. Associations involving cerebrovascular pathways warrant further investigation. Examination of other indicators of SES (e.g., occupation, wealth, debts) and region-specific WMH may help clarify the role of SES in modifying the link between glycemic level and brain health.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"20 S9","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.094021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143249085","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}
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