INTRODUCTION: Blood-based biomarkers offer scalable, non-invasive tools for Alzheimer's disease (AD) detection. We investigated the performance of plasma biomarkers associated with AD on the automated Beckman Coulter Access DxI 9000 analyzer. METHODS: This cross-sectional study included 262 individuals from across the AD continuum. Plasma phosphorylated tau at threonine 217 (p-tau217), amyloid beta (Aβ)42, and their ratio were measured. Diagnostic accuracy for amyloid positron emission tomography (PET) positivity (Centiloid > 20), using a dual cutoff approach, was assessed via receiver operative characteristic curve. Associations with tau PET (n = 76) were also assessed. RESULTS: The p-tau217/Aβ42 ratio showed the highest diagnostic accuracy for amyloid PET positivity (area under curve = 0.943) and the smallest indeterminate zone (8.0%). It correlated strongly and consistently with tau PET across Braak stages and with AD-related cortical atrophy. DISCUSSION: The p-tau217/Aβ42 ratio was the most reliable plasma biomarker, closely tracking tau PET. It has potentials for clinical use in diagnosis and treatment monitoring. HIGHLIGHTS: This is the first validation of the Beckman Coulter plasma immunoassay. The plasma phosphorylated tau at threonine 217 amyloid beta 42 ratio showed the highest accuracy across the full Alzheimer's disease (AD) spectrum. Plasma biomarkers correlated with tau positron emission tomography and AD-related brain atrophy. Glial fibrillary acidic protein offered complementary value reflecting astrocytic activation.

Abstract Background Assessing amyloid‐positivity in patients with mild cognitive impairment (MCI) is crucial as amyloid‐positive individuals have a higher risk of dementia conversion than amyloid‐negative patients. This study aimed to investigate whether the asymmetry of white matter lesions (WML) on T2‐fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), measured by artificial intelligence (AI) hyperintensity segmentation, could be a potential indicator for amyloid positron emission tomography (PET) positivity in patients with MCI. Method This retrospective cohort study included MCI patients who visited the memory clinic of Yeouido St. Mary’s Hospital. All participants underwent a set of clinical and neuropsychological assessments, brain MRI, and amyloid PET using [18F]‐Flutemetamol. Our in‐house AI software was utilized on paired T1 and T2‐FLAIR MRIs to process to segment and separate WML into left and right hemispheres. From the processed segmentation, we measured the subjects' individual WML differences through a volumetric assessment. Results Total 122 subjects were enrolled in this study. By the amyloid‐PET positivity, 53 and 69 patients were in the amyloid‐negative and amyloid‐positive groups, respectively. The two groups were comparable with no significant differences of age (p = 0.189), sex (p = 0.057), education years (p = 0.411) and MMSE scores (p = 0.861). However, the amyloid‐positive group had a significantly higher frequency of having an e4 allele of APOE genotype (p = 0.033) and Clinical Dementia Rating scale (p = 0.024). The average volume between hemispheres significantly differed in the amyloid‐negative group (p = 0.020) but not in the amyloid‐positive group (p = 0.220). Both groups had a larger WML volume in the left hemisphere, which did not differ significantly between groups. Conclusion Our findings suggest that evaluating the asymmetry of WML rather than the total hyperintensity lesion load is necessary in MCI patients, particularly in those without amyloid pathology. In conclusion, WML asymmetry may serve as a potential indicator of amyloid positivity in MCI patients.

Abstract Background Multimer detection system‐oligomeric amyloid‐ß (MDS‐OAß) measures plasma OAß level, which is associated with earlier pathology of Alzheimer’s disease (AD). Previous studies showed that plasma levels of MDS‐OAβ were higher in patients with dementia due to AD than in cognitive normal older adults (CN), and they correlated well with conventional AD biomarkers including standardized uptake value ratio (SUVR) of Pittsburgh compound B (PiB) and CSF level of Aβ 42 , p‐Tau, and t‐Tau. However, no previous study investigated MDS‐OAβ difference in CN with or without cerebral Aβ burden. In addition, associations among MDS‐OAß, cerebral Aß deposition, aberrance of white matter integrity, and cortical thickness in CN is not elucidated. Method We studied 34 CN with amyloid‐PET negative and 23 CN with amyloid‐PET positive results who received MDS‐OAβ, structural MRI, and diffusion tensor imaging (DTI). Result Amyloid‐PET positive group showed higher MDS‐OAß level than amyloid‐PET negative group, but two groups did not differ in WM integrity or cortical thickness. MDS‐OAβ level was significantly higher in amyloid‐PET positive group than in amyloid‐PET negative group. MDS‐OAβ positive group had significantly higher cerebral AB deposition, or mean global SUVR values, than MDS‐OAβ negative group. There was a positive correlation between MDS‐OAβ level and PET‐SUVR. In terms of DTI analysis, MDS‐OAβ positive group had significantly lower FA in the left forceps minor of corpus callosum and right superior longitudinal fasciculus than in lower MDS‐OAβ negative group. In addition, the FA values were negatively correlated with MDS‐OAβ level (figure 1). MDS‐OAB positive group showed a significant reduction in the cortical thickness in the left fusiform when compared with the MDS‐OAB negative group Conclusion Plasma MDS‐OAβ value might reflect cerebral amyloid status and global cerebral Aß retention in CN. We elucidated toxic role of OAβ by showing that the plasma OAβ value were associated with decrement of WM microstructural integrity in the early pathological process of AD. Cortical thickness did not differ according to cerebral Aβ burden but rather was associated with higher plasma OAβ level. Thus, MDS‐OAβ value might reflect earlier, and different, pathology than cerebral Aß retention measured using amyloid PET scan in CN with AD continuum.

Abstract Background Multimer detection system‐oligomeric amyloid‐ß (MDS‐OAß) measures plasma OAß level and is associated pathology of Alzheimer’s disease (AD). However, no study investigated MDS‐OAß and cerebral Aß deposition among difference stages within AD spectrum. Method We studied 40 normal control (CN), 30 amyloid‐PET (A‐PET) negative mild cognitive impairment (MCI), 31 A‐PET positive MCI, and 22 A‐PET positive dementia. Result The one‐way analysis of variance showed group difference in MDS‐OAß. Post‐hoc analysis showed that MDS‐OAß was lowest in CN group and highest in A‐PET positive MCI group. Both A‐PET negative MCI and A‐PET positive dementia groups showed lower MDS‐OAß than A‐PET positive group dementia group (MDS‐OAß: CN < A‐PET negative MCI = A‐PET positive dementia < A‐PET positive MCI) (Figure 1). MDS‐OAß showed a positive correlation with global and regional cerebral Aß deposition measure using A‐PET. Conclusion Our results suggest that MDS‐OAβ shows a reverse U‐shape: increase with disease onset or when clinical symptoms appear, even before Aß pathology is evident in A‐PET, and then elevate as disease progresses but lower down as the disease becomes severe.

INTRODUCTION: Blood-based biomarkers offer scalable, non-invasive tools for Alzheimer's disease (AD) detection. We investigated the performance of plasma biomarkers associated with AD on the automated Beckman Coulter Access DxI 9000 analyzer. METHODS: This cross-sectional study included 262 individuals from across the AD continuum. Plasma phosphorylated tau at threonine 217 (p-tau217), amyloid beta (Aβ)42, and their ratio were measured. Diagnostic accuracy for amyloid positron emission tomography (PET) positivity (Centiloid > 20), using a dual cutoff approach, was assessed via receiver operative characteristic curve. Associations with tau PET (n = 76) were also assessed. RESULTS: The p-tau217/Aβ42 ratio showed the highest diagnostic accuracy for amyloid PET positivity (area under curve = 0.943) and the smallest indeterminate zone (8.0%). It correlated strongly and consistently with tau PET across Braak stages and with AD-related cortical atrophy. DISCUSSION: The p-tau217/Aβ42 ratio was the most reliable plasma biomarker, closely tracking tau PET. It has potentials for clinical use in diagnosis and treatment monitoring. HIGHLIGHTS: This is the first validation of the Beckman Coulter plasma immunoassay. The plasma phosphorylated tau at threonine 217 amyloid beta 42 ratio showed the highest accuracy across the full Alzheimer's disease (AD) spectrum. Plasma biomarkers correlated with tau positron emission tomography and AD-related brain atrophy. Glial fibrillary acidic protein offered complementary value reflecting astrocytic activation.

Abstract Background Assessing amyloid‐positivity in patients with mild cognitive impairment (MCI) is crucial as amyloid‐positive individuals have a higher risk of dementia conversion than amyloid‐negative patients. This study aimed to investigate whether the asymmetry of white matter lesions (WML) on T2‐fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), measured by artificial intelligence (AI) hyperintensity segmentation, could be a potential indicator for amyloid positron emission tomography (PET) positivity in patients with MCI. Method This retrospective cohort study included MCI patients who visited the memory clinic of Yeouido St. Mary’s Hospital. All participants underwent a set of clinical and neuropsychological assessments, brain MRI, and amyloid PET using [18F]‐Flutemetamol. Our in‐house AI software was utilized on paired T1 and T2‐FLAIR MRIs to process to segment and separate WML into left and right hemispheres. From the processed segmentation, we measured the subjects' individual WML differences through a volumetric assessment. Results Total 122 subjects were enrolled in this study. By the amyloid‐PET positivity, 53 and 69 patients were in the amyloid‐negative and amyloid‐positive groups, respectively. The two groups were comparable with no significant differences of age (p = 0.189), sex (p = 0.057), education years (p = 0.411) and MMSE scores (p = 0.861). However, the amyloid‐positive group had a significantly higher frequency of having an e4 allele of APOE genotype (p = 0.033) and Clinical Dementia Rating scale (p = 0.024). The average volume between hemispheres significantly differed in the amyloid‐negative group (p = 0.020) but not in the amyloid‐positive group (p = 0.220). Both groups had a larger WML volume in the left hemisphere, which did not differ significantly between groups. Conclusion Our findings suggest that evaluating the asymmetry of WML rather than the total hyperintensity lesion load is necessary in MCI patients, particularly in those without amyloid pathology. In conclusion, WML asymmetry may serve as a potential indicator of amyloid positivity in MCI patients.

Abstract Background Multimer detection system‐oligomeric amyloid‐ß (MDS‐OAß) measures plasma OAß level, which is associated with earlier pathology of Alzheimer’s disease (AD). Previous studies showed that plasma levels of MDS‐OAβ were higher in patients with dementia due to AD than in cognitive normal older adults (CN), and they correlated well with conventional AD biomarkers including standardized uptake value ratio (SUVR) of Pittsburgh compound B (PiB) and CSF level of Aβ 42 , p‐Tau, and t‐Tau. However, no previous study investigated MDS‐OAβ difference in CN with or without cerebral Aβ burden. In addition, associations among MDS‐OAß, cerebral Aß deposition, aberrance of white matter integrity, and cortical thickness in CN is not elucidated. Method We studied 34 CN with amyloid‐PET negative and 23 CN with amyloid‐PET positive results who received MDS‐OAβ, structural MRI, and diffusion tensor imaging (DTI). Result Amyloid‐PET positive group showed higher MDS‐OAß level than amyloid‐PET negative group, but two groups did not differ in WM integrity or cortical thickness. MDS‐OAβ level was significantly higher in amyloid‐PET positive group than in amyloid‐PET negative group. MDS‐OAβ positive group had significantly higher cerebral AB deposition, or mean global SUVR values, than MDS‐OAβ negative group. There was a positive correlation between MDS‐OAβ level and PET‐SUVR. In terms of DTI analysis, MDS‐OAβ positive group had significantly lower FA in the left forceps minor of corpus callosum and right superior longitudinal fasciculus than in lower MDS‐OAβ negative group. In addition, the FA values were negatively correlated with MDS‐OAβ level (figure 1). MDS‐OAB positive group showed a significant reduction in the cortical thickness in the left fusiform when compared with the MDS‐OAB negative group Conclusion Plasma MDS‐OAβ value might reflect cerebral amyloid status and global cerebral Aß retention in CN. We elucidated toxic role of OAβ by showing that the plasma OAβ value were associated with decrement of WM microstructural integrity in the early pathological process of AD. Cortical thickness did not differ according to cerebral Aβ burden but rather was associated with higher plasma OAβ level. Thus, MDS‐OAβ value might reflect earlier, and different, pathology than cerebral Aß retention measured using amyloid PET scan in CN with AD continuum.

Abstract Background Multimer detection system‐oligomeric amyloid‐ß (MDS‐OAß) measures plasma OAß level and is associated pathology of Alzheimer’s disease (AD). However, no study investigated MDS‐OAß and cerebral Aß deposition among difference stages within AD spectrum. Method We studied 40 normal control (CN), 30 amyloid‐PET (A‐PET) negative mild cognitive impairment (MCI), 31 A‐PET positive MCI, and 22 A‐PET positive dementia. Result The one‐way analysis of variance showed group difference in MDS‐OAß. Post‐hoc analysis showed that MDS‐OAß was lowest in CN group and highest in A‐PET positive MCI group. Both A‐PET negative MCI and A‐PET positive dementia groups showed lower MDS‐OAß than A‐PET positive group dementia group (MDS‐OAß: CN < A‐PET negative MCI = A‐PET positive dementia < A‐PET positive MCI) (Figure 1). MDS‐OAß showed a positive correlation with global and regional cerebral Aß deposition measure using A‐PET. Conclusion Our results suggest that MDS‐OAβ shows a reverse U‐shape: increase with disease onset or when clinical symptoms appear, even before Aß pathology is evident in A‐PET, and then elevate as disease progresses but lower down as the disease becomes severe.

Abstract Background Recent studies have demonstrated the pivotal implications of the locus coeruleus (LC) and in the early phase of Alzheimer’s disease (AD). However, the effects of apolipoprotein E4(APOE4) carrier status on the LC functional connectivity (FC) in preclinical AD remain elusive. We aimed to demonstrate disparities in LC FC in preclinical AD with regard to APOE4 carrier status. Methods A total of 112 patients with who were amyloid beta (Aβ) positive([18F] flutemetamol +) were recruited in the study, and they all had normal cognition. Seed to voxel analysis was conducted to measure LC FC differences between APOE4 non‐carrier and carrier. In addition, group by amyloid beta (Aβ) interactive effects on FC values were analyzed with a general linear model. Result The LC FC with intracalcarine cortex, lingual gyrus, occipital fusiform gyrus of the both hemispheres was reduced in APOE4 carrier. Moreover, there was a statistically significant group by regional standardized uptake value ratio interactions in LC FC with frontal, occipital cortices, the precuneus and the cerebellum. Conclusion The aforementioned findings suggest that there are differential patterns of LC FC in APOE4 non‐carrier and carrier with preclinical AD, which interact with regional Aβ deposition.

Introduction: Women have a higher risk of developing Alzheimer's disease (AD) than men, with hormonal changes during menopause being a potential factor. However, the exact relationship between these hormonal changes, cognitive function, and AD pathology is not fully understood. This study investigates the differential associations between serum follicle-stimulating hormone (FSH) and estradiol levels with cognitive function and cerebral amyloid-βeta (Aβ) deposition, quantified using amyloid positron emission tomography, in postmenopausal women across the spectrum from cognitively normal aging to AD dementia. Methods: A total of 884 postmenopausal women, aged 60 years or older, were enrolled in the study. Participants were classified into three groups based on their cognitive function: cognitively normal (CN), mild cognitive impairment (MCI), and AD dementia. Results: Higher FSH levels were associated with poorer cognitive performance and greater cerebral Aβ deposition in postmenopausal women. FSH levels were highest in women with AD dementia, followed by those with MCI, and lowest in CN participants. No significant relationship was observed between estradiol levels and cognitive outcomes or Aβ burden. Further analysis showed a positive correlation between FSH levels and global as well as regional cerebral Aβ deposition. Mediation analysis indicated that FSH's impact on cognitive function was mediated by cerebral Aβ burden. Estradiol levels, however, had no significant association with either cognitive performance or Aβ pathology. Discussion: Elevated FSH, not low E2, is linked to cognitive decline and Aβ pathology in postmenopausal women. FSH may be a key risk factor for cerebral Aβ deposition and cognitive decline in older women. Further research is needed to elucidate the mechanisms involved and explore hormonal interventions for AD.

INTRODUCTION: Determining apolipoprotein E (APOE) ε4 allele status, a key genetic risk factor for Alzheimer's disease (AD), requires molecular genotyping infrastructure not widely accessible beyond specialized centers. METHODS: A fully automated high-throughput apoE E4 proteotyping immunoassay was evaluated for clinical performance (460 participants across three cohorts) and analytical validity. Concordance with polymerase chain reaction (PCR)-based genotyping and measures of analytical validity were reported. RESULTS: The apoE E4 immunoassay demonstrated 99.6% (95% confidence interval [CI]: 98.4% to 99.9%) concordance with PCR-based APOE ε4 genotype results across the pooled clinical cohort; 100.0% (95% CI: 97.1% to 100.0%) in those with AD (N = 127) and 99.4% (95% CI: 97.8% to 99.8%) in those without AD (333). The assay met analytical validity criteria for E4 isoform specificity, interference, precision, and stability. DISCUSSION: The apoE E4 immunoassay demonstrated high concordance with PCR-based genotyping and robust analytical validity, offering an accessible alternative for APOE ε4 zygosity assessment. HIGHLIGHTS: A novel high-throughput plasma-based proteotyping immunoassay for APOE ε4 zygosity classification was developed and evaluated for clinical performance and analytical validity. The apoE E4 immunoassay demonstrated high concordance (99.6%) with PCR-based APOE ε4 genotyping across a diverse international cohort, and a robust analytical profile. An apoE E4 immunoassay may offer a more cost-effective and accessible alternative to DNA genotyping approaches currently used for AD risk evaluation and anti-amyloid treatment decisions.

Additional file 1. Fig. S1. Quality control and clustering of integrated scRNA-seq data from AD-COs (#1–2) and NAC-COs (#1–2). Fig. S2. Characterization of AD-COs and NAC-COs by single-cell transcriptomic profiling. Fig. S3. Representative Ca2+ oscillation traces in NAC-CO and AD-CO#1 cocultured with either NTSCs-H or NTSCs-SC for 5–6 days. Fig. S4. Presence of Muse cells (SSEA3+/CD105+) populations in initially purified Muse cells from NTSCs and in cultured Muse cells (NTSCs-SC). Table S5. Summary of therapeutic effects according to Muse cell proportion in NTSCs.

Additional file 1. Fig. S1. Quality control and clustering of integrated scRNA-seq data from AD-COs (#1–2) and NAC-COs (#1–2). Fig. S2. Characterization of AD-COs and NAC-COs by single-cell transcriptomic profiling. Fig. S3. Representative Ca2+ oscillation traces in NAC-CO and AD-CO#1 cocultured with either NTSCs-H or NTSCs-SC for 5–6 days. Fig. S4. Presence of Muse cells (SSEA3+/CD105+) populations in initially purified Muse cells from NTSCs and in cultured Muse cells (NTSCs-SC). Table S5. Summary of therapeutic effects according to Muse cell proportion in NTSCs.