bluuebunny/crossref_metadata_2025 huggingface dataset:
Not all lipoprotein plays a crucial role in Alzheimer’s disease
Authors: An Dinghao , Xu Yun
Published: January 2025

Background

Hyperlipoprotein cholesterolemia increases the risk of Alzheimer’s disease(AD). LDL is mainly responsible for the risk. However, lipoprotein have different densities, different particle sizes, and different compositions. We wanted to know how lipoprotein increases the risk of AD and whether it is related to its particle size and different compositions.

Method

The GWAS summary data of the lipoprotein panel comes from Borges CM in 2020, data of AD is from Benjamin Woolf in 2022. We investigated the causal relationship between different‐density lipoprotein particles, their compositions, and AD by performing bidirectional Mendelian Randomization analysis. The study is divided into four parts. First, we performed correlation analyses of particle sizes of different‐density lipoprotein. Second, we performed correlation analyses of the concentration of particles of different particle sizes in different‐density lipoprotein. Third, we performed correlation analyses of the content of specific compositions in different‐density lipoprotein with different particle sizes, respectively. Fourth, we performed correlation analyses of specific compositions and specific ratios of different particle sizes in different‐density lipoprotein, respectively.

Result

In the panel, we found that some factors could increase the risk of developing AD, which included Phospholipids in IDL(p = 0.008) Free cholesterol in LDL(p<0.001) Total lipids in LDL (p = 0.001) Cholesterol in small LDL(p = 0.001) Phospholipids in large LDL(p = 0.001) Free cholesterol in medium LDL(p<0.001) Cholesterol in medium VLDL(p = 0.003) Cholesteryl esters in medium VLDL(p = 0.003) Free cholesterol in medium VLDL(p = 0.012) Cholesterol to total lipids ratio in large HDL (p = 0.033) Phospholipids to total lipids ratio in medium LDL(p<0.001) Free cholesterol to total lipids ratio in small HDL(p = 0.009) Cholesteryl esters to total lipids ratio in small VLDL(p = 0.004) Free cholesterol to total lipids ratio in small VLDL(p<0.001) Cholesterol to total lipids ratio in very large VLDL(p = 0.013) Cholesteryl esters to total lipids ratio in very large VLDL(p = 0.010). On the contrary, Phospholipids in medium HDL(p = 0.035) could decrease the risk of AD. However, we did not find other factors that affect the risk of AD.

Conclusion

We first found a genetic association between AD and different parts of lipoprotein, specifically about particle size and lipoprotein compositions. Therefore, not all lipoprotein can affect the risk of AD. The continuous advancement of electrophoresis technology allows for the stratification of different particle sizes of lipoprotein and compositions.
Potential causal association between mucosal proctocolitis and Alzheimer’s disease: A Mendelian Randomization Study
Authors: An Dinghao , Xu Yun
Published: January 2025

Background

The gut microbiota plays a certain role in Alzheimer’s disease, and various types of enteritis can also cause disturbances in the gut microbiota. Recently, researchers have substantially highlighted the effect of some enteritis on Alzheimer’s disease incidence and development. In this study, we elucidated the correlation between mucosal proctocolitis and Alzheimer’s disease and possible mechanism.

Method

The association between mucosal proctocolitis and the risk of Alzheimer’s disease was evaluated by using two‐sample Mendelian randomization(MR), Five methods were used to perform MR analysis: the inverse variance‐weighted, weighted median, MR‐Egger, Simple mode, and Weighted mode methods. Furthermore, Heterogeneity test, MR‐Egger intercept test, MR Pleiotropy Residual Sum and Outlier test, and leave‐one‐out analysis were performed to analyze sensitivity. MR‐PRESSO and MR‐RAPS were performed to further evaluate the robustness.

Result

After implementing multiple test corrections, we observed that genetic susceptibility to mucosal proctocolitis was associated with an increased risk of Alzheimer’s disease. However, a causal relationship between mucosal proctocolitis and markers of Alzheimer’s disease was not observed. We also found mucosal proctocolitis can also affect a certain microbial community that can cause a high risk of developing Alzheimer’s disease. Sensitivity analysis confirmed the robustness of the results.

Conclusion

We confirmed the causal relationship between mucosal proctocolitis and Alzheimer’s disease, thereby providing a novel viewpoint on the prevention and treatment of Alzheimer’s disease. However, we did not observe any AD‐related gut microbiota may play a mediating role. Our findings suggest the integration of intestinal system protection and maintenance of intestinal probiotics health into routine clinical care to enhance the effectiveness of Alzheimer’s disease treatment.
Robustness and generalizability of a speech‐based digital biomarker derived from recordings of the Clinical Dementia Rating (CDR) interview
Authors: Spilka Michael J , Xu Mengdan , Toth Balazs , Hashemifar Somaye , Amora Rainier , Robin Jessica , Teng Edmond , Monteiro Cecilia , Simpson William
Published: January 2025

Background

Progressive language changes are established clinical characteristics of Alzheimer’s disease (AD). Advances in Natural Language Processing (NLP) enable more objective, nuanced measurement of language, facilitating the development and validation of speech biomarkers for tracking longitudinal decline in language function. We examined the robustness and generalizability of our previously published speech biomarker score (Robin et al., 2023) in an independent clinical trial dataset.

Method

We analyzed CDR interview recordings at screening, baseline, week 25, and week 49 from 81 English‐speaking mild‐to‐moderate AD patients enrolled in the placebo arm of the Lauriet Phase 2 trial of semorinemab (NCT03828747). We extracted acoustic and linguistic features from the “recent experience” section of the interview, and computed our previously published biomarker score by combining 9 features (6 linguistic, 3 acoustic), derived from recordings from the development dataset (a subset of patients with prodromal‐to‐mild AD from the Tauriel Phase 2 study [NCT03289143]). We then compared the longitudinal trajectory, correlations with clinical endpoints and test‐retest reliability (by computing the difference between screening and baseline recordings) between the development dataset and Lauriet.

Result

Comparison of baseline speech biomarker scores confirmed that the AD population in Lauriet had more severe language dysfunction than the development dataset. The biomarker showed a significant effect of change over time (β = 0.26, p = 0.0003), in line with the development dataset (β = 0.29, p<0.0001). Test‐retest reliability was also comparable (Lauriet ICC = 0.616, p<0.0001; development ICC = 0.50, p<0.0001). Baseline correlations with clinical endpoints were broadly similar (Lauriet vs. development dataset: ADAS‐Cog11 r = 0.22 vs. r = 0.21, CDR‐SB r = 0.24 vs. r = 0.37, ADCS‐ADL r = ‐0.28 vs. r = ‐0.29), while change score correlations showed greater variation (Lauriet vs. development dataset: ADAS‐Cog11 r = 0.37 v. r = 0.17, CDR‐SB r = 0.31 vs. r = 0.45, ADCS‐ADL r = ‐0.35 vs. r = ‐0.22). While the magnitude of individual correlation values differed between datasets, all baseline and change score correlations maintained their direction of association and achieved statistical significance (p’s<0.05).

Conclusion

We replicated prior speech biomarker findings in an independent, more severe AD population, suggesting that the speech characteristics within this score are robust and aligned with clinical progression across disease stages. Additional validation work is ongoing, including the development of comparative biomarkers leveraging the combined dataset.
Salience Network Segregation Mediates the Effect of Tau Pathology on Mild Behavioral Impairment
Authors: Iordan Alexandru D , Ploutz‐Snyder Robert , Ghosh Bidisha , Rahman‐Filipiak Annalise , Koeppe Robert A. , Peltier Scott J , Giordani Bruno , Albin Roger L. , Hampstead Benjamin M.
Published: January 2025

Background

The recently developed construct of mild behavioral impairment (MBI) provides a diagnostic framework for early signs of behavioral dysfunction that may appear even before other symptoms of cognitive decline and dementia in older adults. However, the links between MBI, brain function, and Alzheimer’s disease (AD) biomarkers are unclear.

Method

Using data from 128 participants with diagnosis of amnestic mild cognitive impairment or mild dementia of the Alzheimer’s type, we test a novel model assessing direct relationships between AD biomarker status (amyloid and tau PET) and MBI symptoms, as well as mediated effects through the functional segregation of the salience, default‐mode, and frontoparietal control networks from the other high‐level, association networks.

Result

We identified a mediated effect of tau positivity on MBI through functional segregation of the salience network from the other association networks. Specifically, individuals who were positive for both amyloid and tau showed lower overall segregation of the salience network compared to those who were AD biomarker negative (β = ‐0.25, p = 0.007). Lower overall segregation of the salience network was associated with more severe MBI symptoms (β = ‐0.441, p = 0.013). There were no direct effects of AD biomarkers status on MBI.

Conclusion

Our findings suggest that the effect of tau pathology on MBI may operate through the modulation of salience network functional integrity. This mediated relationship was unique for the salience network since including the default‐mode and frontoparietal control networks in our models did not change the tau‐specific findings. To the best of our knowledge, this is the first study to integrate MBI with AD PET biomarkers and network‐level brain functionality within a unified framework.
Analysis of the types of social activity participation of older adults living in the community and the health level and quality of life by types: Applying Latent Class Analysis
Authors: Kim sang Geun , Jeong Yunyeong , Hwang chae Yeon , Park Kang‐Hyun
Published: January 2025

Background

Participation in various social activities of elderly has a significant impact on overall health and quality of life, including physical and metal health. Therefore, in this study, we aim to analyze the types of social activity participation among community‐dwelling elderly and examine differences in characteristics, health status, and quality of life according to these types of participation of social activities. Thus, we purpose to utilize the findings of this study as a foundation basis for research aimed at promoting services and intervention related to social activities of elderly in community.

Method

This study utilized the 9th wave (2022) panel data from the Korean Longitudinal Study of Elderly Employment(KLoSA). Latent class analysis was utilized to explore types of social activities. To assess the goodness of fit of the latent model, χ² (Chi‐square) test, Akaike Information Criteria (AIC), Bayesian Information Criteria (BIC), Sample‐Size Adjusted Bayesian Information Criteria (SABIC) indices, and Lo‐Mendell‐Rubin adjusted Likelihood Ratio Test (LMR‐LRT) were employed. One‐way ANOVA was conducted to examine characteristics across different types.

Result

The study included a total of 6,057 elderly individuals aged 60 and above residing in the local community for analysis. The results demonstrate four distinct types of social activity participation among the elderly. These four groups were named based on the types of social activities they engaged in: “Religious and Social Activity Centered,” “Social and Leisure Activity Centered,” “Social Activity Centered,” and “Inactive.” The analysis of characteristics across these types showed statistically significant differences in demographic factors such as age, marital status, and religion. In terms of health‐related aspects, subjective health and overall quality of life indices exhibited statistically significant differences among the types.

Conclusion

Social activities among the elderly were analyzed into four distinct types based on the activities they engaged in. The participation of elderly individuals in various social activities is considered a crucial indicator for improving health and quality of life. It is hoped that this study will serve as a foundational basis for developing services and intervention programs for elderly individuals in the community, aimed at facilitating their participation in diverse social activities.
Development and Validation of the Dementia‐Perceived Abuse and Neglect Questionnaire (D‐PANQ) among Family Caregivers of People Living with Dementia
Authors: Peter Seelia , Devi Elsa Sanatombi , Prabhu Mukhyaprana , Bhandary Rajeshkrishna , Chakrabarthy Jyothi , V Binil
Published: January 2025

Background

Abuse of older adults is a sociopolitical issue that is often hidden. People living with dementia are more vulnerable to abuse due to their cognitive and physical impairments. Caring for a person with dementia is quite challenging. The caregivers abuse the older adults they take care of due to the increasing caregiving demands, caregiver burden, stress, depression, or anxiety. The caregivers often know what the potentially abusive behaviors are and what not to do, but at times they tend to behave in an abusive way. Some of the situations that happen in a day that are abusive are not perceived as such by them due to the normalization of what they have been doing for years. A vignette‐based tool helps to collect data regarding sensitive issues like abuse. The objective of this study was (1) to analyze the psychometric properties of the Dementia‐Perceived Abuse and Neglect Questionnaire (D‐PANQ) among family caregivers of people living with dementia regarding abuse using a newly developed vignette‐based tool. (2) to assess the perception of family caregivers of people living with dementia regarding abuse.

Method

This cross sectional study will be completed among 300 caregivers of people living with dementia. The study is ongoing, with data collected from 190 caregivers. The tool is a 22‐item, 4‐point scale with a maximum score of 66. The higher scores show a high perception of abuse, and the low scores show a low perception of abuse.

Result

The interim analysis among 190 caregivers shows that the perception of abuse is high. The mean DPANQ score was 42.86, with a standard deviation of 16.01. The reliability of the tool was established by Cronbach’s alpha. It was found to be 0.82. Further analysis of the questionnaire’s feasibility, reliability, internal consistency, content validity, and construct validity (factor analysis and convergent validity) will be done once the study is completed.

Conclusion

The initial analysis shows that the tool is valid, reliable, and feasible to assess the perception of family caregivers of people living with dementia regarding abuse, and this would be the first tool to assess the perception of dementia carers towards abuse and neglect.
Communication Training For Medical Professionals: Proof Of Concept
Authors: Brown Nancy L
Published: January 2025

Background

Despite the prevalence of patients living with dementia, physicians and medical students, in particular, have received little or no dementia‐specific training to help them communicate effectively with this population. Connecting and communicating with persons living through cognitive change requires specific skills: developing empathy and identifying coping mechanisms, symbols, and the stages of resolutions for those living with cognitive decline. These skills were taught in the beta test, Validation for Physicians and Medical Provider training, based upon the evidence‐based Validation method by Naomi Feil.

Method

The pilot program included physicians and other healthcare professionals. In this single‐group design, pre‐ and post‐surveys consisted of a knowledge scale and SRDB (self‐efficacy) ranked on a Likert scale of 1 to 5 and analyzed using SPSS. Post‐training individual interviews concluded the beta‐testing. Thirty professionals enrolled in the training; eight participants completed every aspect of the beta‐testing.

Result

Despite the small sample size, the validated measurements used showed trends approaching significance in knowledge and self‐efficacy. Participants highly valued the training’s content and pedagogy.

Conclusion

Technical problems were the main reason for attrition. Overall, the Validation method was found useful in practice and improved confidence, knowledge, and communication behaviors. Improvements are needed in the choices for validated measures and the online platform. “Validation has made me a better doctor. It has changed my perspective on aging” (participant).
Site‐specific hyperphosphorylation of tau and C‐terminal alteration of PP2A catalytic subunit in tau pathogenesis seeded by proteopathic tau
Authors: Liu Fei , Gu Jianlan , Zhou Yan , Hu Wen , Wu Ruozhen , Tung Yunn Chyn , Gong Cheng‐Xin , Iqbal Khalid
Published: January 2025

Background

Regional distribution of neurofibrillary tangles consisting of hyperphosphorylated tau correlates strongly with the progression of Alzheimer’s disease (AD). Misfolded proteopathic tau templates the conversion of naive tau into a pathological state in a prion‐like fashion, which underlies the spreading of tau pathology in the brain. Whether hyperphosphorylation triggers tau aggregation or hyperphosphorylation occurs after aggregation is under much debate.

Method

In the present study, by using oligomeric tau derived from AD brain (AD O‐tau) as proteopathic tau seeds, we determined the role and molecular mechanism of site‐specific hyperphosphorylation in seeded‐tau aggregation in cultured cells and in vivo in mice.

Result

We found that seeded‐tau aggregation in cultured cells and in vivo was accompanied by site‐specific hyperphosphorylation of tau and by reduction in the level of PP2A catalytic subunit (PP2Ac) determined by a body of antibodies targeting its C‐terminus, but not its middle region. PP2Ac immunoreactivity with the C‐terminal antibodies was reversely correlated with the hyperphosphorylation of tau in cultured cells and in AD brain. Site‐specific hyperphosphorylation of tau and reduction of PP2Ac immunoreactivity were co‐existed in RIPA‐insoluble fraction and associated with seeded tau aggregation. Blocking the site‐specific hyperphosphorylation by mutating Ser/Thr to Ala suppressed the seeded‐tau aggregation and the decline of PP2Ac immunoreactivity. Knockdown and overexpression of PP2Ac enhanced and suppressed seeded‐tau aggregation in cultured cells and tau pathology in vivo, respectively.

Conclusion

These findings strongly suggest that site‐specific hyperphosphorylation of tau is essential for seeded‐tau aggregation. Site‐specific hyperphosphorylation of tau, tau aggregation, and C‐terminal alteration of PP2Ac work synergistically to produce tau pathology. Interrupting this vicious cycle may enable inhibition of the propagation of tau pathology and the progression of AD and related tauopathies.
Examining the impact of hormone therapy and Alzheimer’s disease risk factors on depressive symptoms in the Harvard Aging Brain Study
Authors: Garcia Kelly A. Lopez , Klinger Hannah M , Properzi Michael J , Gatchel Jennifer R. , Marshall Gad A , Donovan Nancy J , Shirzadi Zahra , Schultz Aaron P , Chhatwal Jasmeer P. , Sperling Reisa A , Coughlan Gillian T , Buckley Rachel F
Published: January 2025

Background

Hormone therapy (HT) is often used to manage symptoms related to menopause, but its longer‐term effects on depressive symptoms in older women remains unclear. Previous literature reports inconclusive results on whether HT use is protective against or associated with increased depressive symptoms over time in older women. The objective of this study was to examine the associations of self‐reported HT use with baseline and longitudinal later life depressive symptoms. We also investigated whether Alzheimer’s disease (AD) risk factors such as APOEe4 status, white matter hyperintensities (WMH), and Aβ status moderated the association between HT use and depressive symptoms.

Method

We identified 593 participants from the Harvard Aging Brain Study and ancillary studies (58% Female, Agemean(SD) = 72(8) years) with longitudinal data for the 30‐item Geriatric Depression Scale (GDS) and baseline self‐reported HT use for women. A subset of 355 participants had baseline Aβ status available and 266 participants had baseline WMH MRI data available. Linear regressions and linear mixed‐effects models examined the associations between baseline HT use and baseline and longitudinal GDS, using HT users as our reference group. We also tested the interaction of baseline HT use with 1. APOEe4 status, 2. Log transformed baseline WMH normalized to intracranial volume, and 3. Baseline Aβ status on longitudinal GDS. All models adjusted for age, education, and ethnicity.

Result

42% of women reported past or current HT use. HT use was not associated with GDS at baseline. HT users reported significantly greater depressive symptoms over time relative to men (β = 0.11, p = 0.035) and exhibited a sub‐threshold trend of higher depressive symptoms relative to non‐users (β = 0.10, p = 0.069). APOEe4, WMH, and Aβ status did not modify the effect of HT status on longitudinal GDS.

Conclusion

While our study revealed that HT users exhibit increased depressive symptoms over time relative to men, further research is needed to confirm this trend relative to non‐users and to better understand how AD risk factors moderate this relationship. Our findings are limited by lack of information on HT use, such as type, dose, and duration, which should be considered to provide insight into the complexities of women’s brain health in aging populations.
Impact of gantenerumab amyloid removal therapy on established Alzheimer Disease fluid biomarkers
Authors: Ibanez Laura , Li Yan , McDade Eric , Llibre‐Guerra Jorge J. , Clifford David B. , Mills Susan , Santacruz Anna , Wang Guoqiao , Supnet‐Bell Charlene , Benzinger Tammie L.S. , Gordon Brian A. , Klein Gregory , Baudler Monika , Doody Rachelle S. , Kerchner Geoffrey A. , Bittner Tobias , Atri Alireza , Bateman Randall J.
Published: January 2025

Background

Anti‐amyloid monoclonal antibody therapies have successfully removed amyloid plaque as measured using imaging techniques. However, the characteristic fluid biomarker trajectories following plaque removal remains understudied, particularly during the preclinical phases of disease. We investigated biomarker trajectories in the context of the gantenerumab open label extension (OLE) of the Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN‐TU) secondary prevention trial (DIAN‐TU‐001) in Autosomal Dominant Alzheimer’s disease (ADAD) mutation carriers.

Method

Cerebrospinal fluid (CSF) amyloid beta 1‐42/40 (ABeta 42/40) ratio, total tau, phosphorylated Tau 217 (pTau217) and microtubule‐binding region of tau containing residue 243 (MTBR‐Tau243) were measured using Immuno‐Precipitation followed by Mass Spectrometry (IP‐MS) in all participants. Linear mixed‐effects models assessed temporal changes in biomarker levels. Correlations between biomarker measurements, clinical data, and imaging parameters were evaluated, considering estimated age at onset (EYO), and dosage.

Result

During both the DIAN‐TU‐001 double‐blind and OLE phases, we observed a significant increase in the CSF ABeta 42/40 ratio, notably among presymptomatic individuals. This change approached the levels considered to be healthy (11.58%), even in participants beyond their EYO. In addition, CSF pTau 217 levels declined in the participants treated with gantenerumab compared to the placebo group during the double blind and OLE phases in both asymptomatic and symptomatic groups. Higher doses were associated with faster rates of change for both biomarkers. A significant decrease in total tau was observed across treatment groups (gantenerumab and placebo) during the OLE phase. No changes were observed for MTBR243.

Conclusion

Treatment with amyloid‐removing therapy induced changes in biomarker measurements consistent with a healthier state. Improvement in biomarker levels in individuals receiving treatment prior to their EYO supports the potential of early amyloid‐removal therapy to mitigate the risk of progression. Importantly, the rate of biomarker change was directly proportional to dosage, suggesting potential dose‐dependent benefits. Additional trials are warranted to elucidate the progression of both biomarkers and clinical symptoms after effective brain amyloid removal.
Extracellular CIRP induces neurotoxic A1 astrocytes via TREM‐1 in Alzheimer’s disease
Authors: Sharma Archna , Aylar Dilara , Lee Yongchan , Brenner Max , Marambaud Philippe , Wang Ping
Published: January 2025

Background

While A1 astrocytes are reported in Alzheimer’s disease (AD), the underlying molecular mechanisms are complex and remain elusive. Proinflammatory extracellular cold‐inducible RNA‐binding protein (eCIRP) is released by microglia in response to AD‐associated neuronal amyloid‐β. eCIRP activates the triggering receptor expressed on myeloid cells‐1 (TREM‐1). Thus, we hypothesized that increased levels of eCIRP in AD due to inflammatory stress induce A1 via astrocytic TREM‐1.

Method

ELISA was performed in the AD patients’ cerebrospinal fluid (CSF; in‐house Alzheimer’s Disease Center repository) or plasma (Precision Biospecimen Solutions, Bethesda, MD) or hTau.P301S mice (Dr. Michel Goedert, Cambridge, UK) plasma. C8‐D1a cells (ATCC) or magnetically purified primary astrocytes, from C57BL/6 mice ± small anti‐CIRP peptide M3 or from TREM1‐KO mice, were stimulated with eCIRP. C57BL/6 mice were injected intracerebroventricular (icv) with eCIRP. Expression of mRNA was quantified by qPCR, protein by immunoblotting and released levels by ELISA or R&D proteome profiler. Student’s t‐test was used for two‐group analysis, one‐way analysis of variance (ANOVA)‐SNK test for multigroup analysis, and Spearman’s‐Rho analysis for correlations, with significance if p < 0.05.

Result

Levels of eCIRP were elevated in the CSF and plasma of AD patients, in hTau.P301S mice, and plasma eCIRP strongly correlated with astrocyte activation marker glial fibrillary acidic protein (GFAP) in AD patients (Fig. 1). eCIRP strongly induced A1 astrocyte‐specific genes and astrocyte release of proinflammatory and neurotoxic factors in C8‐D1a cells, primary astrocytes and icv eCIRP‐injected mice brains. In particular, eCIRP increased Complement 3, an A1 astrocytic marker involved in neuroinflammation‐associated neurodegeneration. Primary astrocytes from TREM‐1 knockout mice were resistant to eCIRP induction of A1 astrocytes. Moreover, astrocytes exposed to eCIRP had higher TREM‐1 total and surface protein levels, increased Syk phosphorylation, and upregulated NFκB mRNA. Importantly, M3 effectively inhibited eCIRP’s induction of A1 astrocytes and their release of proinflammatory and neurotoxic mediators.

Conclusion

Collectively, our data provides a strong correlation of eCIRP with astrocyte reactivity in AD patients, identifies a novel molecular mechanism by which eCIRP induces A1 astrocytes via TREM‐1 and M3 peptide attenuation of eCIRP‐induced A1 astrocytes. These findings point to a novel therapeutic opportunity targeting neurotoxic A1 astrocytes in AD.
New proteomic signatures in Alzheimer Disease identification and Mild Cognitive Impairment Classification
Authors: Hu Manyue , Robinson Oliver J , Lill Christina C , Matton Anna , Puerta Raquel , Ruiz Agustin , Middleton Lefkos T
Published: January 2025

Background

Emerging technologies and novel biomarker tools are transforming the field of Alzheimer’s disease, allowing for a more in‐depth exploration of biological mechanisms underpinning the disease aetio‐pathogenesis. In this context, there is growing recognition of the potential of plasma proteomics for AD risk assessment and disease characterization. On the other hand, differences between proteomics platforms introduce uncertainties regarding cross‐platform applicability.

Method

Elastic net analysis was applied to 190 analytes measured by the Luminex xMAP platform in plasma from 566 participants [58 cognitively normal (CN), 396 with mild cognitive impairment (MCI) and 58 with dementia due to AD], from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Validation was conducted on 1303 participants (113 CN, 795 MCI, 395 AD) from the Spanish ACE study, which was analysed by the SOMAscan 7k proteomic platform. MCI participants were classified into MCI stable or decliners according to their follow‐up diagnosis (ADNI: 158 vs. 217, Ace: 449 vs. 346). Signatures derived from our elastic net analysis and other methods applied in prior ADNI proteomic signature studies were compared, with our approach aimed at reducing dimensionality of signatures of AD vs. CN or MCI subgroup classification.

Result

We identified a signature including 11 plasma analytes and sex, age, and APOEε4 gene status, for distinguishing AD from CN, with 94% accuracy on ADNI (sensitivity 88%, specificity 94%) and 95% on Ace (specificity 96%, sensitivity 93%). Another 19‐analyte signature with the above confounders was used for classifying MCI stable and decliners, with a 77% accuracy on ADNI (sensitivity 85%, specificity 40%) and 51% on Ace (sensitivity 68%, specificity 36%). These two signatures share one common analyte, Vitronectin, a protein found to appear in degenerative diseases related abnormal deposits, such as amyloid.

Conclusion

Compared with prior proteomic signature studies, all based on ADNI, our findings attained higher specificity and sensitivity, while utilizing a smaller panel for AD classification. They also confirm the reliability and consistency of a group of plasma proteomic biomarkers across two different platforms.
Oxford Cognitive Screen Brazilian Version: Assessment of Vascular Cognitive Impairment
Authors: Ramos Claudia Cristina Ferreira , Ogusuku Caroline Suemi , Brucki Sonia Maria Dozzi , Nitrini Ricardo
Published: January 2025

Background

Cognitive impairment is very common in stroke patients and is rarely diagnosed. Cognitive deficits involving language functions, praxis, visuospatial, visuoconstructive skills and memory are prominent. The available cognitive assessment tests do not address some specific characteristics of stroke patients and have important limitations in relation to the most compromised cognitive domains.

Method

Observational and descriptive study, with cognitively normal individuals and patients with a history of Cerebral Vascular Accident (CVA) from the Unified Health System of São Caetano do Sul and São Paulo in Brazil from September 2021 to July 2023.

Result

108 participants were included in this evaluation, 50 (46.3%) from the stroke group and 58 (53.7%) from the healthy group. The average age was 67 years for the stroke group and 69 years for the healthy group. Our total average number of years of study was 9 years. When comparing the OCS‐Br scores between the groups, we found that there was a significant difference between the groups in writing tasks, executive functions (attention, change of strategy) and memory (Table 1). The comparison of scores on the OCS‐Br by classification of cognition was carried out with a group stratified between Cognitively Healthy and Cognitive Impairment With and Without Dementia, with a statistically significant result between the groups in orientation (p<0.013), visual field (p< 0.045), free evocation (p<0.002), recognition (p<0.010) and circles in seconds (p<0.008).

Conclusion

With our results, the need for adequate monitoring and rehabilitation of post‐stroke patients becomes more evident. The advantages of the OCS‐Br are: focus on specific cognitive aspects of stroke, such as visual inattention and visual field testing; assessment in patients with aphasia and visual impairment and prognostic value to predict long‐term functioning
Alzheimer’s Biomarkers in the Community: Learnings and Best Practices from the SiteRx Neurology Network
Authors: Gautieri Daniel , Stalder Michael
Published: January 2025

Background

Alzheimer’s Disease community care is rapidly evolving as investigative therapies receive approvals and many more investigative molecules continue to show promising late phase data. While interventional approaches have been shown to have real clinical application, implementation of new diagnostics such as blood‐based biomarkers for beta‐amyloid confirmation has lagged in the community setting. This narrative explores Alzheimer’s biomarkers within the SiteRx Alzheimer’s Real‐World Data network, the challenges stakeholders (physicians, patients, and biomarker infrastructure) are facing, and best practices for adoption of continually emerging interventions and diagnostics.

Methods

SiteRx analyzes data related to the uptake of biomarkers (e.g., CSF, PET Amyloid, blood‐based) within SiteRx’s Alzheimer’s Real‐World Data network, along with HCP and practice‐level qualitative insights to identify bottlenecks in initial and sustained adoption of biomarkers in the community‐setting. This mix of primary and secondary data highlights disparities across the community ranging from provider readiness (e.g., awareness or buy‐in) to implementation readiness (e.g., connectedness with diagnostics infrastructure).

Result

While uptake of biomarker use is fragmented in the community‐setting, there is increasing utilization of diagnostics and a growing cohort of biomarker‐positive patients within the SiteRx Alzheimer’s Real‐World Data network. The primary lagging indicator of adoption is Leqembi uptake, with physicians prescribing the mAb administering 5‐10x more diagnostics than. non‐prescribers. Anecdotally, the challenge for low‐to‐no adoption physicians is primarily driven by a lack of clear direction on how to navigate the diagnostics infrastructure. On the other end, high prescribers face mounting difficulty coordinating continued diagnostic requirements for patients on Leqembi due to required support staff, limited availability of PET amyloid appointments, and other factors.

Conclusions

The uptake of Alzheimer’s diagnostics has been slow overall, but continues to increase, especially in certain geographies and practices. As more diagnostic methods emerge, providers are becoming more well‐equipped to understand the disease and develop enhanced care plans for those living with Alzheimer’s disease. In turn, SiteRx’s Alzheimer’s Real‐World Data network is enriched with biomarker‐positive patients, growing the potential pool of interested and suitable patients for breakthrough therapies, promising investigational therapies, and further utilization of disease‐characterizing diagnostics.
Facebook Interaction as a Potential Marker of Cognitive Decline
Authors: Qansuwa Esraa M , Mohamed Abdelhamid , Elbekery Aliaa , El‐Kafrawy Passent , Eldawlatly Seif , Salama Mohamed
Published: January 2025

Background

The growth of social media and the continuous improvement of machine‐learning algorithms suggest that social media‐based screening methods for mental diseases will become increasingly feasible with high accuracy in the next few years. Additionally, Artificial Intelligence, particularly predictive machine learning (ML) Models, has been established as one of the more powerful approaches to building reliable models that might be useful as an early predictor for Mental disorders. Specifically, one of the current challenges in brain disorders is identifying patients with Mild Cognitive Impairment (MCI) that might be converted to Alzheimer’s (AD) or other types of dementia. Cognitive decline in older adults is associated with decreased social interaction and behavioral changes features.

Method

Using vast quantities of historical Facebook data from participants aged 50 and above who conducted the MoCA test as a Cognitive Assessment Tool, checking the changes in their written language mistakes and a range psychological features derived from Natural Language Processing (NLP) algorithms, LIWC 2022 dataset, and emotion dataset, using supervised Classification ML tools, such as support Vector Machine Model (SVM) and XGB Model to predict MCI using among (n = 225) participants. We consider formulating Language mistakes and social interactions. Then, we will perform a longitudinal and cross‐sectional examination of the data to examine the changes in a range of features extracted from Facebook subjects’ data over time.

Result

SVM and XGB classification machine learning models show significant promising predictive results, differentiating between patients and normal subjects. SVM Recall is 66%. XGB Recall is 67.5%. Therefore, using our suggested pipeline, which shows promising primary results in building a predictive model, can detect MCI in the early stages.

Conclusion

Facebook data could allow us to investigate the relationship between objective daily activity patterns and objective psychological digital markers of cognitive decline. This would be a promising project that provides an ML model for Facebook activity features among subjects that can be correlated to cognitive changes. Additionally, it matches common diagnostic practices with knowledge acquired from Facebook. We seek to scale this project up globally and build decision support for a diagnostic framework for practitioners that can be used independently.
Lecanemab induces phenotypic change in glial and microglial cells in Alzheimer’s disease models: vitro and vivo evidences
Authors: Callizot Noelle , Henriques Alexandre , Esther Steidl , Rouviere Laura , Waly Bilal El , Wojcinski Alexandre , Poindron Philippe
Published: January 2025

Background

Alzheimer’s disease (AD) is characterized by the extracellular accumulation of senile plaques composed of beta‐amyloid (Aβ) and the intracellular deposition of neurofibrillary tangles composed of hyperphosphorylated tau (Tp). Aβ induces a chronic neuroinflammation that contributes to the neurite network disorganization and finally neuronal death.

Lecanemab, a humanized monoclonal antibody (Ab) that recognizes protofibrils/oligomers and prevents Aβ deposition, is the first US approved Ab for AD. Its mode of action especially on inflammatory cells is still vague. We investigated Lecanemab’s effects in vitro in microglial cells and astrocytes phenotype after Aβ stress and in an aged mouse brains exposed to Aβ1‐42 (model of AD) and treated with Lecanemab

Method

Primary rat cortical neurons, co‐cultured with microglia and astroglial cells were used. After 11 days of culture, cells were injured with Aβ up to 72h. Lecanemab was applied one hour before Aβ injury. After fixation, microglia and astroglia phenotype were analyzed. For both cell types, pro and anti‐inflammatory markers were assessed. Aged mice were stereotaxically infused with Aβ oligomeric fraction in CA1 hippocampal area. Animals were chronically treated with Lecanemab up to 4 weeks after the lesion. Histological analysis on brains was performed, inflammation markers were investigated.

Result

Application of Aβ induced a proliferation of astrocytes and microglial cells. In addition, a significant increase in M1 microglia was observed (TREM2/OX‐41 and Iba1) 72h after Aβ application followed with an increase of phagocytosis phenotype. A strong reduction of CD206 (M2 markers) was also detected. For astrocytes, a moderate astrogliosis was observed. Interestingly, Lecanemab treatment was able to increase number of S100A (+) cells (A2 population), associated with a moderate increase of GFAP area. In AD aged mice, cognition performances were improved and were associated with a significant reduction of brain amyloidic load in treated animals. Hippocampal section showed an increase of microglial activation (M1 and M2), and large astrogliosis.

Conclusion

Lecanemab was able to decrease Aβ1‐42‐induced toxicity and modulated the Aβ1‐42‐induced neuroinflammatory response. These important and intriguing changes were observed both in vitro and in vivo. This study attempted to decipher the complex and unclear mode of action of Lecanemab.
Sex Differences in Tau Biomarkers and Brain Functional Connectivity in Alzheimer’s Disease
Authors: Yang Jack Lei , Williamson Jordan , Yang Yuan
Published: January 2025

Background

As of 2024, an estimated 6.9 million individuals reside in the United States with Alzheimer’s Disease (AD). Previous studies suggest that AD disproportionately affects females, who exhibit a higher incidence rate, poorer performance on various neuropsychological tasks, and more significant total brain atrophy. Recent investigations reveal differences in hippocampal functional connectivity based on sex, potentially contributing to the observed sex‐related disparities in AD. Moreover, individuals carrying higher levels of the tau protein show reduced hippocampal functional connectivity.

Method

Using Resting State fMRI and T2 MRI data from participants with AD (n = 20, female = 9) and cognitively normal individuals (n = 20, female = 9) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we employed the Functional Connectivity Toolbox (CONN) for analysis.

Result

Our findings revealed differences in hippocampal functional connectivity between individuals with higher and lower levels of plasma NT1‐tau levels in each group. Additionally, sex differences in hippocampal functional connectivity were observed among AD participants with higher tau protein levels.

Conclusion

These results enhance our understanding of the complex interplay between sex, tau levels, and hippocampal function in AD. Such insights into biomarkers may inform the development of sex‐specific interventions aimed at enhancing AD treatment efficacy.
Novel fluid biomarker detects TDP‐43 loss of function in individuals at elevated risk of Alzheimer’s disease
Authors: Irwin Katherine E , Sinha Irika , Wilson Rachael E , Carlsson Cynthia M. , Zetterberg Henrik , Johnson Sterling C. , Ling Jonathan P , Wong Philip C
Published: January 2025

Background

TDP‐43 nuclear clearance and cytoplasmic aggregation occur in an estimated 30‐60% of cases of Alzheimer’s disease (AD), but this pathology can currently only be established at autopsy. Nuclear clearance of TDP‐43 leads to inclusion of cryptic exons in pre‐mRNA, some of which are spliced in‐frame and translated into proteins carrying novel cryptic exon‐encoded epitopes. We developed a Meso Scale Discovery (MSD) ELISA against the TDP‐43‐associated cryptic neoepitope within the HDGFL2 protein and found significantly elevated levels of this cryptic neoepitope in biofluids of presymptomatic ALS‐FTD (Irwin et al., Nature Medicine, 2024), indicating that cryptic HDGFL2 could serve as a biomarker for loss of TDP‐43 function. Here, we used our MSD assay to analyze TDP‐43 dysfunction in individuals at increased risk of AD due to family history.

Method

A total of 266 CSF samples from 107 individuals (average age = 66.6 years, 40.8% phosphorylated‐tau181/Aβ42 ratio positive) in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) were analyzed for cryptic HDGFL2 by MSD.

Result

Sixty‐eight samples (25.6%) showed elevated levels of cryptic HDGFL2. These cryptic HDGFL2‐positive samples had a significantly higher proportion of phosphorylated‐tau/Aβ42‐positive cases (64.1%, p = 0.001). Twenty‐nine of the 107 individuals (27.1%) analyzed were positive for cryptic HDGFL2 at least once longitudinally. In 10 of the 29 (34.5%) individuals, cryptic HDGFL2 levels increased across each longitudinal sample collection, while they decreased longitudinally in 13 (44.8%). In six (20.7%), cryptic HDGFL2 levels displayed a peak during the longitudinal sampling. Twenty‐three of the 29 individuals had associated cognitive data. Eight individuals (34.8%) were from the group with increasing cryptic HDGFL2 levels, 11 (47.8%) from the group with decreasing levels, and four (17.4%) from the group displaying a peak. Each of these individuals was cognitively normal, besides one person in the decreasing group with Mild Cognitive Impairment (MCI). In this individual, cryptic HDGFL2 levels were already elevated prior to MCI diagnosis.

Conclusion

The proportion of individuals with elevated cryptic HDGFL2 levels corresponds with the expected percentage of AD cases with co‐pathology of TDP‐43. Our findings of TDP‐43 dysfunction in many cognitively normal individuals suggest that TDP‐43 loss of function is an early event in disease that can precede symptom development.
Improving access to global neuroimaging through locally sustained technology
Authors: Harper Joshua , Evans Tavia E , Obungoloch Johnes , Adams Hieab H.H.
Published: January 2025

Background

It is estimated that at least two‐thirds of the world lacks access to neuroimaging, including Magnetic Resonance Imaging (MRI). Yet neuroimaging is one of the most informative tools for neuroscience, potentially biasing advances toward populations with access to this technology. This is evident in Alzheimer’s disease (AD) research, where genetics and environment play important roles in disease development and treatment. Recent advances in low field MRI (LFMRI) have demonstrated the utility of this affordable and portable technology, despite lower image quality. Of the existing technologies, the OSII ONE developed by the open‐source imaging initiative is the only device that has been reproduced in low resource settings using primarily local resources. Here we highlight two pilot studies in Uganda and Paraguay to build and sustain OSII ONE devices for neuroimaging studies. We present preliminary results regarding construction, sustainability, and image processing for use in AD and offer suggestions for its inclusion as a tool to increase access to neuroimaging in low‐resource populations.

Method

An OSII ONE system was reproduced in Uganda and Paraguay. In Uganda, all system components were importanted and local human resource guided by international experts was used to complete the build. In Paraguay, only key physical components not available locally were imported and all available local components (including exclusively local human resources) were used for construction.

Result

While the Uganda build was completed more quickly (11 days in Uganda, 6 months in Paraguay), quality was maintained across sites despite difference in personnel and the use of local components in Paraguay. Both projects are maintained locally and current image processing methods could provide adequate quality for brain analysis in AD.

Conclusion

We show the feasibility LFMRI in lower resource settings. Despite the reduction in image quality, valuable structural information can be obtained, extending access to rural populations. This has significant implications for the future of AD imaging in global settings especially considering recent approval of disease modifying therapies that require safety monitoring with MRI. Future work collecting paired LFMRI and conventional MRI with AD patients in South America will further demonstrate the utility of this technology in the field.