bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of Alzheimer’s disease immunotherapies using conformationally constrained β‐strands and β‐hairpins from Aβ and tau
Authors: Kreutzer Adam , Zhu Jason , Plancarte Jovanna , Ruttenberg Sarah , Nowick James
Published: January 2025

Background

Peptide antigens that mimic disease‐related conformations of Aβ and tau were designed and created, and antibodies against these peptide antigens were generated and characterized.

Method

The peptide antigens were designed to mimic β‐strands formed by Aβ and tau in the cryo‐EM structures of the Alzheimer’s disease brain‐derived fibrils. Peptide antigens were also designed to mimic β‐hairpins of Aβ and oligomers formed by the β‐hairpins. These β‐strand and β‐hairpin antigens were then used to generate antibodies in rodents. Ex vivo immunohistochemical and biochemical studies in Alzheimer’s disease brain‐tissue and cell‐based studies were performed to characterize the antibodies.

Result

The antibodies raised against the Aβ‐derived peptide antigens recognized Aβ plaques in Alzheimer’s disease brain tissue and in 5xFAD mouse brains and protected iPSC‐derived human neurons from Aβ toxicity. Biochemical characterization of these Aβ‐derived antibodies showed that the antibodies exhibit some selectivity for aggregated forms of Aβ. The antibodies raised against the tau‐derived peptide antigens recognized tau neurofibrillary tangles in Alzheimer’s disease brain tissue and inhibited tau seeding in a cell‐based tau biosensor assay.

Conclusion

Antibodies generated against conformationally constrained β‐strand and β‐hairpin antigens designed to mimic disease‐related conformations of Aβ and tau exhibit characteristics beneficial for immunotherapy, such as recognition of Aβ and tau pathology, and protection against Aβ cytotoxicity and inhibition of tau seeding.
Chemical chaperones mitigate chronic short sleep induced cognitive impairment
Authors: Sengupta Kamalini , Scherbakova Katya , Mason Sydney , Naidoo Nirinjini
Published: January 2025

Background

Epidemiological studies indicate that chronic short sleep and/or disrupted sleep are all associated with metabolic dysfunction, cardiovascular risk, cognitive impairments, and increased risk for Alzheimer’s disease. We have shown that acute sleep deprivation disrupts proteostasis, leading to the activation of an adaptive endoplasmic reticulum (ER) stress response known as the unfolded protein response (UPR). However, prolonged ER stress triggers the integrated stress response, which has been implicated in memory impairments. In this study, we investigated the effects of chronic short sleep (CSS) exposure in young adult wild‐type (WT) mice on learning and proteostasis in the presence and absence of chaperone therapy.

Method

2‐month‐old male and female C57BL/6 mice underwent 4 weeks of CSS for 8hrs/day; 3 days/week by exposure to an enriched environment with or without 4‐phenyl butyrate (PBA) treatment. Control mice were left undisturbed, (n = 10/group/condition). Following CSS and recovery for 2 weeks mice were tested for hippocampal dependent learning. Brains were harvested for histology and biochemical analyses.

Result

Spatial object recognition testing revealed no differences between any of the groups 2 weeks post CSS. However, SOR at 5 weeks post CSS revealed that the vehicle treated male CSS mice performed worse than the rested vehicle treated mice (p<0.02) and the PBA treated CSS mice performed better than the saline treated CSS mice (p<0.04). Similar results were observed in the female mice but at 7 weeks post CSS. Preliminary histological analyses for integrated stress markers indicate that PBA reduces PERK activation and signaling in the hippocampi of CSS mice. Analyses of other markers are in progress.

Conclusion

Our data suggest that relieving proteostatic stress with chemical chaperones mitigates the effects of CSS on learning and memory.
Diet, APOE‐e4, and cognition in middle‐aged women at increased risk of Alzheimer’s disease
Authors: Wessinger Chadsley M , Park Kyoung Shin , DuBois Samantha L , Kibildis Samuel , Som‐Pimpong Hadassah , Vance Jarod C , Armstrong Brittany D , Wideman Laurie , Etnier Jennifer L
Published: January 2025

Background

Improving modifiable risk factors, like diet quality, can protect against Alzheimer’s disease (AD). The association between diet and cognition in midlife as a function of APOE‐e4 genotype, a strong risk factor for AD, remains unknown. Therefore, this study examined the relationship between dietary intake and executive function (EF) in middle‐aged sedentary women with a family history of AD (FH+), and if the association was moderated by APOE‐e4 carrier status.

Method

Baseline data from an ongoing clinical trial (NIH‐R01AG058919) were analyzed. Participants (n = 102, age = 56.9±5.8 yrs) were cognitively normal, middle‐aged women with (FH+). APOE genotype was determined from passive drool saliva samples (carriers, n = 41, non‐carriers, n = 61). Dietary data were collected using the Diet History Questionnaire III (DHQ‐III) and Healthy Eating Index (HEI), a measure of diet quality, was computed based on adherence to the Dietary Guidelines for Americans. Core EF was assessed via NIH Toolbox Flankers Test and Spatial Working Memory test (SWM). Linear regression moderation analyses were conducted using PROCESS v4.2 in SPSS including Flankers and SWM as the outcome, HEI as the predictor, APOE‐e4 carrier status as the moderator, and age, BMI, and education as covariates.

Result

HEI did not predict Flankers performance after controlling for covariates (p = 0.14). However, the interaction between HEI and APOE‐e4 status trended towards significance (p = 0.05). After controlling for covariates, better HEI scores predicted better SWM performance (p<0.001). The interaction between HEI and APOE‐e4 carrier status was also statistically significant (p<0.05), suggesting APOE‐e4 carrier status moderated the relationship between HEI and SWM performance. For both the Flankers and SWM, better HEI predicted better EF in non‐carriers (p<0.05 and p<0.01, respectively) but not in carriers.

Conclusion

While better HEI predicted better EF in non‐ APOE‐e4 carriers, carriers did not experience this effect, suggesting that improving diet quality may not offset the negative effects of APOE‐e4 on cognition in middle‐aged women at increased risk of AD. Future research should explore if the effects of prescriptive dietary interventions on cognition vary by APOE genotype. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Chimeric antigen receptor T cell targeting colony‐stimulating factor 1 receptors alleviates amyloid‐β and tau pathologies in Alzheimer’s disease‐pathologic male mice
Authors: Xu Jun , Wang Yanli , Yu Feng , Wang Xiaohong , Jiang Jiwei , Jiang Tianlin
Published: January 2025

Background

Microglia play a critical role in the pathogenesis and development of Alzheimer’s disease (AD). Selective small‐molecule colony‐stimulating factor 1 receptors (CSF1R) inhibitor, designed to deplete microglia, could be used to meliorate AD. This study aimed to investigate the effects and mechanisms of chimeric antigen receptor T (CAR‐T) cells targeting CSF1R in 6‐month‐old APP/PS1 male mice.

Method

The Morris water maze test, Y‐maze test, tail suspension test, swimming test, nesting score assay, and three‐chamber social interaction assay were performed to assess cognitive function. Western blotting, immunofluorescence staining, enzyme‐linked immunosorbent assay, and Bio‐Plex Pro Mouse Cytokine 23‐plex assays were conducted to explore AD‐core pathologies, neuroinflammation, microglial activation and polarization, and pyroptosis.

Result

iCSF1R.CAR‐T cells ameliorated cognitive deficits and reduced β‐amyloid load, tau hyperphosphorylation, and synapse‐related proteins, as well as microglial activation and polarization in 6‐month‐old APP/PS1 male mice. Furthermore, iCSF1R.CAR‐T cells significantly inhibited pyroptosis and attenuated neuroinflammation in these mice.

Conclusion

The results suggest that iCSF1R.CAR‐T cells improve cognitive decline and neuroinflammation, possibly by suppressing caspase‐1/GSDMD‐mediated pyroptosis. Consequently, iCSF1R.CAR‐T cells could be a potential therapeutic approach for AD and other neurological disorders characterized by microglial dysfunction.
Investigation of structural connectivity in the whole brain and frontoparietal network in groups at risk of Alzheimer’s disease dementia
Authors: Tahara‐Eckl Lenore T , Morgan Catherine A , Roberts Reece P , Dell'Acqua Flavio , Kirk Ian J , Melzer Tracy R , Dalrymple‐Alford John C , Anderson Tim J , Cutfield Nicholas J , Tippett Lynette J
Published: January 2025

Background

Brain connectivity patterns, measured with Magnetic Resonance Imaging (MRI), have been recently studied as a potential biomarker for Alzheimer’s disease dementia (AD). A ‘disconnected brain’ has been associated with greater cognitive impairment in pathological aging (Bennett & Madden, 2014), but it is unclear how this occurs in groups at risk of AD.

Method

Participants (n = 227; aged 55+ years) from the Dementia Prevention Research Clinic, New Zealand, were classified as control (C; n = 35), subjective cognitive decline (SCD; n = 60), single‐domain amnestic mild cognitive impairment (aMCI; n = 54), multiple‐domain MCI (mMCI; n = 52), and AD (n = 26). Longitudinal changes (over two years) were investigated in a subset (total n = 119). Using diffusion MRI, we measured the white matter connections between brain regions with fiber bundle capacity (FBC), a proxy of white matter connection strength (Smith et al., 2022).

Result

Cross‐sectionally, a significant linear trend of lower FBC was found across groups (C > SCD > aMCI > mMCI > AD; p < .05), mostly affecting interhemispheric connections (see Figure 1). Over time, FBC significantly decreased in only one connection between the left precentral and left parahippocampal region, but several intrahemispheric connections FBC connections increased over time (see Figure 2). A significant interaction (F(4, 114) = 10.60, p < .001, η2
= 0.27) showed that the AD group had significantly decreased structural connectivity than all other groups over time (see Figure 3).

Conclusion

We explored different threshold/processing strategies to ensure robust results. The preliminary results show the following: widespread disruption in structural connectivity was found cross‐sectionally in groups at higher risk of AD. Lower interhemispheric structural connectivity across groups may reflect degenerated commissural white matter tracts (e.g., corpus callosum) found in MCI and AD. The unexpected increasing intrahemispheric structural connectivity over time may suggest some structural reorganization, possibly in response to disrupted interhemispheric connections, or inflammation of the tracts. Alternatively, a general degeneration of commissural tracts may also explain an apparent increase of associative connectivity.

Bennett & Madden (2014). Neuroscience. https://doi.org/10.1016/j.neuroscience.2013.11.026

Smith et al. (2022). Aperture Neuro. https://doi.org/10.52294/apertureneuro.2022.2.neod9565
Intercept‐AD: Development and qualification of a highly sensitive immunoassay to detect total sabirnetug (ACU193) in human CSF
Authors: Zhang Hao , Monsheimer Sarah , Gillies Jennifer , Johnson Derrick , McOwen Nathan , Cline Erika N , Rafizadeh Mahsan , Dean Robert A , Moore Jerome A , Jerecic Jasna
Published: January 2025

Background

Sabirnetug (ACU193) is a humanized monoclonal antibody targeting soluble amyloid beta (Aβ) oligomers, which are early contributors to the pathogenesis of Alzheimer’s Disease (AD). An ultrasensitive assay was developed to measure sabirnetug pharmacokinetics (PK) in CSF of individuals with early AD in the Phase 1 study INTERCEPT‐AD (NCT04931459).

Method

The immunoassay was developed on the Meso Scale Diagnostics (MSD) S‐PLEX with improved sensitivity through TURBO‐TAG® technology. Twenty‐four anti‐sabirnetug antibody pairs were screened. Assay selectivity, target interference, dilutional linearity, and stability were evaluated. Assay accuracy and precision were tested, and the lower limit of quantitation (LLOQ) was determined. Target interference was tested by spiking various concentrations of Aβ oligomers and monomers into the sabirnetug calibrators prepared in CSF. Total drug (sabirnetug bound and unbound to AβOs) concentrations were measured in individual study participant CSF samples.

Result

Two anti‐idiotypic antibodies against sabirnetug were selected for capture and detection based on sensitivity and background of blank matrix. Final minimal required dilution (MRD) was 1:4. Optimized concentrations for capture and detection antibodies were 0.0625 µg/mL and 0.2 µg/mL. Assay stability was 12 hours room temperature and 5 freeze/thaw cycles. No interference with recovery of standard curve was observed with Aβ oligomers or monomers. Dilutional linearity data showed accurate dilution up to 1:65,536. Five selectivity CSF samples were spiked with sabirnetug at high, medium, and low doses. Recovery of selectivity samples at all doses met acceptance criteria. Nine of 10 independent accuracy and precision runs met acceptance criteria. LLOQ (6 pg/mL) and upper limit of quantitation (6000 pg/mL) were established through 9 reproducibility runs. All pre‐dose CSF sabirnetug concentrations were <LLOQ. All post‐dose concentrations were measurable in a dose‐dependent manner.

Conclusion

An ultra‐sensitive CSF total sabirnetug immunoassay was successfully developed on the MSD S‐PLEX platform. Assay qualification demonstrated sensitivity, accuracy and precision, selectivity, specificity, dilutional linearity, and stability of the method. Analysis of CSF samples collected during INTERCEPT‐AD showed the method is applicable for quantification of total drug exposure of sabirnetug in clinical trials.
Study Protocol: Quantitative evaluation of The Agitation in Alzheimer’s Screener for Caregivers AASC™, a novel tool for improving recognition of agitation in Alzheimer’s dementia
Authors: Clevenger Carolyn K , Brubaker Malaak , Jackson William C , Stroud Jared , Peschin Sue , Fehnel Sheri , Brown T. Michelle , Bratlee‐Whitaker Emily , Bucior Iwona , Patel Mehul , Grossberg George T
Published: January 2025

Background

Agitation, manifesting as aggressive and non‐aggressive behaviors, is one of the most common neuropsychiatric symptoms in Alzheimer’s dementia, presenting in approximately half of all patients. Despite the high prevalence, recognition of agitation in Alzheimer’s dementia (AAD) remains a challenge that impacts timely diagnosis and treatment. The International Psychogeriatric Association (IPA) established a new standard definition of agitation in cognitive disorders, which provides guidance for advancing recognition and improving patient care. The Agitation in Alzheimer’s Screener for Caregivers (AASC™), an easy‐to‐use and pragmatic tool, was developed based on IPA criteria to support caregivers and healthcare professionals (HCPs) in recognizing AAD, thereby facilitating caregiver‐HCP discussions and supporting timely treatment planning.

Method

The AASC™ was developed and qualitatively evaluated through a rigorous, iterative process involving clinical experts, patients, and caregivers. For quantitative validation, this prospective, multisite, single‐visit observational study will calculate predictive metrics for the identification of agitation by comparing responses on the AASC™, completed by caregivers, to HCPs judgement based on implementation of the IPA criteria (Figure 1). Community‐dwelling patients must have a recorded diagnosis of Alzheimer’s dementia; caregivers must be aged 18‐85 years, provide patient care ≥10 hours/week, and attend the office visit. Data will be collected and analyzed in 2 parts: an interim analysis (n = 50 dyads) will determine the rate of agreement (yes/no), and a final analysis (n = 150 dyads) will determine sensitivity and specificity of the AASC™. Caregiver‐reported items include caregiver and patient demographics and AASC™ responses. HCPs will complete assessments for the presence of IPA‐defined agitation and the severity of Alzheimer’s dementia.

Result

Results will include: descriptive statistics, the percentage agreement and Cohen’s kappa coefficient characterizing the interrater reliability between the caregiver‐completed AASC™ and IPA‐based HCP decision (part 1), sensitivity, specificity, positive and negative predictive values of the AASC™ against the HCP decision, goodness of fit metrics (e.g., concordance), and receiver operating characteristic curves (part 2).

Conclusion

The AASC™ was developed following a rigorous process established to support its medical credibility and implementation in clinical practice. Results from this study will quantitatively validate the AASC™, leveraging caregiver observations to aid in facilitating earlier identification and treatment of AAD.
Research Trends on Social Isolation: A Bibliometric Analysis
Authors: YANG HYUN , Shin Jiwon , Yun Sohyeon , Kim Inhye , An Hyunseo , Park Hae Yean
Published: January 2025

Background

Research on social isolation has been ongoing, recognizing it as a significant social problem due to the disruption or absence of meaningful relationships providing essential resources for life maintenance. This study aims to analyze the social isolation research trend using quantitative bibliographic methods.

Method

This study collected literature containing 'social isolation' in the title using the Web of Science database and analyzed the number of publications anually and research fields. VOS viewer generated a visualization map based on document relationships, along with academic journals, countries/regions, institutes, and keyword analyses. Additionally, CiteSpace analyzed research keyword trends on social isolation.

Result

From 1980 to March 4, 2024, 2,874 documents were surveyed, with a rapid increase in publications from the 2010s. Neuroscience dominates, with PLOS One leading in publications. The United States leads in research activity, but influential studies from British institutes have a higher total link strength. Keyword analysis highlights ‘Loneliness’, ‘Health’, ‘Depression’, and ‘Mortality’. The top three keyword clusters were classified through the analysis of keywords by time, and each was described as ‘harmfulness of social isolation and loneliness’, ‘social isolation and mental health’ and ‘deepening of social isolation and influencing factors’.

Conclusion

This study identifies research trends in social isolation, providing a basis for future research revival and development
E2025, a novel anti‐EphA4 antibody, enhances EphA4 cleavage, and suppresses tau pathologies in a transgenic model of AD
Authors: Inoue Eiji , Yamada Akio , Deguchi Maki , Yamamoto Ikuko , Arita Yoshihisa , Nakatani Aki , Kawakatsu Tomomi , Nakatani Ryunosuke , Sakamoto Yoshimasa
Published: January 2025

Background

Synaptic degeneration is characteristic of neurodegenerative diseases. Amyloid‐beta (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau are known to induce the synapse pathologies directly or indirectly in Alzheimer’s disease (AD). EphA4 is a member of the ephrin receptor subfamily which is predominantly expressed in the brain. Activation of the EphA4 is involved in neurodegeneration in several neurological diseases, including AD. E2025 is a humanized anti‐EphA4 antibody specifically binding to EphA4. We provide evidence that our novel anti‐EphA4 antibody E2025 suppresses neurodegeneration by modulating the EphA4 via direct binding to EphA4.

Method

E2025 was characterized in several in vitro assays for evaluating binding property of E2025 to EphA4, receptor subfamily specificity and potential to inhibit ligand binding. The pharmacological effects of E2025 were assessed using rat primary cultured hippocampal neurons. The in vivo effects of E2025 were investigated in human Tau P301L transgenic mice (Tau tg mice) by immunohistochemical analysis.

Result

E2025 specifically bound to EphA4 with high affinity, inhibiting binding of its ligand to EphA4. In rat primary cultured neurons, E2025 enhanced cleavage of EphA4. In vivo experiments demonstrated that repeated injection of mouse surrogate antibody of E2025 significantly suppressed tau pathology measured by anti‐phosphorylated tau (AT8) antibody.

Conclusion

E2025 specifically suppresses the EphA4 pathway via multiple modes of action, and suppresses progression of tau pathology in a transgenic tau model of AD.
A spouse’s perspective on communication breakdowns and supportive strategies for semantic variant primary progressive aphasia
Authors: Nakkawita Surani G , Utianski Rene L
Published: January 2025

Background

The language symptomology associated with semantic variant primary progressive aphasia (svPPA), namely word finding difficulties with loss of word meaning, leads to multimodal communication difficulties. Given that communication plays an intricate role in establishing and sustaining relationships, svPPA can impact relationships, including those with spouses, in a manner that can only be understood by firsthand experiences. This study aimed to describe a spouse’s experiences of communicating with an individual with svPPA along with the role of communication supports and expectations for speech‐language therapy.

Method

A semi‐structured interview using open‐ended questions was conducted with the spouse of an individual with svPPA. The interview transcript was reviewed and analyzed using thematic analysis by both authors.

Result

The themes that emerged when discussing living with an individual with svPPA included: the role of communication in their prior life; changes in communication and behavior; emotional impact; adjustments and accommodations; and community engagement and supports. Themes associated with communication supports included: external tools; adaptive strategies; individualization and adaptation; and utility. The spouse in the current study described a tool, specifically a notebook in the form of a dictionary that was initiated and developed by the individual with svPPA. The tool increased his confidence in communication as it aided comprehension and recognition of words. Caregiver inclusion, learning about the patient, and evolving strategies are themes surrounding the spouse’s expectations from speech therapy.

Conclusion

The study revealed challenges in the spouse of an individual with svPPA understanding and expressing thoughts to her partner, which resulted in feeling more distant as well as changes in social dynamics. The study also describes the benefits of communication supports for both the spouse and the individual with svPPA. Additionally, the study revealed the important role the SLP, and the community plays in enhancing well‐being. Although the findings from the current study cannot be ubiquitously generalized, it provides insight into the changing dynamics of a couple navigating svPPA and reiterates the importance of including patients and their care partners in treatment planning and the benefit of communication supports and speech therapy across the disease course.
Safety of higher doses of gantenerumab in the open‐label extension of the DIAN–TU‐001 trial
Authors: Llibre‐Guerra Jorge J. , Li Yan , Yen Daniel , Joseph‐Mathurin Nelly , Wang Guoqiao , Aschenbrenner Andrew J. , Xiong Chengjie , Hassenstab Jason J. , Gordon Brian A. , Benzinger Tammie L.S. , Perrin Richard J. , Hofmann Carsten , Wojtowicz Jakub , Atri Alireza , McDade Eric , Bateman Randall J. , Clifford David B. ,   Dominantly Inherited Alzheimer Network Trial‐Unit.
Published: January 2025

Background

The double‐blind (DB) period of the DIAN–TU‐001 phase 3 trial with gantenerumab provided evidence of significant but incomplete reduction of amyloid plaques, cerebrospinal fluid total tau, and phospho‐tau181 in dominantly inherited Alzheimer’s disease (DIAD).1Subsequently, eligible participants transitioned to an open‐label extension (OLE) period using higher doses of gantenerumab (1500mg SC‐administered every two weeks [q2w]).

Method

73 DIAD participants entered the OLE period. All participants titrated gantenerumab doses and received at least 3 doses at 120, 255, 510, and 1020mg‐q4wk. Subsequently, titration continued with 1020mg‐q2w for 6 doses and then to 1500mg‐q2w. During the OLE period, 62/73 (84.9%) participants completed titration to the higher doses (1020‐1500mg‐q2w).

Result

Overall, 30.1% (22/73) of the participants experienced ARIA‐E during the OLE (Figure 1); among those, 72.7% (n = 16/22) experienced ARIA‐E at higher doses (1020‐1500mg‐q2w). 2/3 (67%) APOE4 homozygous participants developed ARIA‐E, while 5/19 (26%) and 10/51 (19%) heterozygous or noncarriers developed ARIA‐E. Radiologically, 56.3% of the ARIA‐E episodes at higher doses were multifocal and had a predominant occipital distribution. The largest cross‐sectional diameter of ARIA‐E at initial findings ranged from 3 to 81mm. ARIA‐E lesions improved, generally, while dosing was held with a mean time for ARIA‐E resolution of 59.5 days. ARIA‐E frequency was higher in PSEN1 and APP variants (14/61 (23.0%) and 2/7 (28.6%), respectively) compared to PSEN‐2 variants (0/5). Most of the ARIA‐E cases (16/22) co‐occur with ARIA‐H; however, ARIA‐H also occurred in 14/51 participants who never had ARIA‐E. ARIA‐H risk increases as the disease progresses and is less frequent during asymptomatic phases of the disease and EYO ←10 (Figure 2).

Conclusion

Safety data from the DIAN‐TU‐001 OLE study indicate that tripling the dose of gantenerumab is well tolerated in DIAD populations, with the incidence and severity of adverse events remaining comparable to the DB period1,2 and without new/unexpected safety findings. Most ARIA‐E episodes occurred after titration to doses of 1020‐1500mg‐q2w (16 of 22 participants with ARIA‐E in the OLE) and within the initial 3‐4 months of receiving the higher doses. Risks for ARIA‐E in DIAD parallel reported risks for gantenerumab in sporadic AD, including ApoE4 status and number of MCH.3
Five‐year changes in 24‐hour sleep‐wake activity and risk of mild cognitive impairment and dementia among older women
Authors: Milton Sasha , Cavaillès Clémence , Ancoli‐Israel Sonia , Stone Katie L , Yaffe Kristine , Leng Yue
Published: January 2025

Background

Sleep and circadian disruption have been associated with cognitive impairment in older adults. However, little is known about the longitudinal change in 24‐hour sleep‐wake activity in oldest old adults and how profiles of sleep‐wake changes may be associated with risk of mild cognitive impairment (MCI) and dementia.

Method

We studied 769 women (mean age = 82.5 ± 2.9 years) without cognitive impairment at baseline who had nighttime sleep (sleep duration, sleep efficiency, and wake after sleep onset), napping (duration and frequency) and circadian rest‐activity rhythm (RARs; acrophase, amplitude, mesor, and robustness) parameters assessed using actigraphy at baseline (2002‐04) and follow‐up (2007‐08). The five‐year changes in all parameters were included in a hierarchical clustering on principal components analysis to identify patterns of sleep changes. We used multivariable multinomial logistic regression to evaluate the associations between these patterns and MCI and dementia (assessed at follow‐up).

Result

During a mean follow‐up of 5.0 ± 0.6 years, 184 (24.0%) and 101 (13.1%) women developed MCI and dementia, respectively. We identified three sleep change profiles: 340 (44.2%) women with Stable Sleep (SS; stable sleep or slight improvement), 263 (34.2%) with Declining Nighttime Sleep (DNS; decreased nighttime sleep quality and duration and disrupted circadian RAR), and 166 (21.6%) with Increasing Sleepiness (IS; significant increases in both nighttime and daytime sleep duration and disrupted circadian RAR). After adjustment for age, race, education, body mass index, diabetes, hypertension, myocardial infarction, antidepressant use and baseline cognition, women with DNS [odds ratio, OR (95% confidence interval, CI) = 1.86 (1.01,3.42)] or IS [OR (95% CI) = 2.36 (1.21,4.61)] had approximately twice the risk of dementia compared to women with SS; patterns of sleep changes were not associated with MCI [OR (95% CI) = 0.72 (0.47,1.12) and 1.00 (0.61,1.64) for DNS and IS, respectively].

Conclusion

Compared to those with stable sleep, older women with either declining nighttime sleep or increasing 24‐hour sleepiness over a five‐year period were twice as likely to develop dementia but not MCI. Decline in sleep health may be an important risk factor or marker of dementia in oldest old women.
Impact of Icosapent Ethyl on Lipids, Blood Pressures, and Adverse Events in Cognitively Healthy Veterans Participating in the BRAVE Study
Authors: Cardenas Cecilia A. , Van Hulle Carol A. , Zylstra Hannah , Cronin Kate , Cole Aleshia , Beckman Elena , Eierman Allison C , Blazel Madeleine , Lazar Karen K , Johnson Kevin M. , Rivera‐Rivera Leonardo A. , Chapell Richard , Zetterberg Henrik , Gleason Carey E. , Johnson Sterling C. , Asthana Sanjay , Carlsson Cynthia M.
Published: January 2025

Background

The omega‐3 fatty acid eicosapentaenoic acid (EPA) has positive benefits for cardiovascular risk, reducing inflammation and improving endothelial function. Evidence suggests that Icosapent ethyl, a purified form of EPA, can improve cardiovascular outcomes in at‐risk patients. Veterans are at higher risk for vascular dysfunction, a risk factor of Alzheimer’s disease (AD), thus improving vascular health may be pivotal for delaying or preventing AD among Veterans.

Method

Cognitively healthy VA‐eligible Veterans at William S. Middleton Memorial Veteran’s Hospital in Madison, Wisconsin ages 50 through 75 were invited to enroll into an 18‐month randomized, placebo‐controlled, double‐blind, parallel‐group clinical trial which assessed the efficacy of Vascepa® IPE. 206 Veterans were screened for exclusion criteria, leading to the randomization of 131 Veterans to either the placebo or 4mg daily IPE. Triglyceride, low‐density lipoprotein (LDL) cholesterol, and blood pressure were collected at baseline, 9‐months, and 18‐months. New adverse events were self‐reported at all study visits. Lipid levels, blood pressure, and new adverse events were analyzed to determine any differences between Veterans receiving the study treatment or placebo.

Result

Our preliminary analysis indicated no differences for triglycerides, systolic and diastolic blood pressures, and LDL cholesterol between treatment and placebo at baseline (p‐value range: 0.552‐0.880). Cohen’s d values for these ranged from 0.026‐0.108 at baseline. Individuals in the placebo group reported more new adverse events than treatment group (Fisher test = 0.007). Analyses examining if there is any significant change in lipids and blood pressure due to study drug over study duration will be presented at the conference.

Conclusion

Placebo and treatment groups were well balanced in relation to baseline health measures. Study drug was well tolerated. Analyses of study drug efficacy are ongoing.
Development of Alzheimer’s Disease‐Related Blood Biomarker in Long COVID Patient
Authors: Ruchisrisarod Chanida
Published: January 2025

Background

The COVID‐19 pandemic has a significant global health impact. A substantial number of infected individuals continue to experience post‐acute sequelae that affect daily life activities. This study aims to assess blood biomarkers for Alzheimer’s disease, inflammatory markers, and antibody indices related to various organ symptoms, particularly neuropsychiatric and other pro‐inflammatory conditions, in Long COVID patients.

Methods

Patients with symptoms as defined in criteria regardless were recruited in this study. Assessment on clinical conditions was done. Blood samples were collected for analysis of antibodies to COVID. Cytokines assay and Assay for accumulation of abnormal beta amyloid as ratio between 42/40, p‐Tau 181 and brain damage markers (NFL neuro filament light chain and GFAP glial fibrillary acidic protein) was also done in parallel. Data analysis performed in correlation with clinical symptoms.

Results

One hundred and seventy‐five individuals. All antibody panels were similar in pattern except antibody to N protein, indicative of infection found almost exclusively in patient. Antibody to ACE 2 was found in approximately 10% and much diminished thereafter suggesting a nonsignificant role in contributing prolonged symptoms. Cytokine profiling determined as individual group and between groups of all visits followed roughly similar pattern in both groups with markedly elevated IL‐1b, gamma interferon, IL‐12p70 and IL‐33. Cytokine responses in patients who had amyloid positive were gamma interferon IL 33, IL10 IL 17a and IL 18, IL10, IL 18 and IL12p70 in Tau positive IL 10, IL 18, IL33, IL6 and IL12p70 in NFL positive. GFAP was prominent in patient. This suggests that brain damaging process may not entirely resolved since astrocyte activation (GFAP positive) leads to amyloid induction and Tau pathology albeit disappearance of all symptoms. This is also true in cytokines response that remained elevated.

Conclusions

This knowledge can be applicable not only to the current pandemic but also to future ones. Significant associations between specific neurological biomarkers and long COVID symptoms have been observed. Further studies can attempt to identify neurological biomarkers in the blood and utilize them as diagnostic and management tools for long COVID patients in clinical practice.
Moderate coffee and tea consumption is associated with slower cognitive decline: data from UK Biobank
Authors: Gardener Samantha L , Sewell Kelsey R , Brown Belinda M. , Martins Ralph N , Rainey‐Smith Stephanie R
Published: January 2025

Background

Worldwide, coffee and tea are two of the most popular beverages consumed. Studies have suggested a protective role of coffee and tea, including reduced risk of Alzheimer’s disease. However, longitudinal data from large cohorts of older adults reporting associations of coffee and tea intake with cognitive decline is limited.

Method

Cognitively unimpaired participants (n = 8,451) from UK BioBank (≥60 years of age) with at least 2 follow up visits (average follow up time 8.83 years) were included. Baseline self‐report coffee and tea intake (cups per day) were collected using a questionnaire. Cognitive assessment included Pairs Matching test (errors), Reaction Time test, Numeric Memory test, and Fluid Intelligence. Linear mixed models assessed the relationship between categorical coffee and tea intake and cognitive outcomes, including covariates age, sex, qualification, Townsend deprivation index, ethnicity, Apolipoprotein E ε4 status, and body mass index.

Result

Daily coffee intake predicted the slope of decline in Fluid Intelligence across follow‐up (β = ‐0.02, SE = 0.007, FDR corrected p = .004). Those never consuming coffee and those with moderate coffee consumption (1‐3 cups) had slower declines in Fluid Intelligence compared to those with high coffee consumption (³4 cups, β = 0.06, SE = 0.02, p = .005; β = 0.07, SE = 0.02, p<.001, respectively).

Daily tea intake predicted decline in Fluid Intelligence across follow‐up (β = 0.02, SE = 0.007, FDR corrected p = .044), such that those who never drank tea showed a greater decline in Fluid Intelligence compared to those who had moderate and high tea consumption (β = 0.06, SE = 0.02, p = .009; β = 0.06, SE = 0.02, p = .003, respectively).

Conclusion

Our results support the hypothesis that coffee and tea intake may be a protective factor against cognitive decline, particularly for maintaining Fluid Intelligence. However, our results show an upper limit to coffee intake with a maximum of 3 cups/day being consumed for beneficial effects, and no coffee intake being more beneficial than ³4 cups. Conversely, high tea consumption provided positive effects on cognition in addition to moderate consumption, with high tea consumption being more beneficial than no tea consumption. Additional longitudinal observational and intervention studies are required to validate our findings and confirm this hypothesis.

This research has been conducted using the UK Biobank Resource under Application Number 108907.
Assessing the impact of trauma on Locus Coeruleus integrity in healthy older adults ‐ Preliminary results
Authors: Leiman Marina , Gurusamy Guruprasath , Dünnwald Max , Behrenbruch Niklas , Schumann‐Werner Beate , Molloy Eóin N. , Schwarck Svenja , Garcia‐Garcia Berta , Hochkeppler Anne , Fischer Larissa , Baldauf Kathrin , Schulze Peter , Incesoy Enise I , Kreissl Michael C. , Maass Anne , Betts Matthew , Düzel Emrah , Hämmerer Dorothea
Published: January 2025

Background

Previous studies have examined the impact of post‐traumatic stress disorder and chronic stress on the Locus Coeruleus‐Noradrenergic System (LC‐NA) revealing significant neurobiological alterations (Aston‐Jones & Cohen, 2005; McCall et al., 2015). However, while animal studies have yielded valuable insights regarding the effects of traumatic experiences on the LC‐NA system, translation to human models remains relatively underexplored. Thus, our study aims to address this gap by investigating the relationship between traumatic experiences and LC‐NA integrity in human participants. Here, we present preliminary results on the association between traumatic events, resilience, and LC integrity.

Method

We recruited 90 healthy older adults (mean age: 68.17 ± 5.36) from the SFB‐1436 Cohort. We acquired neuromelanin‐sensitive 3T MRI scans using a Magnetization Transfer Contrast (MTC) sequence optimized for enhancing the visibility of the LC. We performed LC segmentation using an automated approach (based on Dünnwald et al., 2021) and assessed traumatic experiences using a self‐reported modified version of the Life Events Checklist for DSM‐5 (LEC‐5; Weathers et al., 2013). We conducted a linear regression analysis to examine whether traumatic experiences could predict LC integrity.

Result

A linear regression analysis was carried out to assess if traumatic events, age, and sex could predict LC integrity in healthy older adults. The results suggest a trend towards significance for individuals reporting Low traumatic events (p = 0.059) and Highly traumatic events (p = 0.082), indicating potential positive relationships with LC integrity, while controlling for age and sex. The overall model explained a small, non‐significant proportion of the variance in LC integrity (Adjusted R‐squared = 0.028, p = 0.1927).

Conclusion

The analysis indicates a potential association between LC integrity and traumatic events, particularly for low and high levels of trauma. However, the overall model including traumatic events, age, and sex did not explain a significant proportion of interindividual differences in LC integrity. This suggests that while there may be trends indicating associations, they are not robust enough to be considered statistically significant in this sample. Further mediational and moderational analyses will be conducted to gain a deeper understanding of interindividual differences in this regard.
Ultrastructural characterization of tau pathology in the human post‐mortem Alzheimer’s disease brain
Authors: Stähli Daniel A. , Travers Louis , Vialaneix Eglantine , Schneider Philippine L. , de Berg Wilma D.J. Van , Stahlberg Henning , Lewis Amanda J.
Published: January 2025

Background

Neuropathological tau tangles in Alzerheimer’s disease (AD) have been roughly characterized into pre‐tangles, mature tangles and ghost tangles. However, to date, their maturation in the human brain is poorly understood. Here, we aimed to define the structure and composition of tangle maturation stages in the AD brain using correlative light and electron microscopy (CLEM).

Method

Chemically fixed (4% paraformaldehyde, 0.1% glutaraldehyde) entorhinal and hippocampal formation of two diseased AD patients were analyzed using CLEM (6 more cases are currently being analyzed). Vibratome sections were stained with different relevant markers (AT8, AT180, 44744, etc; Amytracker; DAPI) and imaged using a fluorescence microscope. Brain sections were then processed for electron microscopy (heavy metal staining and resin embedding). Ultra‐thin alternate sections were collected on glass slides and electron microscopy grids.

Result

We have characterized the ultrastructure of several mature tangles, dystrophic neurites, a few putative pre‐tangles and one putative ghost tangle. While we observed no tau fibrils in pre‐tangles, high contents of tau fibrils were present in mature tangles that often formed distinct clusters. Multilamellar bodies, damaged mitochondria and small membranous vesicles were present. Dystrophic neurites were swollen and filled with a mix of tau fibrils and multilamellar bodies. Often the twist of individual fibrils was visible. Fibrils in the putative ghost tangle had a fuzzy appearance, were densely packed and compartmentalized by a membrane. Compartmentalized clusters of multilamellar bodies were present as well.

Conclusion

A prominent difference between mature tangles and neuritic pathology was the increased presence of multilamellar bodies in dystrophic neurites. This could be explained by differences in the aggregation process of tau fibrils, depending on the cellular context (neuron soma vs dendrite). In most previous studies, the staining with amyloid markers suggested the absence of fibrils in pre‐tangles, while one report found fibrils in pre‐tangles using EM. Our results support the hypothesis of the absence of tau fibrils in the earliest form of pre‐tangles. Further work is needed to identify the tau tangle stage at which fibrillar tau first occurs. The here presented preliminary data needs to be expanded with additional earlier and later stages of tau pathology.
Efficacy and sustainability of 40 Hz high‐definition transcranial alternating current stimulation (tACS) in the treatment of sleep disturbances in mild neurocognitive disorders due to Alzheimer’s disease
Authors: Lu Hanna , Li Jing , Ni Xi , Yang Natalie Shu , Wing Yun Kwok , Ma Suk Ling , Lam Linda Chiu Wa , Zhang Li
Published: January 2025

Background

To investigate the effects of 40 Hz high‐definition transcranial alternating current stimulation (HD‐tACS) on subjective sleep quality and domain‐specific cognitive functions in mild neurocognitive disorders due to Alzheimer’s disease (NCD‐AD).

Method

This study was a double blind, sham‐controlled randomized clinical trial. Ninety‐nine mild NCD‐AD patients were randomly assigned to receive a 4‐week course treatment of either 40 Hz HD‐tACS, HD transcranial direct current stimulation (HD‐tDCS), or sham transcranial current stimulation (HD‐tCS). Global cognition was assessed by Montreal Cognitive Assessment (MoCA). Subjective sleep quality was assessed by Pittsburgh Sleep Quality Index (PSQI). PSQI total score>5 was defined as sleep disturbances.

Result

The mean score of PSQI was 11.7 in mild NCD‐AD patients. Repeated sessions of 40 Hz HD‐tACS and HD‐tDCS treatments significantly enhanced the subjective sleep quality and cognition. Compared with HD‐tDCS, the individuals who received 40 Hz HD‐tACS had more improvement on sleep quality (score changes of PSQI: 6.01 vs. 3.72, p<0.001) and cognitive function (MoCA: 2.5 vs.1.5, p<0.01) during a 2‐month follow‐up period.

Conclusion

Mild NCD‐AD patients with sleep disturbances who received 40 Hz HD‐tACS had pronounced enhancement in subjective sleep quality and global cognition. To identify novel modality of transcranial brain stimulation is important toward an effective strategy for the comorbidities in preclinical AD.
Does Neurodegeneration Lag Behind Tau Deposition in Alzheimer Dementia?
Authors: Shah Ujashi , Xie Long , McGrew Emily , Wolk David A , Das Sandhitsu R.
Published: January 2025

Background

Alzheimer’s disease (AD) is defined by the presence of ß‐amyloid (Aß) plaques and tau‐based neurofibrillary tangles (NFTs). Understanding the temporal relationship of NFTs with atrophy in early AD regions, specifically the medial temporal lobe (MTL), is critical for monitoring disease progression. Accumulation of NFTs has been suggested to precede atrophy because cross‐sectional measures of atrophy are more weakly associated with baseline tracer uptake than prospective longitudinal ones. However, longitudinal measures may be more sensitive to disease‐related atrophy at early AD stages. To address this, we examine cross‐sectional versus longitudinal measures before or after the time of tau PET.

Methods

Data from patients with mild cognitive impairment (MCI) or dementia due to AD (n = 69, amyloid PET positive (Aß+) symptomatic adults) were analyzed. Tau PET date was the anchor point and MRI atrophy measures from earlier, ≤2 years before, and later, ≤2 years after, scans were derived. Hippocampal volumes and thickness of Brodmann area (BA) 35, the region of earliest tau accumulation, as well as their annualized rates of volume loss were extracted as atrophy measures. MTL tau was measured as tracer uptake in a combined BA35/ERC region. Cross‐sectional and longitudinal analyses included Pearson correlation between MTL tau and atrophy and Pearson and Filon’s z test to compare these correlations.

Results

As expected, there was a significant correlation between atrophy and tau in the cross‐sectional analysis, which was generally stronger for later time points. Specifically, there was a statistically significant difference (p <0.05) for right hippocampal volume and BA35 thickness. In longitudinal data, while the correlation between annualized atrophy rate and tau was generally greater at both time points compared to the cross‐sectional data, these longitudinal correlations did not differ between the two time points.

Conclusions

Here we show longitudinal atrophy rates before or after tau scans are similarly correlated. Later cross‐sectional measures have stronger correlations than earlier, likely due to more time to accrue atrophy relative to other sources of variation. These results question prior arguments of a lag between deposition and atrophy, which may be based on differences of sensitivity of cross‐sectional and longitudinal measures.