bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comprehensive Neurological Study on the Relationship Between Smoking Cigarettes and Alzheimer’s Disease: Potential Effects of Transitioning to E‐Cigarettes
Authors: Ismail Youssef A. , El‐Satar Youssef M. Abd , Haitham Youssef , Mohamed Hazim , Walid Mohammad
Published: January 2025

Background

Undergoing intense research and investigation, smoking has garnered attention due to its extensive implications for public health, particularly focusing on cardiovascular and pulmonary issues. however In comparison, the neurological effects of nicotine have not yet been thoroughly investigated. Our objective is to investigate the relationship between smoking cigarettes and Alzheimer disease (AD) and possible effects of switching to E‐cigarettes.

Methods

We reviewed database searches through October 2023 in MEDLINE, PsycINFO, and the Cochrane Central Register of Controlled Trials; and additional searches for ongoing trials through ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and Current Controlled Trials (ISRCTN Register).

Results

Nicotine has been observed to yield cognitive benefits and alleviate cognitive deficits associated with neurological diseases, such as Alzheimer’s disease (AD), in certain studies. Conversely, a notable increase in the risk of AD has been linked to active smoking in other studies, while another investigation suggests no discernible distinction between smokers and non‐smokers in this context. Although e‐cigarettes generally entail fewer adverse health effects, the neurological impact persists, attributed primarily to nicotine. As of July 2023, approximately 1.3 billion individuals, constituting approximately 16.2% of the global population, are smokers according to the World Health Organization (WHO). In the United States, 17.2% of adults are active smokers, with 11.1% employing traditional smoking methods. Notably, there is an observable decline in cigarette smoking, decreasing from 14.4% in 2019 to 11.1% in 2023, while the use of E‐cigarettes among US adults has risen from 4.4% to 6.1%. This trend is even more pronounced among youth, with around 14.1% of high school students and 3.3% of middle school students reporting e‐cigarette usage.

Conclusion

The divergent findings regarding the impact of nicotine on cognition suggest the existence of an overlooked co‐factor associated with the effects of nicotine on the brain, warranting further investigation. Nevertheless, our analysis indicates that the shift to e‐cigarettes potentially elevates the risk from a neurological standpoint, as evidenced by documented cases of nicotinic overdosing, a phenomenon not possible with traditional cigarettes.
Molecular biomarkers for Alzheimer’s disease and related dementias – improved methods to facilitate global studies
Authors: Zetterberg Henrik
Published: January 2025

Background

Recent advancements in sample collection and storage methods, as well as biomarker measurement technologies, have made it possible to determine highly accurate biomarkers for Alzheimer’s disease (AD) in regular plasma samples collected by venipuncture or as dried plasma spots.

Methods

A novel ultrasensitive biomarker measurement method called NUcleic acid Linked Immuno‐Sandwich Assay (NULISA), which improves the sensitivity of traditional proximity ligation assays to attomolar level, by suppressing assay background via a dual capture and release mechanism, was evaluated against Single molecule array (Simoa) technology for AD biomarker measurement. Dried plasma spots were evaluated in relation to regularly collected EDTA plasma samples.

Results

Proteins from dried plasma spots, stored at room temperature over weeks, can be eluted and AD‐related biomarkers, including P‐tau217, neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), can be accurately quantified with r values above 0.80 (p<0.00001) compared with validated Simoa‐based measurements. Absolute concentrations of biomarkers in dried plasma spots are lower than in regularly collected venous samples. NULISA was at least 10‐fold as sensitive to measure AD‐related biomarkers compared with Simoa; a multiplexed NULISA method allows for the measurement of P‐tau217, NfL and GFAP concentrations in a single blood drop. Data from under‐represented populations will be presented.

Conclusion

The measurement of biomarkers in dried plasma spots using novel ultrasensitive measurement technologies is feasible for biomarker assessment in remote populations with limited access to healthcare resources. Dried plasma spot‐specific reference limits are needed. Combining this with digital assessment tools for cognitive function should facilitate studies of the global epidemiology of dementia.
Inclusive Approaches To Promote Participation of Diverse Demographic Groups in Preclinical AD Clinical Trials Through Centralized Recruitment
Authors: Molina‐Henry Doris P.
Published: January 2025

Background

Recruitment of demographically diverse participants into Alzheimer’s disease (AD) clinical trials, encompassing both screening and randomization, remains a consistent and persistent challenge contributing to underrepresentation of certain groups. Despite the exciting prospects of identifying therapeutic interventions for biomarker‐eligible, cognitively unimpaired individuals, these studies grapple with the inherent complexities of AD trials coupled with intricate and time‐consuming screening processes. Addressing this the issue of underrepresentation necessitates concerted and intentional efforts that prioritize inclusivity and equitable access to enroll adults meeting study criteria, reflecting the demographic and social diversity of North America. This presentation delves into the strategic approach undertaken by the Recruitment, Engagement, and Retention Unit (the Unit) within the National Institute on Aging‐funded Alzheimer’s Clinical Trials Consortium (ACTC).

Methods

The Unit defines and monitors populations of emphasis across dimensions of diversity such as race, ethnicity, sexual and gender minorities (LGBTQ+), and socially minoritized and underserved groups to underscore inclusivity. Guided by principles of research access, media outreach, site engagement, and community partnerships, the Unit implements a dynamic multi‐pronged strategy across clinical trials that span several stages of the disease.

Result

Research access involves evaluating and adapting messaging in digital and print formats, ensuring linguistically compatible communication, and providing informational resources tailored to these specific groups. Media efforts include earned and print media interviews across a variety of outlets focused on engaging communities of emphasis. ACTC’s Coordinating Center’s central activities are a supplement and in complement to local site endeavors via continued and robust community and site engagement. Thus far, these strategies have resulted in increased engagement and screening in preclinical AD trials across diverse communities.

Conclusion

As we actively implement and expand these strategies, discussions evolve around early successes, lessons learned, and new and persisting challenges. We discuss centrally coordinated community screening pilot studies that are currently under evaluation and will help identify eligible individuals based on biomarker assessments before site referral. Additionally, we explore opportunities to further improve inclusivity by expanding into other dimensions of diversity through the study of social determinants of health that may influence cognitive health in groups that are disproportionately biomarker‐ineligible for AD trials.
New anti‐tau VHH: from biophysical characterization to proof‐of‐concept in experimental models
Authors: Danis Clément , Caillierez Raphaelle , Mortelecque Justine , Bégard Séverine , Zejneli Orgeta , Rain Jean‐Christophe , Colin Morvane , Dupre Elian , Landrieu Isabelle , Buee Luc
Published: January 2025

Background

Tau proteins aggregate in a number of neurodegenerative disorders known as tauopathies. Various studies have highlighted the role of microtubule‐binding domains in the intracellular aggregation of Tau protein.

Method

Using a library of synthetic VHHs humanized in collaboration with Hybrigenics, we have developed a number of anti‐tau VHHs. We use a combination of biophysical and biochemical methods, cell‐based assays, viral vectors and tau transgenic mice to explore the ability of these VHHs to target intracellular tau protein.

Result

A dozen anti‐tau VHHs were obtained near and in microtubule‐binding regions. After screening and optimization, three of them (F8‐2, H3‐2 and Z70) were selected for further studies and AAV vector delivery to tau transgenic mice. Biochemical characterization of F8‐2 has already been published [1]. VHH Z70 targeting the PHF6 epitope has already demonstrated its ability to reduce tau seeding in cellular FRET assays and by lentiviral vectorization in animals [2]. Here, using AAV vectors, we demonstrate its safety in wild‐type mice and its efficacy in tau transgenic mice. VHH H3‐2 has a unique mode of action which will be discussed.

Conclusion

In our tau pipeline, we have developed innovative new therapeutic tools, which are at various stages of development for preclinical validation.

References

[1] Danis C, et al. (2022) Inhibition of Tau seeding by targeting Tau nucleation core within neurons with a single domain antibody fragment. Mol Ther, 30(4):1484‐1499

[2] Dupré E, et al. (2019) Single chain antibody fragments as new tools for studying the neuronal Tau protein physiopathology. ACS Chemical Neurosci, 10(9):3997‐4006
Understanding the Prescription Drug Costs among People with ADRD and Comorbidities: Evidence from Nationally Representative Datasets 2003‐2021
Authors: Jang Seyeon , McCoy Rozalina G. , Chen Jie
Published: January 2025

Background

Escalating drug costs are likely to disproportionately burden individuals with Alzheimer’s disease and related dementias (ADRD) as they often have multiple chronic conditions (MCC). This study aimed to estimate the incremental total and out‐of‐pocket (OOP) drug costs associated with ADRD and MCC across the drug cost distributions.

Method

The study used a nationally representative cross‐sectional dataset from 2003 to 2021 Medical Expenditure Panel Survey. The study sample comprised of 83,667 elderly community dwelling individuals aged 65 and above, among which 3,046 individuals had ADRD diagnosis and 2,710 had both ADRD and MCC. To address the skewed distribution of the drug costs, quantile regression models were used to examine the associations between prescription drug costs and having ADRD/MCC across the drug cost distributions at 25th, 50th, 75th, and 90th percentiles, after adjustment for other sociodemographic factors. MCC was defined as having two or more chronic conditions. Survey weights were applied to all estimates.

Result

ADRD patients and those with ADRD and MCC had significantly higher incremental costs at the upper end of the total and OOP drug cost distributions than at the lower end of the distributions, compared to those who had no ADRD diagnosis. The incremental OOP drug costs of ADRD at the 90th percentile were over 14 times higher than that at the 25th percentile ($624.43, p<0.001, 90th percentile; $42.66, p<0.001, 25th percentile), while the incremental total drug costs of ADRD at the 90th percentile was about 9 times higher than that of ADRD at the 25th percentile ($3,372.27, p<0.001, 90th percentile; $381.31, p<0.001, 25th percentile). Similarly, the incremental OOP drug costs among individuals with ADRD and MCC at the 90th percentile were 11 times more than that at the 25th percentile ($756.91 vs. $68.55, respectively), while the incremental cost difference for the total drug costs was 7 times higher among individuals with ADRD and MCC at the 90th percentile than those at the 25th percentile ($3,940.53 vs. $548.80, respectively).

Conclusion

The results of the study highlighted that ADRD patients with and without MCC who are heavy prescription drug users face a disproportionately greater burden in OOP payments.
The mapping of active sites of amyloid‐targeting compounds through the utilization of immobilized fragments of amyloid hexamers
Authors: Cho Illhwan , Yoon Soljee , Kim Hye Yun , Kim YoungSoo
Published: January 2025

Background

As amyloid‐β (Aβ) aggregates are considered as the biomarkers and key factors in the pathology of Alzheimer’s disease, there has been extensive investigation into Aβ‐targeting compounds for the development of diagnostics and drug discovery related to the disorder. However, the polymorphic and heterogenous nature of Aβ aggregates impedes the structural understanding of their structure. Consequently it is a major challenge to develop new diagnostic and therapeutic development of AD and to study the mechanism of Aβ‐targeting compounds.

Method

Utilization of solid‐phase peptide synthesis, 37 Aβ hexameric Aβ fragments were synthesized. These fragments were immobilized on the 96‐well microplane to develop a mapping plate for investigating the active sites of Aβ‐targeting compounds. To confirm the mapping potential of our plate, previously reported fluorescent Aβ‐imaging agents (CRANAD‐28, bis‐ANS), Aβ aggregation inhibitors (curcumin, scyllo‐inositol), and Aβ aggregate dissociators (necrostatin‐1, sunitinib) were treated.

Result

Using the mapping plate, we confirmed that CRANAD‐28 interacted with three domains of Aβ HHQKLVFF (Aβ13‐20), IIGLMV (Aβ31‐36), and GGVVIA (Aβ37‐42), and bis‐ANS were bound to the predominant parts of Aβ sequences except N‐terminal regions. We further determined that curcumin inhibited three distinct fragmental regions of Aβ (Aβ14‐21, Aβ29‐35, and Aβ37‐42) and scyllo‐inositol targeted VHHQKLVFF (Aβ12‐20), VGSNKGAIIGL (Aβ24‐39), and GGVVIA (Aβ37‐42) sites. Lastly, we confirmed that both necrostatin‐1 and sunitinib strongly dissociated GLMVGGVVIA (Aβ33‐42), the C‐terminal hydrophobic residue.

Conclusion

This mapping plate can be employed to understand the active sites of Aβ‐targeting compounds, even in the lack of a comprehensive structural understanding of Aβ aggregates. Moreover, the insights gained from identifying targeting sites using this mapping plate can contribute to the rational approach in the development of diagnostic and therapeutic strategies for Alzheimer’s disease (AD).
PENSA study, results of a 12‐month personalized intensive multimodal lifestyle intervention complemented with epigallocatechin gallate (EGCG) to prevent cognitive decline in APOE‐ ɛ4 carriers with Subjective Cognitive Decline: a randomized, double‐blinded clinical trial
Authors: Forcano Laura , Soldevila‐Domenech Natalia , Boronat Anna , Lorenzo Thais , Cuenca‐Royo Aida , Pizarro Nieves , Puig‐Pijoan Albert , Piera Iris , Gomis Maria , Diaz‐Pellicer Patricia , Aldea Ana , Grau‐Rivera Oriol , Sánchez‐Benavides Gonzalo , Fauria Karine , Minguillon Carolina , Gispert Juan Domingo , Molinuevo Jose Luis , de la Torre Rafael
Published: January 2025

Background

Lifestyle interventions targeting multiple Alzheimer’s disease (AD) risk factors are effective strategies to prevent cognitive decline. Emerging evidence suggests synergistic effects between various intervention components, including lifestyle modifications, supplements, and pharmacological approaches. The PENSA study, part of the World‐Wide FINGERs network, is a randomized, double‐blind clinical trial following the Finger 2.0 Model. This work aims to show the results of the effectiveness of this 12‐month intensive personalized multimodal lifestyle intervention (MI) encompassing diet, physical activity, cognitive/social stimulation combined with epigallocatechin gallate (EGCG), in mitigating cognitive decline in individuals with Subjective Cognitive Decline (SCD) carriers of the APOE‐e4 allele. Aspects related to the nature and intensity of the intervention that might influence cognitive improvements will be discussed.

Method

129 individuals aged 60‐80 years, APOE‐ε4 carriers meeting SCD, were enrolled and randomized into MI+EGCG (N = 52) or MI+placebo (N = 52), or allocated to a control group (CG) (receiving healthy lifestyle recommendations) (N = 25). The primary efficacy outcome was cognitive performance measured with the modified PACC‐exe battery. eHealth and mHealth tools/devices were used for the continuous monitoring of MI.

Result

Although specific numerical results are not reported due to the upcoming submission for peer‐reviewed publication, we can anticipate that the results reflect promising results in cognitive performance, among participants undergoing MI + EGCG and a reduction in the risk of dementia as measured by the LIBRA index. Adherence to intervention components was very high (90.3% nutrition, 62.1% gymnasium, 72.6% cognitive training, 79.0% psychoeducation sessions, 89.0% daily ecological momentary assessments). Global findings will be shared in their integrity during the meeting.

Conclusion

The PENSA Study is the first clinical trial exploring the effectiveness of integrating an intensive personalized MI with a pro‐cognitive complement, EGCG, in slowing cognitive decline in APOE‐ɛ4 carriers with SCD. Our findings emphasize the feasibility and effectiveness of a personalized MI for cognitively healthy individuals at higher risk of AD, applying an intense approach and incorporating new technologies. In the upcoming discussion, we will delve into the results and their broader implications.
Potential effects of sweet almond oil in the treatment of Alzheimer’s disease targeting BDNF and TrkB: An In Silico Molecular docking and ADMET Evaluation Study
Authors: Salis Rahmat Hassan , Umana Uduak Emmanuel , Sadeeq Adamu Abubakar
Published: January 2025

Background

Alzheimer’s disease (AD) is the most prevalent cause of dementia accounting for an estimated 60% to 80% of cases. Despite advances in the research field, developing truly effective therapies for AD symptoms remains a major challenge. Sweet almond contain nutrients that have the potential of combating age‐related brain dysfunction, by improving learning, memory and neurocognitive performance. Neurotrophins are molecules that support neuroplasticity and are capable of promoting neuronal survival, controlling cell proliferation and neuronal differentiation. Brain‐derived neurotrophic factor (BDNF) is the most abundant neurotrophic factor that signals through the tropomycin receptor kinase B (TrkB). It plays a critical role in learning and memory by promoting survival of neurons and modulating synaptic connectivity. Loss of BDNF/TrkB signaling has been reported to play a role in AD, suggesting a pathologic involvement.

Method

42 compounds in sweet almond oil were identified using GC‐MS analysis. The 2D structures of all the compounds were retrieved from PubChem database and the 3D structures of BDNF (PDB: 1B8M) and TrkB (PDB: 1WWB) were downloaded from RCSB database. BDNF and TrkB were prepared using PyMOL software and ligand preparation/docking were carried out using PyRx software. ADMET evaluation of the compounds was performed using ADMETlab 2.0 server.

Result

12 compounds were found to have a higher binding affinity than Memantine, a drug that was reported to upregulate BDNF/TrkB expression in the brain. The docking results revealed that CID‐2116, CID‐6421311, CID‐5357430, CID‐541960, CID‐543355, CID‐37153, CID‐67513, CID‐543450, CID‐31039, and CID‐35698 have binding affinity of ‐11.2 kcal/mol, ‐7.4 kcal/mol, ‐6.8 kcal/mol, ‐6.6 kcal/mol, ‐6.1 kcal/mol, ‐6.0 kcal/mol, ‐6.0 kcal/mol, ‐5.8 kcal/mol, ‐5.7 kcal/mol, ‐5.7 kcal/mol respectively against BDNF that exceeded Memantine (‐5.6 kcal/mol). The result also revealed that CID‐2116, CID‐141010, CID‐31039, and CID‐549641 have binding affinity of ‐9.3 kcal/mol, ‐6.6 kcal/mol, ‐6.1 kcal/mol, and ‐6.0 kcal/mol respectively against TrkB receptor that exceeded Memantine (‐5.7 kcal/mol). All of these compound showed positive BBB penetration, 0 alert on acute toxicity rule and obeying Lipinski’s rule of five parameters.

Conclusion

The results of this study revealed that some compounds of sweet almond oil have potential therapeutic activity against BDNF/TrkB expression with low systematic toxicity.
Impact of Rater Change on MMSE Data. A Post‐Hoc Analysis
Authors: Kott Alan , Wang Xingmei , Miller David S.
Published: January 2025

Background

Rater change is inevitable in often lengthy clinical trials in Alzheimer’s disease. Other groups have previously assessed the impact of rater change on data variability. Their conclusions varied, possibly due to differing methodologies (e.g. ‐ comparing actual vs. absolute change; analyzing data per trial and visit or by combining all trials and visits). Here, we analyze the impact of rater change of MMSE data ‐ using both actual and absolute change ‐ looking only between Screening and Baseline visits.

Method

MMSE and MMSE change from Screening data were obtained from 11.084 Baseline assessments collected across 13 Alzheimer’s disease clinical trials. Data were broken into 2 groups by the presence of rater change between Screening and Baseline. Two regression models were fitted to the data. In the first model the dependent variable was the MMSE actual change from Screening to Baseline, in the second model the MMSE absolute change was tested. Rater change, clinical trial and their interaction were used as predictors and MMSE Baseline value entering in a cubic form as a covariate.

Result

In the first model using actual MMSE change, neither rater change, nor the interaction between protocol and rater change was significant. Removing the interaction term, rater change decreased the MMSE change by 0.1 MMSE points (p = 0.06). In the second model, the effect of rater change differed from study to study. Among studies that showed significant rater change effect, the absolute MMSE change increased by 0.46 points on average.

Conclusion

Our results indicate that rater change may indeed have an impact on MMSE data but the impact is inconsistent. While the actual change was affected only insignificantly, the absolute change as a measure of variability was significantly increased. Substantial differences were observed between individual studies and in only 6 of the 13 studies, rater change significantly increased MMSE absolute change. Given the results, rater change should be considered a risk factor to assessment reliability. Therefore, reasonable efforts should be taken to minimize both its occurrence and its impact on study data.
Active immunotherapy, ACI‐24.060, induces anti‐Abeta antibodies with binding profiles mirroring clinically validated monoclonal antibodies
Authors: Fiorini Emma , Babolin Chiara , Carpintero Rakel , Rigotti Stefania , Siegert Stefanie , Morici Catherine , Balachandiran Harishini , Wagg Jonathan , Fournier Nicolas , Herriott Lara , Donati Piergiorgio , Delpretti Saskia , Mendonca Nuno , Pfeifer Andrea , Derouazi Madiha , Kosco‐Vilbois Marie , Vukicevic Marija
Published: January 2025

Background

The key advantage of active immunization is the induction of sustained, polyclonal antibody responses that are readily boosted by occasional immunizations. Recent clinical trial outcomes for monoclonal antibodies lecanemab and donanemab, establish the relevance of targeting pathological Abeta for clearing amyloid plaques in Alzheimer’s disease. ACI‐24.060 is a liposomal anti‐Abeta vaccine, using Abeta 1‐15 as the immunogen. In non‐human primates (NHPs), ACI‐24.060 induced antibodies binding to pathological Abeta species: 1) pyroglutamate, target of donanemab and 2) oligomers, with a high preference versus monomers, similar to lecanemab, suggesting a potential for Abeta clearance in humans.

Method

Cynomolgus monkeys were immunized monthly with ACI‐24.060 (generated using the SupraAntigen® platform). Immune sera obtained after seven immunizations were tested using a competitive inhibition assay involving preincubation of immune sera or lecanemab with Abeta monomers or oligomers. Binding profiles to pyroglutamate‐Abeta and Abeta oligomers were established for vaccine‐induced antibodies, lecanemab, and donanemab, using ELISA‐based assays. Published lecanemab and donanemab exposure‐response models were utilized to simulate Amyloid‐PET lowering profiles for antibodies evoked by ACI‐24.060.

Result

Immunization of NHPs with ACI‐24.060 induced a sustained polyclonal response with strong binding to Abeta toxic species, i.e. pyroglutamate‐Abeta and oligomers. The competitive inhibition assay demonstrated that the antibodies generated by active immunization of NHPs with ACI‐24.060 gave a 3‐log preferential binding for oligomeric over monomeric Abeta, similar to the differential observed with lecanemab. Binding activity of the vaccine‐induced antibodies to pyroglutamate‐Abeta and Abeta oligomers was in the range of levels of donanemab (11‐48 µg/mL) and lecanemab (18‐26 µg/mL), which are relevant for Abeta plaque clearance in human AD patients. Exposure‐response modelling in these ranges of ACI‐24.060‐induced antibodies demonstrated a potential for Abeta clearance in humans.

Conclusion

ACI‐24.060 induced antibody responses in NHPs with 3‐log preferential binding to oligomeric versus monomeric Abeta, similar to lecanemab and strong binding to both Abeta oligomers and pyroglutamate‐Abeta species. Induced antibodies were in the range of levels of donanemab and lecanemab relevant for Abeta clearance in human AD patients. Therefore, ACI‐24.060, with its dual target effect (pyroglutamate‐Abeta and Abeta oligomers) and its FDA Fast Track designation, represents a potential breakthrough active immunotherapy for Alzheimer’s disease.
Results from COG0201: A Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐ Group, Phase 2 Study to Evaluate the Safety and Efficacy of CT1812 in Subjects with Mild to Moderate Alzheimer’s Disease
Authors: Vijverberg Everard G.B. , Catalano Susan , Hamby Mary E. , Grundman Michael , Iaci Jennifer , Devins Theresa , Caggiano Anthony O
Published: January 2025

Background

CT1812 is an experimental therapeutic sigma‐2 receptor modulator in development for Alzheimer’s disease (AD) and dementia with Lewy bodies. CT1812 reduces the affinity of Aβ oligomers to bind to neurons and exert synaptotoxic effects. This phase 2, multi‐center, international, randomized, double‐blind, placebo‐controlled trial assessed safety, tolerability and effects of CT1812 on cognitive function in individuals with AD.

Method

Consenting participants with confirmed brain amyloid and baseline MMSE scores of 18 to 26 were randomized equally to receive oral placebo, 100 or 300mg of CT1812 daily for 6 months. Exploratory efficacy outcomes included ADAS‐Cog11 and 13, Neurophysiological Test Battery, ADCS‐Clinical Global Impression of Change and ADCS‐Activities of Daily Living. The primary statistical analysis is treated (combined 100 and 300mg CT1812) versus placebo change from baseline in ADAS‐Cog11. Canonical AD biomarkers were assessed in CSF and plasma.

Result

One hundred fifty‐three participants were randomized. An interim analysis of the first 24 participants was performed where baseline demographics included mean age of 71.7 years, 15 females and a mean MMSE of 21.1. In the interim analysis there were twenty‐two TEAEs (7, 8, 7 in the 100, 300mg CT1812 and placebo groups, respectively) reported and in the CT1812 groups, all TEAEs were mild or moderate and there were no treatment related SAEs. There was a trend within these 24 participants for slower progression at six months in the CT1812 treated group with ADAS‐Cog11 improved 3.1 points relative to placebo according to the prespecified statistical model. Complete data from all participants including AEs, cognitive performance and canonical biomarkers will be presented with the ADAS‐Cog11 change from baseline relative to placebo for the pooled CT1812 treated group prespecified as the first cognitive assessment with ApoE4 status as a covariate.

Conclusion

CT1812 is an oral sigma‐2 modulator that displaces Aβ oligomers from neurons. Encouraging trends have been observed in previous studies (NCT03493282, NCT03522129, NCT04735536) and in an interim analysis of this phase 2 trial (NCT03507790). This trial will provide proof of concept data indicating if CT1812 can slow progression in people with mild to moderate AD. This study was supported by a grant from the NIH (AG058660).
Association of impaired olfactory identification with prevalent mild cognitive impairment and regional brain atrophy: the Hisayama Study
Authors: Nakazawa Taro , Ohara Tomoyuki , Minohara Toshifumi , Hata Jun , Shibata Mao , Ninomiya Toshiharu
Published: January 2025

Background

Few population‐based studies have comprehensively examined the association between impaired olfactory identification and the prevalence of mild cognitive impairment (MCI) and regional brain volumes in a general older population without dementia.

Method

A total of 1,292 participants without dementia aged 65 years or older underwent a Japanese Pocket Smell Test, an assessment of cognitive function, and a brain magnetic resonance imaging scanning in 2017‐2018. Impaired olfactory identification was defined as incorrect identification of three or more odors in the Japanese Pocket Smell Test, where participants sniffed eight microencapsulated odors (strawberries, chocolate, mint, smoke, soap, grapes, onions, and roses) and selected the corresponding odor from four choices for each odor. The association of impaired olfactory identification with prevalent MCI was estimated by a logistic regression analysis. Regional brain volumes were estimated separately by applying two different Methods: voxel‐based morphometry (VBM) and analysis by FreeSurfer software. The association of impaired olfactory identification with regional gray matter volumes was analyzed using multiple regression analysis.

Result

Out of 1,292 participants, 427 (33.05%) had an impaired olfactory identification. The crude prevalence of MCI in participants with and without impaired olfactory identification was 18.97% and 8.09%, respectively. Participants with impaired olfactory identification had a significantly higher likelihood of MCI than those without after adjusting for confounders (odds ratio 1.97, 95% confidence intervals 1.34–2.88). In the FreeSurfer analysis, impaired olfactory identification was significantly associated with lower gray matter volume of entorhinal cortex, inferior temporal gyrus, amygdala, thalamus, cingulate, parahippocampal gyrus, and hippocampus. The sensitivity analysis using multivariable‐adjusted VBM analysis without regions of interest also showed that impaired olfactory identification was significantly associated with lower volume of left entorhinal cortex, left amygdala, left hippocampus, and bilateral thalamus.

Conclusion

Our findings suggest that the assessment of olfactory identification may be a noninvasive and convenient method for identifying high‐risk individuals with cognitive impairment, including neurodegeneration.
Study entry, change, and death: learning from decades of follow‐up in clinical‐pathologic studie
Authors: Capuano Ana W. , Barnes Lisa L. , Schneider Julie A. , Bennett David A.
Published: January 2025

Background

Dementia, a growing health crisis, disproportionally affects persons from racial/ethnic backgrounds and individuals with comorbidities. Latelife change in cognition is complex and nonlinear, as well as differential for these individuals. These individuals are also largely underrepresented in clinical trials. We discuss analytical methods using cognitive aging data from participants in well‐characterized clinical‐pathologic studies with long follow‐ups that may inform the design of more inclusive clinical trials.

Method

We examined harmonized data from older adults enrolled in one of four ongoing clinical‐pathologic studies of cognitive aging: the Religious Orders Study (ROS); Rush Memory and Aging Project; Minority Aging Research Study and African American Clinical Core. Trajectories of cognition were ascertained with different models including Changepoint and Sigmoidal Mixed Models. Trajectories were compared by race, ethnicity, neuropathological profile, and relevant comorbidities such as insulin resistance. We studied fractions of the trajectory that could be observed in trials using composites such as the Alzheimer’s Prevention Initiative Preclinical Composite Cognitive (APCC) and the Preclinical Alzheimer’s Composite with Semantic processing (PACC5).

Results

The RADC cohorts started as early as 1994 with the first (ROS) having accumulated up to three decades of follow‐up (16‐27 years for the others). Using different techniques we demonstrated that change in cognition was marked by a small retesting effect at the very beginning of the trajectory and a nonlinear accelerated decline in the years that preceded death. Using matched samples we identified similar s or rates of decline in Latinx but lower initial levels and less accelerated declines in Black older adults. We identified different smooth late‐life accelerations as a function of factors such as insulin resistance, BMI, and neuropathology. Later acceleration can start much earlier, entering segments of the trajectory potentially used in clinical trials. Trajectory characteristics (slope and variability) changed with composite, which is important in translating cohort information to the statistical planning of clinical trials.

Conclusion

The examination of the trajectories with long follow‐ups using different modeling techniques can provide insights into profiles of cognitive aging. The use of these data can be one source among several to inform the design of more inclusive clinical trials.
Fear of Alzheimer’s disease in older women with a family history of dementia and what we can do about it: results from an observational study and randomized controlled trial
Authors: Farina Francesca R , Bennett Marc P , Griffith James W
Published: January 2025

Background

Alzheimer’s disease (AD) is highly feared. Fear can prevent individuals from seeking help. By age 65, women’s risk of developing AD is 1 in 5. Women also make up the majority of dementia carers. Therefore, older women may be particularly vulnerable to dementia‐related fear and its negative impacts. Across two studies, we examined (1) associations between dementia‐related fear and psychosocial functioning and (2) the effectiveness of a brief intervention to reduce fear in older women with and without a dementia family history.

Method

Participants were women aged >55 years without a dementia diagnosis. In study 1, participants completed measures of dementia‐related fear and memory failures. In study 2, participants were randomized into intervention (psychoeducation, mindful grounding, exposure/behavioral activation) or control groups (psychoeducation, mindful grounding), and completed measures of dementia‐related fear, memory failures, depression, social function, and well‐being.

Result

Study 1 included 285 women (66.1±7.1 years; Fx = 45.6%). Dementia‐related fear was positively associated with memory failures (r = .64, p<.001); fear was elevated in women with a dementia family history (p = .002, η2 = .03; Fig. 1A). Study 2 included 58 women (64.6±6.0 years; Fx = 55.2%) randomized to intervention or control groups. Again, dementia‐related fear was associated with memory failures (r = .59, p<.001); fear was elevated in women with a dementia family history (p = .013, η2 = .02). Fear was also associated with depression (r = .52, p<.001), and lower well‐being and social participation (rs>‐.59, ps<.001). Fear effects on depression and social participation were stronger for women with a dementia family history (ps<.027, η2s = .11). Fear scores decreased from pre‐ to post‐intervention (p<.001, η2 = .06). The biggest reduction was observed for women in the intervention group with a dementia family history (p = .004, η2 = .03; Fig. 1B).

Conclusion

Older women with a family history of dementia are particularly fearful, and these fears are inversely related to mood, perceived memory functioning, social participation, and well‐being. A low‐cost, low‐intensity intervention can reduce dementia‐related fear and may be particularly beneficial for older women with a dementia family history. Targeting dementia‐related fear in women has important implications in the era of biomarker disclosure and direct‐to‐consumer genetic testing.
Women’s history of breastfeeding is positively associated with post‐menopausal cognitive function
Authors: Fox Molly , Bramen Jennifer E. , Kwon Dayoon , Raj Sonel , Chang Marcus , Crandall Carolyn , Porter Verna R. , Espeland Mark A. , Siddarth Prabha
Published: January 2025

Background

Women’s reproductive experiences may enact reorganization of physiological systems with lifelong health consequences. We test the hypothesis that women’s history of breastfeeding will be positively associated with neurocognitive benefits in post‐menopausal women. This hypothesis is justified by breastfeeding’s well‐established benefits for mothers’ glucose homeostasis, beta‐cell function, adipose tissue mobilization, and lipid metabolism, which would plausibly be beneficial for later‐life brain health.

Method

The Women’s Health Initiative (WHI) was a long‐term, large, US health study in the 1990s‐early 2000s. The WHI Memory Study (WHIMS) was an ancillary study in which cognitively healthy women at baseline were annually assessed. A subset of WHIMS participants were recruited into the WHI Study of Cognitive Aging (WHISCA), which included more comprehensive annual assessments of cognitive function and mood. We use WHIMS participant scores on the Modified Mini Mental State Exam “3MS,” which measures global cognitive functioning, and WHISCA participant scores on the California Verbal Learning Test‐Long Delay (CVLT‐LD), which measures long‐term memory. We employed linear mixed‐effects models to examine the association of 3MS and CVLT‐LD scores with women’s breastfeeding history, controlling for the effects of parity, age, reproductive span, hormone therapies (HT) and duration, and time since HT cessation.

Result

In the WHIMS (N = 6,069) and WHISCA (N = 1,932) cohorts (Table 1 demographics), we found that the number of children a woman breastfed was positively associated with better global cognition (b = 0.059, p = 0.047) and long‐term memory (b = 0.176, p = 0.016). The cumulative number of months a woman breastfed was positively associated with better global cognition (b = 0.064, p = 0.024) and long‐term memory (b = 0.198, p = 0.005). Women who had breastfed ever for at least one month, compared to those who did not, exhibited better long‐term memory (b = 0.671, p = 0.005), and no significant effect for global cognition. Women with a higher breastfeeding‐to‐pregnancy duration ratio exhibited better long‐term memory (b = 0.962, p = 0.000), with no significant effect for global cognition (Table 2, Fig. 1).

Conclusion

Our findings indicate long‐term cognitive benefits of breastfeeding for women, above and beyond any effects of parity. It is possible that breastfeeding could be beneficial for women by endowing resilience against neurodegenerative disorders, consistent with our previous observations from two small cohort pilot studies.
LBD around the world – The Latin American experience
Authors: Borda Miguel Germán , Salazar‐Londoño Salomón
Published: January 2025

Up to date, there are no precise reports of the prevalence of dementia with Lewy bodies (DLB) in Latin America. This can be explained by the lack of research studies and general little awareness about the disease. Notably, collaborative clinical studies are lacking, and DLB patients remain underrepresented despite their significant morbidity.

The few studies investigating DLB in Latin America have been based on small samples, resulting in disparities across the region. Challenges include variability in follow‐up regimens and protocols, prompting the need for harmonization to assess the practical benefits for patients. Future efforts should prioritize collaborative initiatives and address knowledge gaps to enhance the understanding and management of DLB in Latin America.

Here, we describe the first multi‐center initiative for the study of DLB in Colombia.

The main objectives of this initiative are: 1) to identify the level of DLB awareness in memory clinics in Colombia, 2) to analyze the use of clinical instruments and biomarkers for DLB, 3) to characterize the Colombian DLB population, and 4) to explore the potential usefulness of biomarkers in combination with other clinical features to improve diagnostic accuracy and prognostic prediction, especially during the early stages of the disease.

This initiative is linked to the European DLB consortium (E‐DLB) using harmonized procedures and protocols, allowing the opportunity to directly compare clinical and biomarker features across continents.
Association of prior alcohol misuse with cognitive impairment and Alzheimer’s disease
Authors: Housini Mohammad , Zhou Zhengyang , O'Bryant Sid E. , Phillips Nicole , Barber Robert , Polimanti Renato A , Pathak Gita
Published: January 2025

Background

Alcohol use is hypothesized to be a risk factor for cognitive impairment (CI) and Alzheimer’s disease (AD). However, its role is often complex in diagnosing and distinguishing alcoholic dementia from AD. Hence, several AD‐focused studies exclude participants with possible alcohol misuse history, creating major challenges to investigate this connection. Given that alcohol use is a prevalent yet modifiable factor, it is crucial to study their connection to provide key insights.

Method

We investigated the association of alcohol misuse history with CI and AD in three major AD studies: Health and Aging Brain Study‐Health Disparities (HABS‐HD, N = 3,035), Texas Alzheimer’s Research Care Consortia (TARCC, N = 14,655), and Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 2,430). Each study collected different metrics of prior alcohol misuse. In HABS‐HD, we used total Alcohol Use Disorder Identification Test (AUDIT) score to define alcohol misuse, while prior alcohol misuse was collected as part of medical history in TARCC and ADNI cohorts. CI was defined as presence of any type of mild cognitive impairment, and AD was defined by each of the respective cohort. We performed the association using regression and two covariate models: Model 1: age, sex, and self‐reported race‐ethnicity; Model 2: Model1+education. To improve statistical power, we performed a meta‐analysis of the three cohorts using fixed‐effects and random‐effects model.

Result

We meta‐analyzed the results from the three for a total sample size of 19,331; 5,345 individuals with AD, 4,820 individuals with CI, and 603 individuals with prior alcohol misuse. We found an association of prior alcohol use with AD (Model 1: OR = 1.87; 95CI = 1.55‐2.26; p‐value = 7.99×10−11; Model 2: OR = 1.75; 95CI = 1.33‐2.29; p‐value = 5.0×10−5), and CI (Model 1: OR = 1.47; 95CI = 1.21‐1.77; p‐value = 6.23×10−05; Model 2: OR = 1.39; 95CI = 1.06‐1.84; p‐value = 1.75×10−02). There was no heterogeneity among the cohort‐specific effects contributing to the meta‐analysis. (heterogeneity p‐value> 0.05).

Conclusion

Leveraging multiple AD cohorts, we show that prior alcohol misuse is associated with CI and AD, warranting further inquiry into possible molecular and biological processes that intersect between AD and alcohol abuse/dependence.
The Impact of Physical Exercise on Hippocampal Atrophy in Mild Cognitive Impairment and Alzheimer’s Disease: A Meta‐analysis in Support of Early Detection and Intervention
Authors: Kress Gavin T , Popa Emily S. , Merrill David A. , Bramen Jennifer E. , Siddarth Prabha
Published: January 2025

Background

Alzheimer’s disease (AD) presents a significant global health challenge, with limited pharmacological interventions available. Physical activity (PA) is a promising therapeutic approach for delaying AD onset and mitigating neuropathology. Only a handful of meta‐analyses have explored the effects of exercise interventions on structural MRI (sMRI)‐estimated brain volumes in adults with mixed cognitive statuses, two of which found positive effects on left and bilateral hippocampal volume (HV). No meta‐analysis to date has solely included studies examining the effect of PA on sMRI outcomes in individuals with cognitive impairment (CI). In this meta‐analysis, we examined whether there is evidence to support the hypothesis that PA interventions positively impact HV in individuals with CI. We also assessed whether the level of CI (Mild Cognitive Impairment (MCI) vs. AD) impacted this relationship.

Method

We identified six controlled trials that investigated effects of PA interventions on HV in older individuals with cognitive impairment and met inclusion criteria (Table 1). These included 236 participants with AD, MCI, or preclinical AD. Data were extracted and analyzed following Cochrane guidelines (Figure 1). We used a random‐effects model (PythonMeta library: Python 3.9) to estimate the mean change in HV pre‐ and post‐exercise intervention. Forest plots, Hedges’ g funnel plots, and Egger’s test were used to assess unbiasedness and visualize intervention effects, and Tau2, Cochran’s Q, and I2 were calculated to assess heterogeneity.

Result

The primary analysis revealed a significant positive effect of exercise on total hippocampal volume (p = .04). However, sub‐group analyses indicated a significant preservation of HV only in individuals with MCI (Table 2; Bilateral: p = 0.05; L: p = 0.003; R: p<0.001), but not in those with AD (Bilateral: p = 0.2; L: p = 0.5; R: p = 0.8). Egger’s test indicated no evidence of publication bias (p = 0.3). Subgroup analyses also revealed significant heterogeneity only within the MCI cohort for the total and left HV.

Conclusion

Exercise interventions demonstrated a moderate, significant effect in preserving HV among individuals with MCI, but not AD, highlighting a potential therapeutic benefit, particularly in earlier disease stages. These findings encourage future investigation of PA as a treatment for MCI and further incentivize earlier detection.