bluuebunny/crossref_metadata_2025 huggingface dataset:
Serotonin 5‐HT2C receptor agonism in presymptomatic APP/PS1 mice rescues seizure‐induced premature mortality Perhaps we just plainly state what is happening
Authors: Sanz Aaron Del Pozo , Davidson Stephanie , Barker‐Haliski Melissa
Published: January 2025

Background

Seizures in Alzheimer’s Disease (AD) are increasingly recognized to occur and can increase cognitive decline and reduce survival compared to unaffected age‐matched peers (Lyou et al. 2018). Administration of antiseizure medicines (ASMs) to AD patients with epileptiform activity may improve cognition (Vossel et al. 2021), yet whether ASMs also beneficially confer long‐term survival benefits in AD is unknown. We have reported that young (presymptomatic) APP/PS1 mice exhibit enhanced chronic focal seizure susceptibility and premature seizure‐induced mortality, which is associated with dysregulated hippocampal serotonin system tone (5‐HT), altered neuroinflammation, and elevated soluble β‐amyloid (Aβ) levels (Del Pozo et al, 2024). We thus hypothesized that lorcaserin, a selective 5‐HT2C receptor agonist, and cannabidiol, a broad‐spectrum anti‐inflammatory and 5‐HT modulating ASM would reduce seizure susceptibility and seizure‐induced excess mortality by attenuating inflammation and normalizing 5‐HT system dysregulation in kindled presymptomatic APP/PS1 mice.

Methods

Male and female 2‐month‐old APP/PS1 and their wild‐type (WT) littermates underwent corneal or sham kindling, a model of chronic focal seizures (Beckman et al. 2020), for 15 days until achieving criterion (N = 8/group/sex). APP/PS1 mice received either lorcaserin [10 mg/kg, (b.i.d.)], cannabidiol [100 mg/kg (q.d.)], or vehicle (VEH) i.p. during kindling. Seizure acquisition and survival were quantified. Kindling‐induced changes in soluble Aβ levels in isolated hippocampus were then measured by western blot. Neuroinflammation was quantified by immunohistochemistry.

Results

Whereas lorcaserin administration in neither male nor female APP/PS1 mice did not affect seizure severity or kindling versus APP/PS1‐VEH, cannabidiol administration blunted female kindling rate. Both male and female APP/PS1 mice treated with lorcaserin exhibited significant improvements in survival. Despite effects on seizure burden in males, an opposite effect of treatment occurred on mortality: only cannabidiol effectively prevented excess seizure‐induced mortality of APP/PS1 mice. The extent of neuroinflammation and other pathological AD hallmarks (soluble Aβ) will be further discussed.

Conclusion

5‐HT2C agonism rescues seizure‐induce premature mortality independently of direct effects on seizure susceptibility in APP/PS1 mice. CBD shows a sex‐dependent effect, only reducing male seizure‐induced mortality. These results support the use of pharmacological reduction of neuronal hyperexcitability as a strategy to modify disease burden and improve long‐term outcomes in AD.
Phosphorylated tau is more closely associated with the spatial extent of tauopathy than with tau load
Authors: Macedo Arthur C. , Rahmouni Nesrine , Therriault Joseph , Wang Yi‐Ting , Servaes Stijn , Tissot Cécile , Hall Brandon J , Arias Jaime Fernandez , Socualaya Kely Monica Quispialaya , Trudel Lydia , Lussier Firoza Z , Brum Wagner Scheeren , Zimmer Eduardo R. , Triana‐Baltzer Gallen , Kolb Hartmuth C. , Ashton Nicholas J. , Benedet Andrea L. , Karikari Thomas K , Blennow Kaj , Zetterberg Henrik , Pascoal Tharick A. , Rosa‐Neto Pedro
Published: January 2025

Background

Recent evidence indicated that cognitive impairment is more closely associated with the spatial extent of tauopathy (SEOT) than with tau load. It remains unclear whether this is also true for other markers of Alzheimer’s disease (AD) severity, such as fluid levels of phosphorylated tau (pTau). Here, we compared the link between fluid pTau and the SEOT and tau load in the brain, as assessed by PET.

Method

We studied individuals across the aging and AD continuum or with non‐AD neurodegenerative diseases from the TRIAD and ADNI cohorts. TRIAD participants underwent [18F]MK6240 tau‐PET and CSF and plasma pTau 181, 217, and 231. ADNI participants were evaluated with [18F]AV1451 tau‐PET and CSF pTau181. We calculated standard uptake value ratios (SUVR) as a proxy of tau load, and the proportion of abnormal voxels as a measure of the SEOT. Abnormal voxels were those 2.5 SD higher than the mean of a group of young adults. Spearman’s correlations assessed the associations of pTau with SEOT and tau load in a temporal meta‐region of interest (ROI) and Braak‐like cumulative ROIs. Correlation coefficients were compared in R using the cocor package.

Result

We included 325 participants from TRIAD (mean [SD] age, 68 [9.8] years) and 417 from ADNI (mean [SD] age, 71.8 [9.0] years). All pTau biomarkers showed significant correlations with SEOT and tau load in all ROIs (Figure 1A‐B). All pTau epitopes were more closely associated with SEOT than with tau load in Braak I‐V and I‐VI (Figure 2). In TRIAD, this was also observed in Braak I‐III and I‐IV for CSF pTau 217 and 231, and in Braak I‐II for plasma pTau 231. In ADNI, this was also seen for CSF pTau181 in Braak I‐II and I‐III. Tau load did not correlate better with pTau in any ROI.

Conclusion

PTau biomarkers seem to inform better on SEOT than on tau load. There is a trend for better performance of SEOT as an imaging correlate of pTau when studying late Braak stages. Future studies should investigate the relationship between these measures and the clinicopathological progression of AD.
Plasma biomarkers are stable for an extended period at –20°C: Implications for resource‐constrained environments
Authors: Ayele Biniyam A. , Whitehead Patrice L. , Gu Tianjie , Arvizu Jamie , Golightly Charles G. , Adams Larry D. , Pericak‐Vance Margaret A , Vance Jeffery M. , Griswold Anthony J.
Published: January 2025

Background

The Recruitment and Retention for Alzheimer’s Disease Diversity Cohorts in the Alzheimer’s Disease Sequencing Project (REAAD‐ADSP) aims to explore ADRD in diverse ancestral groups within the US and nine countries from sub‐Saharan Africa. While most laboratories store plasma samples ‐80°C for biomarkers, no studies at –20°C have been reported past 2 weeks. Only two sites in Africa possess ‐80°C freezers. As biomarkers can be frozen and thawed, we hypothesized they would be stable at –20°C. The present study was designed to investigate the stability of AD plasma biomarkers at –20°C over time to facilitate studies of plasma biomarkers in resource‐constrained regions.

Methods

Peripheral blood was collected from six anonymous volunteers. Plasma was isolated via centrifugation and 200mL aliquots of plasma were made. Two aliquots per participant were stored immediately at ‐80°C and others at ‐20°C for two, four, six and fifteen weeks then moved to ‐80°C. Plasma biomarkers, pTau181 and Aβ42, Aβ40, NFL, and GFAP, were measured for each time point. Each aliquot was run in duplicate in the assay plate and two aliquots per participant per time point were assayed.

Results

There was a range values at baseline for each biomarker across the six participants: pTau181: 1.6‐3.0pg/mL, Aβ42: 3.7‐6.3pg/mL, Aβ40: 56.2‐106.6pg/mL, NFL: 3.5‐14.9pg/mL, GFAP: 42.9‐71.1pg/mL. At week fifteen, the average change in pTau181 was 0.14pg/mL, less than a 10% overall change. The Aβ42/40 ratio showed a decrease of 3.6% in week 15 compared to the baseline. Variability in NFL and GFAP were higher with increases in all subjects in week 15. Such run variance has been noted for these biomarkers by the manufacturer, thus our results suggest that after fifteen weeks at ‐20°C the assays are performing within specifications.

Conclusion

Up to 15 weeks of storage of plasma at ‐20°C does not significantly change AD related plasma biomarker concentrations beyond assay specifications, though there are slight increases in GFAP and NFL. This suggests that locations lacking ‐80°C storage can utilize ‐20°C equipment and still maintain biomarker fidelity, allowing for greater representation of biomarker studies from low‐ and middle‐ income countries, increasing the diversity of studies in AD.
Neuroticism and risk of all‐cause dementia, Alzheimer’s disease, and vascular dementia: exploring modification by genetic risk and mediation by vascular and mental health
Authors: Gao Yaqing , Amin Najaf , Van Duijn Cornelia M , Littlejohns Thomas J
Published: January 2025

Background

Neuroticism is a personality trait that is typically stable across the life course. Higher neuroticism has been linked to a higher risk of developing dementia in studies primarily consisting of small sample sizes. There is a need to explore the association in larger populations, whilst uncertainty remains regarding the mechanisms driving the associations.

Method

We selected 174,164 participants aged 60 years or older who were dementia‐free at baseline from the UK Biobank cohort. Cox proportional‐hazards models were used to assess the association between standardized neuroticism score (z‐score) with risk of all‐cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD). Models were adjusted for age, sex, ethnicity, Townsend‐deprivation index, education, smoking status, alcohol intake, and body mass index. We investigated effect modification by genetic predisposition for dementia and mediation through mental and vascular health conditions. The association between neuroticism and dementia‐related neuroimaging outcomes was investigated in a sub‐sample who underwent an imaging assessment (n = 39,459).

Result

Over a median follow‐up of 13.5 years, 5,974, 2,741, and 1,364 participants developed all‐cause dementia, AD, and VaD, respectively. Each unit increase in neuroticism z‐score corresponded to an 11% (hazard ratio [HR] 1.11, 95% Confidence Interval [CI] 1.08‐1.14), 6% (HR = 1.06, 95% CI 1.02‐1.10]), and 15% (HR = 1.15, 95% 1.09‐1.21) higher risk of all‐cause dementia, AD, and VaD, respectively. The associations remained similar regardless of genetic predisposition for dementia risk. Depression, anxiety and stress‐related disorders, ischaemic heart disease, and hypertension mediated 38.5%, 12.8%, 10.9% and 10.4% of the total association between neuroticism and all‐cause dementia, with similar mediation proportions observed for dementia subtypes. Neuroticism was significantly associated with a lower volume of total grey matter and a higher volume of white matter hyperintensities, a marker of cerebrovascular health.

Conclusion

Neuroticism is associated with an increased risk of dementia, particularly VaD and cerebrovascular pathology, regardless of genetic risk. Mental and vascular health may mediate this association. Neuroticism could represent a marker for dementia risk stratification and addressing the increased burden of mental and vascular health conditions in individuals with higher neuroticism could, if causal, ultimately help prevent or delay the onset of dementia.
Optimization of SHIP1 Inhibitors for the treatment of Alzheimer’s disease
Authors: Jesudason Cynthia D , Lin Peter Bor‐Chian , Soni Disha , Perkins Bridget M , Lee‐Gosselin Audrey , Ingraham Cynthia M , Hamilton Will , Mason Emily R , Jordi Omar El , Souza Sarah , Jacobson Marlene , Salvo Jerry Di , Clayton Brent , Chu Shaoyou , Dage Jeffrey L. , Oblak Adrian L , Richardson Timothy I.
Published: January 2025

Background

SHIP1 is a phosphatidyl inositol phosphatase encoded by INPP5D, which has been identified as a risk gene for Alzheimer’s disease (AD). SHIP1 is expressed in microglia, the resident macrophage in brain. It is a complex, multidomain protein that acts as a negative regulator downstream from TREM2. SHIP1 possesses a phosphatase (Ptase) domain flanked by a pleckstrin‐homology (PH) domain that binds phosphatidylinositol (3,4,5)‐trisphosphate[PI(3,4,5)P3] and a C2 domain that binds phosphatidylinositol (3,4)‐bisphosphate [PI(3,4)P2]. The Ptase domain converts PI(3,4,5)P3 to PI(3,4)P2. SHIP1 also has an SH2 domain that binds to ITIMs and ITAMs where it competes with kinases. Inhibiting SHIP1 is hypothesized to have potential therapeutic benefits, as it may improve TREM2‐mediated microglial responses to neurotoxins and promote an overall neuroprotective microglial phenotype to maintain a more resilient brain and slow the rate of cognitive decline in AD patients.

Method

The IUSM Purdue TREAT‐AD Center recently evaluated SHIP1 inhibitors and proposed 3‐((2,4‐Dichlorobenzyl)oxy)‐5‐(1‐(piperidin‐4‐yl)‐1H‐pyrazol‐4‐yl)pyridine for target validation studies. Structurally related analogs were synthesized and tested for SHIP1 enzyme inhibition, AKT signaling, and microglia activation in a high‐content imaging assay using HMC3 and BV2 microglia‐like cell lines. Primary microglia were treated with an optimized SHIP1 inhibitor, and subsequent changes in fibril Aβ uptake and cell viability were assessed. The NanoString nCounter Neuroinflammation assay was used to measure transcriptomic profiles. For comparison primary microglial derived from both wild‐type and Inpp5d‐haploinsufficient mice were assessed.

Result

Novel SHIP1 inhibitors have been discovered and preliminary Structure Activity Relationship (SAR) studies have been completed. These compounds have shown positive results for biochemical activity, target engagement and cellular pharmacology. Both Inpp5d deficiency and pharmacological inhibition increase amyloid uptake and cell viability in primary microglia. Elevated ERK and AKT phosphorylation, after amyloid exposure, were decreased by Inpp5d deficiency. Functional pathways associated with phagocytosis, apoptosis, cytokine production, and complement system activity were altered.

Conclusion

These data demonstrate that SHIP1 inhibition promotes amyloid uptake through the complement system. SHIP1 inhibition also enhances cell survival and homeostasis in primary microglia. Further studies of SHIP1 inhibition and INPP5D knockdown in animal models may provide a potential therapeutic strategy for Alzheimer’s disease.
Optimizing primary care for cognitive impairment screening using agile implementation
Authors: Summanwar Diana , Brosch Jared R. , Hammers Dustin B. , Fowler Nicole R , Willis Deanna R
Published: January 2025

Background

Screening for cognitive impairment in primary care faces challenges, including time constraints, provider apprehension, and limited diagnostic confidence. An effective initiative for improving screening must include strategies to foster behavioral change, and active provider engagement. Agile implementation science integrates findings from behavioral economics, complexity science, and network science, to address these challenges by confirming the demand to solve the problem; local solution adaptation; and the iterative ‘sprints’, or tests of change, that are focused on execution. This study, which is part of the Davos Alzheimer’s Collaborative (DAC) Early Detection Health System Preparedness Flagship program, explored workflows to support Digital Cognitive Assessment (DCA) in primary care, enhancing early detection of mild cognitive impairment (MCI) and dementia.

Methods

Between June 1, 2022, and May 31, 2023, seven diverse primary care clinics participated in the DAC program. The initiative’s core was the integration of offering and performing Linus Health Core Cognitive Evaluation Digital Cognitive Assessment (DCA) for patients aged 65 and above. The selection of the digital screening tool, process workflows, and improvement cycles were co‐designed by the primary care providers, clinic staff, the Patient Advisory Council, and the implementation team using Agile Implementation. A Brain Health Navigator (BHN) role was designed to fill workflow gaps in primary care evaluation of abnormal screening and facilitate specialty care transition for patients needing referral.

Results

Among the seven sites, five sites engaged in agile implementation and had similar performances, with an increase in DCA completion observed. A total of 1808 DCA screenings were performed on 1722 unique patients. The agile implementation process facilitated clinic‐specific adaptations, which resulted in an increase in the overall number of eligible patients completing the DCA screening.

Conclusions

The adoption of an agile implementation process increased DCA screening uptake in primary care settings. The integration of a BHN and streamlined workflows proved crucial in enhancing the screening, diagnosis, and referral journey. This integration aligns with the principles of person‐centered care and facilitates service coordination. It also supports workforce initiatives and advances the field of health services research, ensuring that each step in the patient’s journey is both effective and efficient.
Dynamic Neurocognitive Adaptation in aging: developing and validation of a new scale
Authors: Cieri Filippo , Francesco Giulia Di , Bender Andrew R. , Cross Chad L. , Caldwell Jessica ZK
Published: January 2025

Background

Up to 40% of current AD cases may have been preventable through protective factors, such as physical and cognitive activities, preventing neurodegeneration. Reserve, resilience, and resistance are key concepts in cognitive neuroscience of aging, and they share common adaptive mechanisms. In this paper we propose a development and validation of a new scale, called dynamic Neurocognitive Adaptation (dNA).

Method

This study included 815 participants (50% women) with a minimum age of 65 years, divided in two subsamples: exploratory factor analysis (EFA), and confirmatory factor analysis (CFA). Data collection utilized survey measures administered via Qualtrics. Our initial scale was composed of 30 items, investigating 7 different dimensions, explored by a 5‐point Likert scale reflecting frequency of activities. We investigated lifetime through 7 time‐windows, from childhood (0‐10) to old age (65+).

Result

Our final scale is composed by 20 items divided among 4 dimensions (physical, cognitive, social, and creative). Scale assessment indicated that there were no issues found related to multi‐collinearity (r< 0.95) or non‐collinearity (r< 0.3). For the final model, KMO = .80 and Bartlett’s test of sphericity indicated all values ≤0.01. Our Cronbach’s alpha was .83.

Conclusion

We have validated a reliable, novel, easy to complete, and comprehensive scale to assess lifetime adaptive behaviors, which can be applied in research on AD risk reduction, MCI, and in clinical practice. We underlined the dynamic role of time and the investigation of the creative dimension in aging. Our dNA can be used to personalize health recommendations in aging.
Individuals with Alzheimer’s disease living alone in Sweden receive limited comprehensive care
Authors: Religa Dorota
Published: January 2025

Background

A significant number of individuals with Alzheimer’s disease (AD) reside independently in their homes, yet there is limited understanding of whether they receive comparable diagnostic and treatment standards for AD compared to their cohabiting counterparts. The prevalence of dementia is rising, particularly among the elderly, with approximately 150,000 individuals affected by dementia in Sweden, two‐thirds of whom have AD. The national quality registry SveDem (Swedish registry for cognitive (dementia disorders) was established to promote consistent and high‐quality dementia care across the country.

Methods

Conducted as a cross‐sectional cohort study utilizing data from the Swedish registry for cognitive/dementia disorders (SveDem), we focused on patients in the community diagnosed with AD between 2007 and 2015 (n = 26,163). Information on medications and comorbidities was extracted from the Swedish Prescribed Drug Register and the Swedish Patient Register.

Result

Among the study participants, 46% (11,878) lived alone, primarily comprising older women. After adjusting for confounding factors, living alone was associated inversely with the likelihood of receiving computed tomography (OR 0.90; 95% CI 0.82‐0.99), magnetic resonance imaging (OR 0.91; 95% CI 0.83‐0.99), and lumbar puncture (OR 0.86; 95% CI 0.80‐0.92). Additionally, living alone was negatively correlated with the utilization of cholinesterase inhibitors (OR 0.81; 95% CI 0.76‐0.87), memantine (OR 0.77; 95% CI 0.72‐0.83), and cardiovascular medication (OR 0.92; 95% CI 0.86‐0.99). Conversely, living alone was positively associated with the use of antidepressants (OR 1.15; 95% CI 1.08‐1.22), antipsychotics (OR 1.41; 95% CI 1.25‐1.58), and hypnotics and sedatives (OR 1.09; 95% CI 1.02‐1.17). When mew data on other dementia were included: among the study participants up to 2018 (n = 80,004), 43.8% (35053) lived alone, primarily comprising older women (58.6%). The mean age was 79.6 (SD 7.9). The following age groups were included under 70 8456 (10.6%), 70‐79 27381 (34.2%), 80‐89 37628 (47.0%) and 90+ 6539 (8.2%).

Conclusion

Individuals with AD living alone receive less comprehensive care compared to their cohabiting counterparts. Finding will be presented on other types of dementia.
Small molecules targeting Progranulin as potential therapeutics for Frontotemporal Dementia (FTD) and other dementias
Authors: Chatterjee Suman , Lorenz‐Guertin Joshua , Santos Junriz O. Delos , Bandyopadhyay Mohna , Tomaszewski Monica , Dilley Kari , Hartman Emma , Sneddon Scott
Published: January 2025

Background

Progranulin (GRN) plays a critical role in familial frontotemporal dementia (fFTD), where GRN haploinsufficiency leads to reduction in PGRN levels in the brain, resulting in degeneration of neurons in the frontal lobe of brain responsible for personality, language, and behavior. FTD is the most common dementia in people under 60. Sortilin (Sort1), expressed by neurons, endocytoses, and delivers PGRN rapidly to lysosomes for degradation. To compensate the lack of PGRN, therapeutic strategies to increase extracellular PGRN have been pursued to address fFTD with no approved treatments currently available.

Methods

We performed an SH‐SY5Y cell‐based assay to identify small molecules that reduce PGRN endocytosis. Validation of lead candidates was performed by the same assay in mouse neuroblastoma cell line, N2a and rat neurons. This was followed by medicinal chemistry for structure optimization to improve the potency and stability of the compounds. Compounds with better in vitro potency and stability were then further optimized through an iterative series of pharmacokinetic (PK), and pharmacodynamic (PD) assessments.

Results

Sharp has discovered a series of structurally related compounds with potent EC50 values in blocking Sortilin‐mediated PGRN endocytosis in multiple cell lines from different species allowing levels of progranulin to increase almost two‐fold. In addition, our lead compound has been shown to increase extracellular PGRN levels in a dose dependent manner. Finally, intraperitoneal administration of our lead compound(s) to mice resulted in a dose and exposure‐dependent increase in PGRN measured in brain tissue extracts and plasma. Lead compounds were further characterized for CNS drug‐like properties including PK, metabolism, brain penetration, and are currently being evaluated in selectivity, and safety assays.

Conclusions

Our approach generated a series of novel small molecules, especially our lead candidates that show favorable drug‐like characteristics in vitro and in vivo and are well‐suited to be clinically evaluated for the treatment of fFTD.
Predicting individual‐level stroke risk associated with risperidone use in dementia using cardiovascular disease history: matched UK population based cohort study
Authors: Choma Nalamotse Joshua , Griffiths Alys , Henley William E , Mueller Christoph , Williams Nefyn , Dennis John , Creese Byron
Published: January 2025

Background

Experiencing behavioural symptoms such as aggression, agitation and psychosis contribute significantly to reduced quality of life amongst people with dementia. These behavioral symptoms can be considered more detrimental to overall well‐being than cognitive impairment. In the UK, risperidone is the sole approved atypical antipsychotic for treating these symptoms, despite its notable risk of serious side effects, including stroke. This project aims to develop personalized stroke risk prediction models based on individual clinical features upon introducing risperidone.

Methods

This research will use data from 358,406 patient records contained in the Clinical Practice Research Datalink (CPRD). These data sets include individuals diagnosed with dementia after age 65 after January 1, 1990. The CPRD data will serve as the primary source of information for our study and will facilitate the analysis of stroke risk associated with risperidone use in this specific patient population. Our analysis will focus on two distinct groups, individuals diagnosed with dementia who have been prescribed risperidone and individuals diagnosed with dementia who have never been prescribed risperidone. To achieve our research objectives, we will analyze and compare the incidence of stroke within these two groups. We will then examine whether risk is moderated by individual clinical history. This thorough investigation will form the basis for our predictive models.

Results

Preliminary findings from the data show a well‐defined cohort of dementia cases with an average age of 82 years at diagnosis, consisting predominantly of females (64%). Of the cohort, 87,858 individuals fall into the 75‐84 age category. Over the study period, 47.0% of the cohort died during the study period. The median survival time is approximately 4.4 years for males and 3.7 years for females in the study cohort. This median survival time increases to 6.8 years for people diagnosed at the age of 65‐74 years.

Conclusions

This project’s success could significantly enhance the safety and efficacy of risperidone prescriptions for people with dementia. By leveraging personalized prediction models based on individual clinical features, our research aims to equip clinicians with tools for more informed and patient‐specific decisions concerning risperidone treatment.
Development of Diverse Carbon Dots to Inhibit Protein Aggregation in Alzheimer’s Disease
Authors: Smith Nathan Scott , Burr Hannah J , Zhang Wei , Wang Chunyu
Published: January 2025

Background

Alzheimer’s Disease (AD) is the leading form of senile dementia, affecting ∼6 million Americans and having a national economic impact of $321 billion, numbers expected to double by 2050. The major pathological hallmarks of AD include Amyloid Beta (Aβ) plaques and Tau neurofibrillary tangles (NFT). The first goal of this research was to develop novel forms of carbon dots (CD) using various precursors. The next goal was to use these unique CDs to inhibit the aggregated hallmarks of AD. Some dots were also conjugated to drug compounds such as chalcones and memantines.

Method

We synthesized CDs from precursors such as urea, Congo red, memantine, and citric acid, according to the Muffle furnace method. We then aimed to utilize the newly synthesized CDs to inhibit tau and Aβ aggregation in vitro. Thioflavin T (ThT) aggregation assays were then selected to quantify the protein aggregation and was verified via atomic force microscopy (AFM) and transmission electron microscopy (TEM) for visualization. Zebrafish models were chosen to confirm blood brain barrier (BBB) penetration.

Result

Almost all CDs demonstrated inhibition of both tau and Aβ aggregation, suggesting their use as dual inhibitors. Some CDs demonstrated IC50 values for inhibition, as low as 0.2 ± 0.1 mg/mL for tau and 2 ± 2 mg/mL for Aβ aggregation. Many of these aggregates were verified using AFM technology and TEM technology to acquire photos of aggregates. As the concentration of CDs increased, the number of visible protein aggregates decreased. Some of the CDs synthesized also demonstrated the ability to penetrate the BBB as shown during experimentation with zebrafish.

Conclusion

Overall, the data suggests CDs have a unique ability to inhibit the aggregation of both AD hallmarks. This data encourages investing further research into CDs for the future treatment of AD.
Revolutionizing Early Detection: A Comprehensive Cognitive Screening Tool for ADRD Through Innovative Mobile App Technology
Authors: Smith Lenora W , O'Brien Charles
Published: January 2025

Currently, there are no curative treatments for Alzheimer’s Disease. It is crucial to develop screening tools that detect early signs of decline, allowing for timely interventions that may impede the progression of cognitive impairment. Neurospective is a mobile application platform designed to facilitate the early detection of cognitive decline, including mild cognitive impairment (MCI) and pre‐clinical Alzheimer’s disease and related dementias (ADRD). It utilizes a unique combination of engaging cognitive assessment games, diverse user data collection, and machine learning to establish a robust and accessible screening tool. Data Collection will include Cognitive Assessments (suite of mini‐games inspired by established screening tests like 3MS, MoCA, and SLUMS); User Metrics including app usage time, success rates, and reaction times, which provide additional insights into cognitive performance; and Surveys gathering demographic information, self‐reported cognitive impairment, and diagnosed ADRD. The primary aim of this study is to establish a relative measure of cognitive health within the population, eventually evolving into a reliable screening tool for early detection of cognitive decline. The innovation of this research is its accessibility, fostering widespread use, particularly in underrepresented populations facing limited access to traditional screening methods; its comprehensiveness with its diverse data collection, encompassing cognitive performance, usage metrics, and personal information, allowing a multifaceted approach to identifying early signs of cognitive decline; and evolving models including machine learning algorithms that continuously refine themselves based on user data, leading to increasingly accurate predictions of cognitive health and potential ADRD risk. Our target populations are people with pre‐clinical symptoms of ADRD and MCI. Our target data set is 25,000+ users with at least 10% survey completion. Both the app and the resulting dataset will be publicly available for further research and development. User privacy is protected through anonymity and voluntary participation. The Neurospective app presents a unique and promising approach to early detection of cognitive decline through its accessible mobile app format, comprehensive data collection, and evolving machine learning models. This project has the potential to significantly improve our understanding of cognitive health and contribute to earlier intervention for individuals at risk of ADRD.
Healthcare resource utilization in cognitively unimpaired individuals 5 years prior to amyloid PET for A4 vs. LEARN eligibility
Authors: Chandler Julie , Kubisiak Joanna , Lee Angelina , Holdridge Karen Chilcott , Robinson Rebecca L. , Yaari Roy , Rafii Michael , Aisen Paul S. S. , Sperling Reisa A
Published: January 2025

Background

Medical history and healthcare utilization in preclinical Alzheimer’s disease (AD) are not well characterized and may reveal indicators associated with asymptomatic stages of AD.

Methods

This retrospective observational study compared 246 Anti‐Amyloid Treatment in Asymptomatic AD study (A4) individuals who met elevated brain amyloid eligibility criteria to 121 individuals in the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration study (LEARN) who were eligible for A4 except did not meet elevated amyloid eligibility criteria. Matched‐controls for A4/LEARN, using a 3:1 match of demographics, Medicare enrollment month, and frailty status, were randomly selected from Medicare beneficiaries without cognitive impairment/dementia claims. Primary outcomes (Medicare claims diagnoses, utilization, payments, medications) were compared up to 5 years before A4/LEARN enrollment.

Results

A4 and LEARN individuals had comparable common comorbidities during 5‐year pre‐study period; hypertension and diabetes were significantly less frequent vs. matched‐controls (Figure 1). Rates of diagnoses associated with AD onset (mood, adjustment, sleep disorders), were generally similar between A4 and LEARN, but significantly higher among A4 but not LEARN individuals vs. matched‐controls (Figure 2).

Utilization for inpatient, emergency room, professional encounters for evaluation/management, surgery, anesthesia, and pathology/laboratory services were significantly higher for A4 vs. LEARN individuals (Table 1). Relative to matched‐controls, A4 and LEARN individuals had generally higher rates of professional encounters; LEARN had lower inpatient episodes.

A4 vs. LEARN individuals had higher payments for ER and anesthesia (Table 1). A4 individuals vs. matched‐controls had higher payments for medicine services/procedures but lower payments for durable medical equipment.

A4 individuals had similar or greater use of all medication categories except for cardiovascular relative to matched‐controls.

Conclusions

Up to 5 years before amyloid testing, individuals who met elevated amyloid eligibility criteria had comorbidity profiles generally comparable to companion study individuals who did not meet amyloid eligibility criteria and matched‐controls, but were more likely than matched‐controls to have diagnoses associated with AD onset, and had greater utilization of medicine services and procedures. The latter may indicate a predisposition to seeking medical care among individuals who participate in clinical studies. Continued follow‐up of these patterns may provide additional insight into early indicators associated with asymptomatic AD.
Online, Community‐Based Workshop for Rural Family Caregivers of Persons Living with Dementia in the United States: Results of a National Randomized Controlled Trial
Authors: Yank Veronica , Santoyo‐Olsson Jasmine , Cheng Jing , Lorig Kate , Gallagher‐Thompson Dolores , Chesla Catherine , Karliner Leah , Covinsky Kenneth E , Romo Elizabeth Macias , Luzanilla Maritza
Published: January 2025

Background

Family caregivers of persons living with dementia (PLWD) in rural areas of the United States (U.S.) are isolated, under‐served, and experience poor health outcomes. We evaluated the impact of an online workshop on the psychological well‐being and health of rural caregivers.

Methods

We conducted a randomized controlled trial of an asynchronous 6‐week online peer‐led small group workshop, Building Better Caregivers, that is designed to increase self‐care and caregiving skills. Caregivers use materials at home whenever they have time, self‐pace their learning, and chat asynchronously with other caregivers through threaded discussion board conversations. Caregivers living in U.S. rural areas, 18+ years old, and giving care ≥ 10 hours a week to a family member or friend living with dementia were randomly assigned in a 3:1 ratio to intervention or attention control (phone calls and caregiver handbook, plus workshop after trial completion). Data were collected at baseline, 1.5 months, and 6 months. Primary outcomes were depressive symptoms and stress. Secondary outcomes were loneliness, caregiving self‐efficacy, and self‐reported health. Longitudinal outcomes were modeled with (generalized) linear mixed effect models and compared with corresponding contrasts between the two groups over time.

Results

409 caregivers participated, and 88% were retained at 6 months. Participants were aged 62.3±11.2 years; 85% identified as female; 90% identified as heterosexual; 86% identified as White; 55% had ≥ bachelor’s degree. (Table 1) Most provided care to a spouse (44%), parent (44%), or other relative (7%), and 76% lived with the PLWD. Among PLWD at baseline, 51% needed assistance with at least two activities of daily living (ADLs), and 39% required assistance with three or more ADLs. Compared to controls at 1.5 months, intervention group participants had lower depression symptoms, stress, and loneliness, and higher caregiving self‐efficacy. (Table 2) At 6 months, intervention group participants had fewer depressive symptoms and were less likely to report poor health than controls. Specifically, intervention group caregivers maintained similar levels of depressive symptoms and self‐rated health throughout the trial whereas controls worsened substantially.

Conclusions

Findings suggest that the Building Better Caregivers online workshop improves the well‐being of rural caregivers who perform high burden care.
Changes in individualized functional brain networks at the preclinical stage of Alzheimer’s disease
Authors: Pappas Ioannis , Xiao Cally , Toga Arthur W.
Published: January 2025

Background

Prior work in preclinical Alzheimer’s disease has shown different phases of hyper and hypo connectivity especially within the default mode network (DMN) (Schultz et al., 2017). However, these analyses often rely on group templates that estimate network connectivity based on predefined parcels, potentially obscuring individual variability. New methods allow us to estimate networks at the individual level and these networks show individual‐specific variation in terms of their connectivity, size, and spatial arrangement (Kong et al., 2019; Gordon et al., 2017).

Method

Individualized networks were extracted data from 121 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset based on availability of functional MRI, amyloid, and tau PET data. Functional MRI data was processed following methods by (Yeo et al., 2011) pipeline. We used methods from (Kong et al., 2019) to obtain individual‐specific networks using the 17‐network parcellation as a prior. In this work we focused on the medial temporal network subcomponent of the DMN (MTN) and examined its connectivity and volume. Amyloid positivity and tau PET standard uptake value ratios (SUVRs) (entorhinal) were derived from the ADNI data.

Result

Out of the initial cohort, 72 individuals had usable fMRI data. MTN connectivity was significantly higher in amyloid positive (A+) versus amyloid negative (A‐) individuals with no cognitive impairment (p<0.01). MTN network volume did not change between A+ and A‐ individuals. When looking at the relationship between network markers and tau PET signal, we found that MTN volume was negatively correlated with tau PET SUVRS in entorhinal cortex (r = ‐0.3; p=0.01). MTN connectivity was not related to entorhinal tau PET signal. No interaction effects were observed between amyloid positivity and tau PET signal when predicting connectivity or volume. Exploratory analysis revealed that baseline MTN connectivity was positively correlated with change in entorhinal tau PET signal over two years.

Conclusion

These results suggest that individualized networks are sensitive to amyloid and tau biomarkers in preclinical Alzheimer’s disease. Network connectivity seems to track amyloid burden while network volume is more related to tau PET signal. Overall, individualized approaches can reveal subtle network changes that can be related to disease biomarkers.
Neighborhood Disadvantage and Cognitive Outcomes: A Narrative Review
Authors: Al‐darsani Zeinah , Kulick Erin R
Published: January 2025

Background

The number of individuals with age‐related cognitive impairment is projected to increase at an unprecedented rate over the next few decades due to demographic shifts. Recent research endeavors have been increasingly aimed at understanding risk factors at the neighborhood level, notably socioeconomic status (SES). This review aims to provide insight into the current state of knowledge on the role of neighborhood disadvantage, defined by neighborhood SES, on late‐life cognitive outcomes.

Method

Out of 138 articles meeting our criteria in PubMed and Embase, 11 U.S.‐based studies were included in this review. We focused on U.S.‐based studies because social and structural factors may vary across countries, potentially influencing the relationship between neighborhood disadvantage and cognitive outcomes.

Result

Nine of the included studies were longitudinal and 2 were cross‐sectional. Three articles used the Area Deprivation Index (ADI), while 8 used a 4 or 6 item US‐Census‐based measure of neighborhood socioeconomic status (NSES) or position (nSEP) to assess neighborhood disadvantage. Three articles reported incident dementia, 5 on global cognitive decline, 2 on domain‐specific cognitive decline, 1 on domain‐specific cognitive function cross‐sectionally, and 1 on global cognition cross‐sectionally. Overall, 73% (n = 8) studies showed a significant association between neighborhood disadvantage and cognitive outcomes. Neighborhood disadvantage was not more strongly associated with a particular cognitive outcome, and results did not seem to differ based on the method of assessing neighborhood disadvantage. Most of the included studies comprised ethnically diverse participants, enhancing the generalizability of the results to the broader U.S. population and allowing exploration of ethnoracial‐specific associations. Among the 8 diverse included studies, 4 reported ethnoracial differences on the association between neighborhood disadvantage and cognitive outcomes. One study found that childhood nSEP, rather than midlife NSEP, was associated with cognitive decline.

Conclusion

Neighborhood disadvantage may be associated with poorer cognition. However, additional research is needed to unequivocally establish an association between neighborhood disadvantage and cognitive outcomes due to the limited extant literature. Nevertheless, this review provides insights for future research, including investigating the influence of other structural health determinants on the relationship between neighborhood disadvantage and late‐life cognition, and as well as applying life‐course approaches to assessments of neighborhood disadvantage.
Unlocking the synergistic potential of HAT activation and HDAC inhibition for rescuing memory deficits in Alzheimer’s Disease
Authors: Calcagno Elisa , Zuccarello Elisa , Staniszewski Anna , van de Loo Jonhatan , Zhang Hong , Acquarone Erica , Stack David K. , Haut Florence , Deng Shi‐Xian , Landry Donald W. , Fiorito Jole , Arancio Ottavio
Published: January 2025

Background

Memory is influenced by epigenetic mechanisms that regulate gene expression. Histone acetyltransferases (HATs), and histone deacetylases (HDACs), are two competitive enzymes regulating histone acetylation. Histone acetylation is reduced in Alzheimer’s disease (AD) brains, and evidence has shown a synergistic regulation of HDACs and HATs activities. Specific HATs such as CREB binding protein (CBP), p300, and PCAF positively influence memory, while HDAC2 and HDAC3 negatively impact it. Maintaining the balance between HAT and HDAC levels and activity is crucial for regulating gene expression profiles essential to memory processes. Consequently, increasing histone acetylation in neurons, while maintaining the balance between HAT and HDAC enzymes, offers the potential to attenuate AD progression by acting at the downstream level of Aβ and tau elevation.

Method

Hippocampal slices from C57Bl6 mice were exposed to Ab oligomers (oAβ) plus the HAT activator YF2 and/or the HDAC inhibitor TSA in electrophysiological experiments assessing long‐term potentiation (LTP), a cellular surrogate of memory formation. The APP/PS1 mouse model of Aβ elevation and the hTau/Mapt‐KO mouse model of tau elevation were used in electrophysiological, behavioral and biochemical experiments aimed at investigating LTP and memory.

Result

Following establishment of subthreshold doses (i.e. doses immediately below the concentration that has a minimal beneficial effect on LTP) for YF2 and TSA alone against Ab‐oligomer induced LTP defect, we found that pairing subthreshold doses of the two compounds rescued the oAβ‐induced LTP impairment. The beneficial effect of the combination was also present when subthreshold doses of YF2 and TSA were administered to 3‐month old APP/PS1 mice and 12 month old hTau/Mapt‐KO mice. Notably, chronic administration of YF2 (0.5 mg/kg) and TSA (0.5 mg/Kg) for 1 month in APP/PS1 mice and 3 months in hTau/Mapt‐KO animals rescued the defects in associative and spatial memory, as well as LTP.

Conclusion

In summary, the synergistic effect observed with the combination of YF2 and TSA not only maintains the balance of HAT/HDAC activity but also enables the use of lower concentrations for both drugs, overcoming the specificity challenges associated with HDAC inhibitors. This compelling combination emerges as a highly promising therapeutic strategy against AD.
Analysing Remote Nocturnal Activity and Sleep Monitoring Data to Develop Predictive Models in Dementia Care
Authors: Barnaghi Payam
Published: January 2025

Background

Close to 23% of unplanned hospital admissions for people living with dementia (PLWD) are due to potentially preventable causes such as severe urinary tract infections (UTIs), falls, and respiratory problems. These affect the well‐being of PLWD, cause stress to carers and increase pressure on healthcare services.

Method

We use routinely collected in‐home sensory data to monitor nocturnal activity and sleep data.

Result

We apply machine learning models to develop a new generation of dementia care solutions to analyse changes in patterns.

Conclusion

Developing machine learning models to analyze in‐home sleep data will help enable detection of sleep changes and timely interventions.
Exercising Physiological Pathways: The Impact of Exercise on Metabolic Aging, Cellular Aging, and Inflammatory Biomarkers in All‐Cause Dementia
Authors: Hanson Mitchell T , Dong Yanbin , Zhu Haidong , Soares Andre , Hergott Colleen , Waller Jennifer L , Young Lufei , Robinson‐Johnson Dawnchelle , Sams Richard , Hamrick Mark , Jehu Deborah A
Published: January 2025

Background

Physiological changes, including metabolic and cellular aging, as well as increased inflammation, occur in people living with dementia (PWD). While there is existing evidence in other populations suggesting that exercise may improve physiological outcomes, their impact in PWD remains unclear. This randomized controlled trial (RCT) aimed to assess the effects of exercise on serum levels of metabolic aging, cellular aging, and inflammatory blood biomarkers relative to usual care alone in PWD.

Method

This pilot RCT involved n=42 PWD (exercise n=21; usual care n=21) in one nursing home and one assisted living facility (NCT05488951). The adapted Otago Exercise Program involved 30 minutes of tailored lower body strength and balance exercises and 30 minutes of walking 3x/week for 6 months. We drew fasted blood at baseline and 6 months. Blood samples were stored at ‐80°F and analyzed for metabolic aging (kynurenine), cellular aging (telomere length), and inflammatory biomarkers (interleukin‐6, IL‐1b, interferon alpha2, IFNg, tumor necrosis factor a, chemokine ligand 2, IL‐8, IL‐10, IL‐12p70, IL‐17A, IL‐18, IL‐23, IL‐33). Generalized mixed models were used for intent‐to‐treat (n=42) and per protocol analyses (usual care: n=21; n=9 exercisers with ≥2/3 adherence), controlling for age, race, sex, and the Montreal Cognitive Assessment.

Result

The intent‐to‐treat analysis revealed no differences in physiological biomarkers between groups. The per protocol analysis revealed a trend for reduced inflammation in IL‐1b (exercise: 9.73 to 6.16 pg/mL; usual care:10.51 to 15.46 pg/mL; p=0.09) and IL‐8 (exercise: 39.34 to 25.92 pg/mL; usual care:78.99 to 93.04 pg/mL; p=0.09). Additionally, the control group increased telomere length compared to the exercise group (exercise:8.0 to 7.9 kb; usual care:7.9 to 8.7 kb; p=0.01).

Conclusions

The trend for exercise reducing inflammation in the per protocol analysis suggests that a greater amount of exercise (i.e., ≥2/3 exercise adherence) may be necessary to reduce inflammation in PWD. The nuanced relationship between exercise reducing cellular aging in the usual care group requires further exploration, as we had a small sample size in our per protocol analysis. Our pilot findings may inform a larger RCT to determine a potential interplay between exercise and physiological biomarkers in PWD.