bluuebunny/crossref_metadata_2025 huggingface dataset:
Age‐specific Barriers and Facilitators to Research Participation Among Underrepresented African Americans
Authors: Nissim Nicole R. , Fudge Michelle R. , Lachner Christian , Lucas John A. , Graff‐Radford Neill R , Day Gregory S.
Published: December 2023

Background

African Americans experience a high dementia burden yet are critically underrepresented in observational studies and clinical trials in memory and aging. Lack of adequate representation increases the likelihood that research findings may not generalize to African Americans. A deeper understanding of the barriers and facilitators that influence participation by younger and older African American adults is needed to support recruitment and retention in studies focused on early‐ and late‐onset neurodegenerative diseases.

Method

African American community leaders collaborated in design of an electronic survey that was distributed via social media focused on local zip codes. Survey respondents rated barriers and facilitators to research participation on a 0–3‐point Likert scale. Responses ≥2 corresponded with barriers/facilitators likely to influence participation decisions. Differences across age groups were evaluated using nonparametric Kruskal‐Wallis tests. Strategies to mitigate barriers and reinforce facilitators were further explored via community‐based focus groups.

Result

Survey data included responses from 240 African Americans (18‐44‐years, n = 76; 45‐64‐years, n = 83; ≥65‐years, n = 81). Requirement to undergo a diagnostic lumbar puncture was a substantial barrier to research participation across all age groups. Attending weekday visits (median = 2.0), including visits ≥2 hours (median 2.0), was a substantial barrier for individuals 18‐44‐years, but not older respondents (p = 0.001). Compensation for meals/transportation was beneficial across all age groups (median = 2.0; p<0.05). The option to attend visits in the local community or on weekends and access to door‐to‐door transportation were substantial facilitators for respondents <65‐years (median = 2.0) vs ≥65‐years (median = 0; p = 0.001). The option to complete some tests at home was a substantial facilitator for younger (18‐44‐years, median = 2.0) but not older respondents (≥65‐years, median = 0; p = 0.001). Focus group results supported survey findings and showed slight variations in priorities across age groups. Older participants (≥65‐years‐old) more frequently cited the longstanding effects of racism as a barrier to research participation compared to younger participants (45‐64‐years‐old; p = 0.008), who more frequently cited concerns regarding testing requirements (p = 0.034).

Conclusion

Perceived barriers and facilitators to research participation vary with age. Age‐specific strategies are needed to increase engagement, address disparities in recruitment, and promote retention of African American participants in studies of memory and aging across the lifespan.
Functional investigation of the gliovascular niche‐related genes and their relevance to Alzheimer’s disease pathomechanisms in zebrafish
Authors: Bhattarai Prabesh , Cosacak Mehmet I. , Lee Annie J , Yilmaz Elanur , Is Ozkan , Wang Xue , Vardarajan Badri N , Ertekin‐Taner Nilufer , Mayeux Richard , Kizil Caghan
Published: December 2023

Background

Recent studies increased the number of genes that are associated with the co‐existence of vascular pathologies and Alzheimer’s disease (AD). However, the biological functions and the mechanism of action by which they contribute to the disease pathology are still to be further elucidated. Therefore, animal models that allow streamlined large‐throughput functional screens in a biologically relevant manner are essential. Towards this goal, we generated adult zebrafish models of amyloid toxicity to functionally analyze candidate genes and how they relate to disease perturbations.

Method

Through cerebroventricular injection of human amyloid‐beta42 monomers into the cerebrospinal fluid of the adult zebrafish brain, we inflict acute amyloid toxicity. By performing immunohistological analyses, single cell transcriptomics, gene editing for generating gene variants or full knockouts, transient functional knockdown of candidate genes, pharmacological intervention of selected signalling pathways and comparing the findings to human AD brain transcriptomics datasets, we determined the similarities and differences of the effects of amyloid pathology on the vasculature in zebrafish in relation to the human conditions.

Results

We found that amyloid pathology in zebrafish brain shows histological and molecular similarities to human brains. Integration of single cell transcriptomics showed remarkable similarities in neurons to amyloid in humans and zebrafish. We identified several molecular mechanisms that underlie this pathology‐induced cellular response and translated to mammalian models including rodent brains. By performing genome‐wide association in AD patients, we identified that the FMNL2 links cerebrovascular disease and AD, by regulating the astroglial and blood vessel interactions and controlling the efficient clearance of toxic proteins from the brain. Our new single cell transcriptomics analyses of the gliovascular niche cells of the zebrafish brain revealed potential cellular interactions and the pathways perturbed in vascular disease and AD.

Conclusion

We propose zebrafish as a useful model for functional investigation of vascular pathology and AD‐related genes identified in clinical studies by providing in vivo biological knowledge on disease mechanisms, on which novel drug development strategies can be based.
Cross‐cohort correlation of plasma biomarkers for Alzheimer’s disease with cognitive measures in the Global Alzheimer’s Association Interactive Network
Authors: Xiao Cally , Gershfeld Seth P. , Pappas Ioannis , Toga Arthur W.
Published: December 2023

Background

Recent advances in assay development for Alzheimer’s disease (AD) biomarkers in the blood have led to increased sensitivity and specificity for detecting proteins such as the 42 amino acid amyloid‐beta (Aβ42), total and phosphorylated tau protein (t‐tau and p‐tau, respectively), and neurofilament light (NfL).

Method

Using data available in the Global Alzheimer’s Association Interactive Network (GAAIN), contributed by several studies such as the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL), the Health and Aging Brain Study: Health Disparities (HABS‐HD), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we correlated AD plasma biomarkers with cognitive diagnosis outcomes in a preliminary analysis. A full study with additional data sets and analysis methods, including controlling for confounding variables such as age, sex, years of education, and co‐existing medical conditions, is planned.

Result

Using logistic regression in the GAAIN Interrogator data analysis tool, we preliminarily found that participants with Aβ42 levels in the upper quartile of all measurements were not associated with mild cognitive impairment (MCI) or dementia diagnoses, the upper quartile of t‐tau and p‐tau181 measurements were associated with dementia but not MCI diagnoses, and the upper quartile of NfL measurements were associated with both MCI and dementia diagnoses.

Conclusion

Blood‐based biomarker assays that detect proteins implicated in Alzheimer’s disease have the potential for early and accurate diagnosis and are less invasive and costly than lumbar punctures for cerebrospinal fluid (CSF) collection and positron emission tomography (PET) imaging. This meta‐analysis contributes to the growing knowledge base of the prognostic utility of blood‐based biomarker assays.
Potentially modifiable factors explaining monozygotic twin discordance in amyloid pathology
Authors: Konijnenberg Elles , Coomans Emma M. , Tomassen Jori , Kate Mara Ten , Landen Sophie M. , Heuvelink Joost , Collij Lyduine E. , Tijms Betty M. , Teunissen Charlotte E. , Barkhof Frederik , van Berckel Bart N.M. , Scheltens Philip , Boomsma Dorret I , de Geus Eco J.C. , Visser Pieter Jelle , Braber Anouk
Published: December 2023

Background

The heritability of global amyloid burden in older adults was previously found to be moderate (41%), suggesting environmental factors to play an important role in early Alzheimer’s disease (AD) pathology. Identifying these factors may aid in the development of successful prevention strategies. Several, potentially modifiable, risk factors for dementia have been previously reported by Livingston and colleagues (Lancet, 2020). We here aim to identify which of these risk factors explain observed twin discordance in amyloid pathology in a sample of cognitively unimpaired monozygotic twin‐pairs.

Methods

We included 31 initially cognitively unimpaired twin‐pairs aged>60 years from the EMIF‐AD PreclinAD study who were discordant on amyloid status (defined by visual read of dynamic [18F]flutemetamol‐PET images). Paired samples t‐tests (continuous measures) and McNemar’s tests (dichotomous measures) were applied to investigate which factors associated with twin discordance. Selected risk factors included comorbid diseases, lifestyle and vascular risk factors (see table 2).

Results

Twins were on average 72.7±7.0 years old, consisted of 48% females, and 58% Apoe‐ε4 carriers (table 1). Twins with a positive amyloid status showed lower body mass index (BMI) and glucose levels compared to their amyloid negative co‐twin (table 2, figure 1A&B). We also observed a trend towards lower diastolic blood pressure in amyloid positive twins (table 2). In accordance with inclusion criteria for the study we observed very low prevalence of comorbid disorders in both groups. Further, no group differences were observed in lifestyle factors, such as smoking, alcohol use, physical activity and sleep quality.

Conclusions

In a sample of monozygotic twin‐pairs discordant for amyloid pathology, we found lower BMI and glucose levels to be associated with the presence of amyloid pathology. Although Livingston and colleagues reported high BMI (obesity) at mid‐life (age 45‐65) to increase the risk for dementia, effects of BMI have previously been found to differ in mid‐ and late‐age populations. In line with our results, lower BMI at later life (>65 years) has previously been found to increase AD‐risk. For the development of prevention strategies, it would be of relevance to further investigate these dynamic age‐related effects.
Team‐Based Learning Approach to Practice Improvements in a Memory Clinic
Authors: Love Marissa C. Natelson , Pilonieta Giovanna , Geldmacher David S.
Published: December 2023

Background

Workface projections indicate an increasing shortfall in neurologists and other medical specialists to treat persons with Alzheimer’s disease and other causes of dementia (Dall et al. Neurology 2013). This problem will be further magnified by available disease modifying therapies aimed at earlier stages of illness, markedly expanding the patient pool (Anderson et al. J Prev Alzheimers 2022; Hlavka et al. Rand 2019). With the Alzheimer’s disease treatment landscape approaching these turning points the University of Alabama at Birmingham Brain Aging and Memory (BAM) Clinic undertook a multidisciplinary expansion to improve access and increase the role of nonphysician professionals to optimize care. Onboarding this interdisciplinary team was complicated by separation of staff members mandated by the COVID‐19 pandemic. These factors, along with emerging use of “team‐based learning” educational models led to the creation of the BAM Learning Club (BAM LC).

Methods

BAM LC is a weekly synchronous online series of didactics, lectures, case discussions, journal reviews, and team‐building wellness activities. Participants include Neurologists, Psychiatrists, Psychologists, RN Case managers, RN Clinical Care Coordinators, Social Workers, Nurse Practitioners, Pharmacists, Caregiver Counselors, Research Scientists, Clinical Trial Coordinators, Postdoctoral Fellows, Residents, and Medical Students. Sessions are recorded for future onboarding and educational needs. Content is generated by the BAM LC members with support from its director.

Results

BAM LC began in June 2021 and has continued weekly with increasing interest and attendance. Shared learning has led to practice improvements, a collaborative environment, and a cohesive multidisciplinary team. Recorded sessions have been used to provide education outside of our cohort and will be maintained for future use.

Conclusion

Team‐based learning has resulted in better academic, clinical, and communication outcomes among health care professionals (Joshi et al. Cureus 2022). Multidisciplinary team‐led learning opportunities focused on dementia care could serve as a tool to promote further practice improvement, collaboration, and cohesion within healthcare organizations. Normalization of synchronous remote learning during the pandemic facilitated acceptance, uptake, and participation across disciplines. This process also has the potential to provide further system‐wide education in health systems to diversify the workforce and improve readiness to treat a rapidly expanding patient population.
Characterize demographics, comorbidities and co‐medications in newly diagnosed United States (US) Alzheimer’s Disease patients using Medicare claims
Authors: Schroeder Krista Marie , Afonso Ana Sofia , Wang Huabo , Grace Sarah , Phipps Adam , Sims John R.
Published: December 2023

Background

Access to Medicare claims provides a unique opportunity to broadly characterize diseases affecting US adults 65+ years of age. This can provide insights into real world populations and a basis of comparison to those in clinical trial populations. To this end, this study characterizes demographics, comorbidities and co‐medications in patients newly diagnosed with Alzheimer’s Disease (AD).

Methods

This study utilized Medicare Part A and B claims (Fee‐For‐Service and Medicare Advantage) limited to patients with at least one 2019 medical encounter. The study’s source population was limited to those 65+ years of age with Medicare Part D coverage and 1‐year pre‐encounter continuous enrollment. From this source population, three newly diagnosed AD cohorts were compiled; cohort 1 utilized the 1‐year Bynum‐Standard Alzheimer’s disease and related dementia (ADRD) claims algorithm, cohort 2 adapted the ADRD algorithm to include only specific AD diagnoses, and cohort 3 was selected based on new use of cholinesterase inhibitors (irrespective of ADRD diagnosis). Demographics, comorbidities, and co‐medications present in the 1‐year pre‐cohort qualification are described.

Results

From 53,890,958 patients with at least one 2019 medical encounter, 33,315,038 qualified for the source population. Of these patients, 861,727 (2.6%) were newly diagnosed with ADRD (cohort 1), 373,798 patients (1.1%) were newly diagnosed with AD (cohort 2), and 395,319 patients (1.2%) were new users of cholinesterase inhibitors (cohort 3). The cohorts were not mutually exclusive. Overall, the three cohorts were similar in terms of demographics (table 1) with 75.1‐85.3% of patients aged 75+ and 61.5‐66.4% female. Common comorbidities (table 2) across the 3 cohorts include cardiovascular (CV) comorbidities such as myocardial infarction (34.1‐41.9%) and heart failure (39.8‐51.4%), diabetes (38.5‐41.6%), arthritis (44.0‐46.6%), stroke (28.9‐34.4%) and anxiety/depression (48.6‐54.5%). Co‐medications received (table 3) such as anti‐hypertensives, lipid modifying drugs, anti‐diabetics, systemic corticosteroids, and anti‐depressants reflect these conditions.

Conclusion

Extensive understanding of a drug’s real‐world target population can inform generalizability of clinical trial results and highlight unaddressed risk. This study stresses the importance of studying new AD drugs in populations with a history of CV risk, diabetes and stroke as well as those that may be immunocompromised due to treatments with systemic corticosteroids.
A Twin Analysis of AD Brain Signatures and Abnormal White Matter
Authors: Williams McKenna E. , Fennema‐Notestine Christine , Lin Shu‐Ju , Gillespie Nathan A. , Franz Carol E , Kremen William S.
Published: December 2023

Background

Alzheimer’s disease (AD) and vascular disease frequently co‐occur and may interact additively or synergistically on risk for cognitive decline, though the degree of shared overlap between these pathologies remains unclear. Our group has demonstrated the utility of AD signatures, or composite MRI metrics in brain regions associated with AD pathology, for prediction of AD‐related changes beginning in midlife. Our novel signature based on gray matter mean diffusivity (MD) aided 12‐year prediction of incident mild cognitive impairment among cognitively unimpaired adults in their 50s, captured unique phenotypic and genetic variance not otherwise explained by an AD signature based on cortical thickness/volume or general brain aging, and robustly predicted thickness/volume signatures over a decade later. Here, we leveraged twin data from the Vietnam Era Twin Study of Aging (VETSA) to delineate shared and unique genetic and environmental influences on two AD signatures and white matter hyperintensities (WMHs), which have been consistently linked to vascular origin.

Method

Participants were 512 men from the VETSA (age = 67.52, SD = 2.60). Our validated thickness/volume signature, novel MD signature based on the same brain regions as the thickness/volume signature, and WMH volume were used in biometrical twin analyses to examine their phenotypic, genetic, and environmental relationships. We adjusted each AD signature for an MRI‐based measure of brain age to detect associations with WMH that were specific to AD‐related brain regions versus general brain aging. We also examined regional WMH parcellations.

Result

Phenotypic and genetic correlations demonstrated significant associations between the MD signature and WMH (rp = 0.26 [95% CI: 0.15, 0.36]; rg = 0.34 [95% CI: 0.10, 0.57]). In contrast, phenotypic and genetic correlations between the thickness/volume signature and WMHs were nonsignificant. Environmental correlations between each AD signature and WMH were similarly nonsignificant. Results were similar for each WMH parcellation, suggesting global WMH effects.

Conclusion

A gray matter MD signature and WMHs share significant genetic influences, whereas a thickness/volume signature was not associated with WMHs. AD signatures based on brain microstructure, such as the MD signature, may capture very early AD‐related and vascular‐related changes that are not captured by a macrostructural signature at the same timepoint.
Educational Attainment and Risk of All‐Cause Dementia, Vascular Dementia, and Alzheimer’s Disease – A Population‐Based Twin Study
Authors: Schwarz Claudia , Iso‐Markku Paula , Palviainen Teemu , Kaprio Jaakko , Vuoksimaa Eero
Published: December 2023

Background

Most studies on the association between educational attainment and dementia have been conducted in unrelated individuals. Dementia‐discordant twin pairs can inform if the protective effect of education on dementia is evident when controlling for environmental and genetic effects. We investigated the association of educational attainment on all‐cause dementia, vascular dementia (VaD), and Alzheimer’s disease (AD) mortality in a population‐based sample of dizygotic (DZ) and monozygotic (MZ) pairs.

Method

Participants were from a population‐based longitudinal older Finnish Twin Cohort study with baseline questionnaire in 1975 (N = 29,784; mean age = 36.9±14.9years). Education was coded as <12 years versus ≥12 years. Registry‐based cause of death data until year 2020 was based on the International Classification of Diseases. We ran individual‐level cox proportional hazard models with sex as a covariate and conditional within‐twin‐pair models for education predicting all‐cause dementia, VaD, and AD mortality. We report hazard ratios (HR) with 95% confidence intervals (CI).

Result

In individual‐level analyses higher education was associated with a decreased risk of all‐cause dementia (HR = .935, 95%CI = .934;.936, p<.001) and VaD (HR = .638, 95%CI = .637;.640, p<.001), but with an increased risk of AD (HR = 1.276, 95%CI = 1.275;1.277, p<.001). In co‐twin analyses of discordant DZ and MZ twin pairs, co‐twins with higher education had lower – although non‐significant – risk of all‐cause dementia (N = 52, HR = .688, 95%CI = .319;1.481, p = .339) or AD (N = 36, HR = .600, 95%CI: .218;1.651, p = .323). Co‐twin analyses were not done for VaD due to small number of discordant pairs (N = 6).

Conclusion

This large population‐based sample showed that higher education is related to lower risk of all‐cause dementia and VaD mortality. Unexpectedly, higher education was related to higher AD mortality, but discordant twin pair analyses were informative regarding this counterintuitive result. This case‐control design, controlling for genetic and environmental effects, did not support any causality from higher education to higher AD risk. Despite the large sample, twin pairs – especially MZ twins – discordant for dementia are rare. Meta‐ or mega‐analysis of multiple large twin studies is needed to clarify if secondary education is related to lower risk of dementia, VaD, and AD mortality when controlling for genetic effects.
Modifiable dementia risk factor associations with AT(N) biomarkers: Findings from the European Prevention of Alzheimer’s Dementia study
Authors: Roccati Eddy , Bindoff Aidan D , Collins Jessica M , Eastgate Joshua , Borchard Jay , Alty Jane E , King Anna E , Vickers James C , Carboni Margherita , Logan Chad , Consortium EPAD
Published: December 2023

Background

There is strong evidence that targeting modifiable risk factors can maintain and improve cognitive function, as well as reducing risk for Alzheimer’s disease (AD) and other forms of dementia. Further, a discrete AT(N) profile exists for hallmark biomarkers: amyloid β (A), p‐tau (T) and neurodegeneration (N), to discriminate between AD and non‐AD pathological changes. Despite evidence of a biologically defined AD continuum and modifiable risk amelioration, there is a paucity of studies investigating modifiable risk factors with respect to AT(N) biomarkers. The aim of this study was to investigate how modifiable risk factors relate to the three hallmark AT(N) biomarkers of AD.

Method

Participants were drawn from the European Prevention of Alzheimer’s Disease (EPAD): a prospective, multicentre, pan‐European cohort study. Eligible participants underwent clinical and neurological assessments, brain magnetic resonance imaging, cerebrospinal fluid (CSF) collection, neuropsychological assessment and completed a variety of demographic, clinical, medical history and lifestyle surveys for 10 binary modifiable risk variables. Data were analysed via the NeuroToolKit Application (NTKApp, BetaVersion, 2022). Generalized additive models with penalized regression splines were used to model the associations between modifiable risk factor adherence and AT(N) biological criterion: A (CSF amyloid‐β 42 [Aβ42 pg/mL]); T (CSF phosphorylated‐tau 181 [p‐tau 181 pg/mL]); N (total hippocampal volume [mm3]).

Result

Of the 2737 participants included, 56% were female (n = 1526), 39% had at least one APOE ε4 allele (n = 1598), with an average age of 66.0 years and 14.4 years of education. Adjusting for age, sex and APOE carrier status: age, APOE and traumatic brain injury (TBI) were significantly associated with CSF Aβ42; age, APOE, body mass index (BMI) and exercise were significantly associated with CSF p‐tau181; and age, sex and education were significantly associated with total hippocampal volume.

Conclusion

Modifiable risk factors of less education, less exercise, TBI and higher BMI were all significantly associated with increased AD biomarker burden. Our results support previous studies identifying associations between modifiable risk factors and AD and suggest that early intervention strategies focused on education and lifestyle factors and improvements in prevention and treatment of TBI may modify risk profiles associated with cognitive decline.
Using depth sensors for a fall risk prediction system for socially vulnerable older adults with cognitive impairment
Authors: Demiris George , Harrison Sean L , Richmond Therese S , Skubic Marjorie , Hodgson Nancy A
Published: December 2023

Falls and fall‐related injuries are significant public health issues for adults 65 years of age and older. Over a third of older adults (OA) fall each year and 10‐20% of falls result in serious injuries such as fractures and head trauma. Cognitive impairment is a leading risk factor for falls in OA. Over 60% of OA with MCI fall annually – two to three times the rate of those without cognitive impairment. OA living in low‐resource neighborhoods with poor housing conditions have twice the risk of falling. We have developed a technology‐based intervention called Sense4Safety that facilitates fall risk management and fall risk reduction for older adults (OA) with cognitive impairment living in low‐resource communities. Specifically, the intervention is designed to to 1) identify escalating risk for falls real‐time through in‐home passive sensor monitoring using depth sensors; 2) employ machine learning to inform individualized alerts for fall risk; and 3) link OA with a nurse tele‐coach who guides them in implementing evidence‐based individualized plans to reduce fall‐risk. The nurse coach is accessible via video‐conferencing or phone to discuss fall prevention and risk reduction strategies with the OA and their trusted other depending on the patterns identified in sensor‐detected changes in functional mobility and gait. The measurable primary outcomes include number of fall and near‐fall events, number of fall‐related hospitalizations, functional mobility, self‐reports of fear of falling and perceived independence. We have conducted an initial feasibility study of the intervention with 10 older adults in low income housing settings for a period of 3 months. The Sense4Safety intervention has the potential to become a feasible and cost‐effective approach to increase safety and quality of life for community dwelling low income OA with cognitive impairment and prevent or reduce falls. Currently, in most cases fall risk is addressed only after an adverse event has occurred or cognitive decline has progressed significantly. This intervention changes that paradigm to maximize safety and promote aging in place.
Network‐based pipeline guides knowledge‐driven prioritization and validation of therapeutic target discovery for Alzheimer’s disease
Authors: Min Yuhao , Wang Xue , Gao Junli , Zhang Cheng , Ung Choong , Chalk Jessica L , Correia Cristina , Golde Todd E , Reddy Joseph S. , Carrasquillo Minerva M. , Zhang Ke , Allen Mariet , Li Hu , Ertekin‐Taner Nilufer
Published: December 2023

Background

Context‐specific networks can capture functionally important genes that may not be differentially expressed. Leveraging seven different gene expression datasets of Alzheimer’s disease (AD) and healthy control brains, we constructed a novel pipeline that includes such network analysis, augmented by in vivo validations and in silico drug repurposing to facilitate prioritization of AD therapeutic targets.

Method

We utilized publicly available gene expression data from 733 AD and 454 control brains across 7 datasets and the NetDecoder (PMID: 26975659) network biology platform to build context‐specific networks. Based on the known protein‐protein interaction and gene expression correlations, information flow from the top differentially expressed genes (DEG) to transcriptional regulator genes was calculated using a process‐guided flow algorithm. Genes with the greatest informational flow changes across AD cohorts were systematically prioritized. We next validated these genes in a medium‐throughput screen of a tau‐transgenic Drosophila model (PMID: 11408621). Further, we identified existing small‐molecule drugs to target the candidate genes utilizing curated databases.

Results

A total of 14 context‐specific networks were constructed across 7 datasets. We found AD‐related genes, such as APP, to have high flow differences between AD and control networks and high connectivity. Notably, many such genes were not DEGs between AD and control, suggesting that the information flow captures novel aspects of AD pathophysiology. We nominated 224 unique genes with the greatest flow differences for functional validation. We screened 111 of the 224 candidate genes with readily available, high‐confidence orthologs in Drosophila. We identified genes that suppress (N = 68) or enhance (N = 27) tau‐related neurodegeneration in this model. We confirmed the effects of previously nominated genes, such as HDAC1, which enhances tau‐neurodegeneration if overexpressed and suppresses it if knocked down. We also identified and validated additional therapeutic targets. Lastly, we applied a network‐proximity‐based algorithm and identified small molecule drugs for the candidate genes.

Conclusion

We present a novel pipeline that integrates analytic approaches, experimental validation, and drug repurposing to facilitate therapeutic discovery in AD. We applied this pipeline and nominated previously known and novel genes implicated in AD pathogenesis. Our pipeline demonstrates a cross‐species, systems‐level approach to therapeutic nomination in AD and related neurodegenerative diseases.
Stress and hypertension self‐care pilot study for Black women caregivers of people living with Alzheimer’s disease and related dementias
Authors: Wright Kathy D , Adams Ingrid K Richards , Helsabeck Nathan P , Ana Wong C , Ibrahim Omar , Kim Bohyun , Moss Karen O , Rose Karen M , Maryanna Klatt D
Published: December 2023

Background

This National Institutes on Aging study protocol (R21AG077069‐01 NIA) will test a behavioral intervention, Mindfulness in Motion plus the Dietary Approaches to Stop Hypertension (MIM DASH), to promote hypertension self‐care in African American women caregivers of people living with Alzheimer’s disease and related dementias.

Method

Twenty‐eight participants will be randomized to MIM DASH or Alzheimer’s Association Caregiver Training groups, delivered 8 weekly, 1‐hour group sessions via telehealth (video and telephone access). Data are collected at baseline, 3 and 9 months that include a) psychosocial surveys and Healthy Eating Index—DASH score and b) blood pressure, hair cortisol, and an objective stress reactivity/stress resilience battery.

Result

MIM DASH will be feasible and acceptable, and will decrease caregivers’ stress and improve quality of life; higher stress resilience will enhance the relationship between MIM DASH and intervention adoption while higher stress reactivity will diminish this relationship.

Conclusion

Substantive contributions to the science of behavior change, design of self‐care interventions, and the adoption of healthy behaviors will be achieved. Results will inform infrastructure for a larger trial to reduce health disparities among African Americans.
Dementia Caregiving 101: The effect of a pilot virtual dementia caregiving course on caregiver role preparedness and self‐efficacy
Authors: Bell Zoe , Mulligan Ryan D , Nguyen Andrew H. , O'Connor Maureen K.
Published: December 2023

Background

Dementia affects approximately 6.5 million people over the age of 65 in the US, most of whom are cared for at home by family members. Dementia caregivers (CGs) have reported inadequate perceived role preparedness and self‐efficacy, in addition to burden, depression, and anxiety that is disproportionate to CGs of those without dementia. We created a virtual Dementia Caregiving 101 course offering psychoeducation and skills training through an immersive structured program. The virtual platform was designed to improve access to dementia caregiving education for the rural CGs we serve. Goals of this course were to increase CG role preparedness and self‐efficacy by providing information about dementia and an overview of the caregiving experience.

Method

Prior to the first class, CGs were administered questionnaires to assess role preparedness and self‐efficacy. Two intervention groups were then conducted simultaneously for ten weeks. Post‐intervention data regarding role preparedness, self‐efficacy, and course feedback were collected.

Result

Fifteen CGs enrolled in the course. Four CGs were lost to follow up by the time of post‐group data collection, and one CG’s data was excluded whose scores were significantly discrepant from the overall pattern (this person joined by phone instead of by video). CGs included spouses/significant others (n = 5), former spouses (n = 1), siblings (n = 2), and adult children (n = 2). CGs ranged in age from 58‐76 (age M = 69.2; SD = 6.4). Diagnoses of CG’s loved ones included vascular dementia (n = 4), Alzheimer’s disease (n = 2), and unspecified dementia/no diagnosis given (n = 4). Total session attendance was high (M = 7.8; SD = 1.9; range = 5‐10). Following course completion, CGs reported an overall increase in role preparedness (Pre‐course score = 175; Post‐course score = 198) and self‐efficacy (Pre‐course score = 417; Post‐course score = 482). Qualitative analysis of CG feedback revealed high satisfaction with the course overall, with particular emphasis on usefulness of the manual, convenience of the virtual platform, and the opportunity to learn from other CGs.

Conclusion

The Dementia Caregiving 101 virtual course appears to be an accessible and effective program for improving CG role preparedness and self‐efficacy, which are important factors in reducing negative CG outcomes. Our preliminary results are encouraging and underscore the benefits of virtual skills‐based interventions for dementia CGs.
Yoga for prevention of cognitive decline in older women with cardiovascular risk factors and cognitive decline.
Authors: Lavretsky Helen
Published: December 2023

Background

Yoga may produce positive effects on cognitive functions in older adults at risk for cognitive decline. In this study (NCT03503669), we investigated neural and peripheral biomarkers therapeutic response in older women with subjective cognitive decline (SCD) and cerebrovascular risk factors (CVRFs) following three months of yoga compared to memory enhancement training (MET).

Method

We conducted a randomized, controlled trial to assess the efficacy of Kundalini yoga (YOGA) and memory enhancement training (MET) on mood and cognitive functioning in a group of older women with CVRFs and SCD. RNA sequencing and cytokine/chemokine assays were analyzed as well as a multimodal MRI (Siemens 3T Prisma scanner).

Result

A total of 79 patients (YOGA = 40; MET = 39) were randomized and 63 completed the 24‐week follow‐up (Mean age = 66.5 years and mean MMSE was 28.4). At 12‐weeks and 24‐weeks, both interventions demonstrated improvement in frequency of forgetting (MFQ‐Factor 1) (F(1, 76) = 0.2, p = 0.7). At 24‐weeks, YOGA participants demonstrated between‐ and within‐groups improvements in seriousness of forgetting/MFQ‐Factor 2 (effect size (95% confidence interval) = ‐0.73 (‐1.26, ‐0.19)). Compared to MET, at 12‐ and 24‐weeks follow‐up, YOGA uniquely modulated targets related to interferon signaling and innate and adaptive immunity. Compared to YOGA, MET participants displayed higher Eotaxin‐1 levels (F(2,67) = 3.94, p = 0.02). On sMRI‐Compared to KY + KK, MET showed reductions in GMV in left prefrontal, pre‐ and post‐central, supramarginal, superior temporal and pericalcarine cortices, right paracentral, postcentral, superior and inferior parietal cortices. Right hippocampal volume increased after yoga. rs‐fMRI analysis showed a left anterior hippocampal subregion assigned to the default mode network (DMN) with greater increases in connectivity with largely ventral visual stream regions with YOGA than with MET (p<.001), in associations with lower stress (p<.05).

Conclusion

At 24‐weeks follow‐up, YOGA yielded a significant, large effect size improvement in subjective cognitive impairment, and a robust mediation of inflammatory‐immune pathways, including suppression of pro‐inflammatory molecules. YOGA also offered neuroprotective effects compared to MET. These results suggest clinical, neural and biological benefits to YOGA for SCD in post‐menopausal women at risk for AD.
Alzheimer’s Disease Genes and Risk by Machine Learning over Evolution: NIA Artificial Intelligence and Machine Learning Consortium
Authors: Lichtarge Olivier
Published: December 2023

Background

Machine learning is compelling but performance depends on the amount of training data available and on the quality of the learning features chosen.

Method

To identify new risk genes for Alzheimer’s Disease (AD) we added a massive amount of new information, derived from evolution, to a machine learning training data set of sequenced genomes from cases and controls. We also introduced a specialized learning feature that interprets variant impact. Finally, we machine learned in multiple ways, gene by gene, over all genes, and in the context of functional interaction networks.

Results

We recovered many genes that: a) were robust to downsampling, b) overlapped, co‐localized or were connected to AD genes from GWAS studies, c) were dysregulated in post‐mortem of AD brain tissues; d) clustered into pathways enriched for AD processes; e) modulated neurodegeneration phenotypes in a live Drosophila model; f) informed a risk model that separated, better than GWAS genes, never seen before genomes of patients and controls; g) could be assigned either pathogenic or protective roles.

Conclusion

Evolutionary augmentation of case‐control studies of human genome variations is a powerful new machine learning modality to uncover genes and pathways associated with AD risk and which present new therapeutic opportunities.
Discovering Genetic Signatures in Very Large Cohorts of Tiled Whole Genomes: The Artificial Intelligence for Alzheimer’s Disease (AI4AD) Consortium
Authors: Zaranek Sarah Wait
Published: December 2023

Authors

Sarah Zaranek, Tom Clegg, Jiayong Li, Adam M. Brickman, Badri Vardarajan, Andrew J. Saykin, Christos Davatzikos, Li Shen, Heng Huang, Paul M. Thompson, Gyungah R. Jun, Duygu Tosun, Timothy Hohman, Paul K. Crane, Kwangsik Nho, The Alzheimer’s Disease Neuroimaging Initiative (as a consortium author), Alexander Zaranek, for the AI4AD Initiative

Background

Artificial Intelligence for Alzheimer’s Disease (AI4AD) is a coordinated national initiative to develop transformative AI approaches for high throughput analysis of next generation sequencing and related imaging, AD biomarker and cognitive data in an effort to address fundamental barriers in AD prevention and drug discovery. One of the project’s initial aims is to discover new genetic signatures in whole genome sequencing (WGS) data that can be used in conjunction with imaging, biomarker and cognitive data.

Method

Currently, the ability to analyze large‐scale WGS data is limited due to both data size and the inability of many existing tools to scale. To address this challenge, we use data “tiling” to efficiently partition whole genomes into smaller segments resulting in a simple matrix of small integers. This lossless representation is particularly suitable for machine learning (ML). We use ML classification methods to predict phenotypes and identify and prioritize tile variants/genetic variants that are possible genetic signatures of AD. Our “baseline” model for AD classification (GLM with Adaptive Lasso and bootstrapping) selects and identifies stable features/tile variants (Figure 2). Age, sex, and the top 10 PCA components are included. Models are run at scale using CWL on Arvados.

Result

We have analyzed 15,000+ genomes from the Alzheimer’s Disease Sequencing Project (ADSP) and Alzheimer’s Disease Neuroimaging Initiative (ADNI). Preliminary results are promising. Best models include ∼10 genomic tile variants of interest that contribute to distinguishing AD cases from controls. As expected, the APOEe4 variant (rs429358) is associated with the highest coefficients. The model shows added predictive value of variants of genes previously to be associated with AD risk, paired helical filament tau measurements, neurofibrillary tangles measurements, and hippocampal atrophy (Figure1, Table 1).

Conclusion

Genomic tiling facilitates efficient and reproducible analysis of large cohorts (100,000+) of WGS samples using modern machine learning methods.
How well is China’s healthcare system prepared to provide access to a disease‐modifying Alzheimer’s treatment?
Authors: Mattke Soeren , Yoong Joanne , YUEN Kah‐Hung , Loh Wei Kok
Published: December 2023

Background

While the majority of patients with Alzheimer’s disease (AD) reside in low and middle‐income countries, little is known of their preparedness for disease‐modifying treatments. We project wait times for access to treatment in China, the world’s most populous and still a middle‐income country.

Method

Markov model to estimate wait times based on population, prevalence and capacity data for 2024 to 2044, by desk research and interviews with 45 experts. Base case assumes that 20% of individuals aged 50 and older with no prior evaluation for cognitive impairment would visit a hospital‐based specialist clinic for evaluation and biomarker testing, and if positive, to confirm presence of amyloid and determine treatment eligibility would be determined with PET scanning (37%) or CSF analysis (63%). In two alternative scenarios, individuals would first see a primary care clinician and be referred to a clinic if (1) a brief test suggested mild cognitive impairment, or if (2) in addition a blood test with sensitivity of 0.89 and specificity of 0.73 suggested presence of AD pathology.

Result

Under current practice in China, where gatekeeping by primary care is uncommon and referrals to AD specialty care not required, specialist capacity would be overwhelmed, resulting in lengthy wait‐times throughout the simulation. (Figure 1). Using a model of specialist referral based on cognitive testing in primary care, wait times would peak at 90 months in 2028 and later remain at 50‐60 months. Confirmatory biomarker testing in specialist clinics would become the rate‐limiting constraint. (Figure 2) Adding an AD blood test would lower peak wait times to 55 months and to about two years later (Figure 3).

Conclusion

We project extremely long wait times in China to gain access to AD treatment under current practice. Triage in primary care, including a blood test before PET/CSF testing would reduce wait times, albeit only to about two years. With dementia specialists per capita comparable to Japan and growing, the main constraint is capacity for confirmatory biomarker testing. Higher performing blood tests, greater reliance on CSF and expanding PET capacity would rein in wait times, provided that growth in specialist capacity is maintained.
Brain volume changes caused by anti‐amyloid beta drugs and association with ARIA
Authors: Alves Francesca M , Kalinowski Pawel , Ayton Scott
Published: December 2023

Background

The potential benefit of anti‐Aβ drugs to cognition in Alzheimer’s disease (AD) remains under active debate. Anti‐Aβ drugs also frequently cause accelerated changes to brain volume. This is concerning because loss of brain tissue is the proximate cause of cognitive dysfunction in AD and volume changes are supportive and objective evidence of disease progression.

Method

PubMed, Embase and Clinicaltrial.gov databases were searched to evaluate brain volume changes caused by different sub‐classes of anti‐amyloid beta (Aβ) drugs trialed in patients with Alzheimer’s disease. The inclusion criteria for this systematic review and meta‐analysis were: (1) randomized controlled trials of patients treated with anti‐Aβ drugs that have demonstrated to favorably change at least one biomarker of pathological Aβ; and (2) detailed MRI data sufficient to assess the volumetric changes in at least one brain region. Amyloid‐Related Imaging Abnormalities (ARIA) were investigated when reported in clinical trials. Of the 145 trials reviewed, 31 were included in the final analyses (n = 8062 to 10279).

Result

A meta‐analysis on the highest dose of each trial on hippocampus, ventricle, and whole brain revealed drug‐induced acceleration of volume changes that varied by anti‐Aβ drug class. Secretase inhibitors accelerated atrophy to the hippocampus (mean difference: ‐37.1 µL [‐19.6% relative to change in placebo]; 95% confidence interval: ‐47.0 to ‐27.1) and whole brain (‐3.3mL [‐21.8% relative to change in placebo]; 95% confidence interval: ‐4.1 to 2.5). Conversely, ARIA‐inducing monoclonal antibodies accelerated ventricular enlargement (mean difference: +2.1mL [+38.7% relative to change in placebo]; 95% confidence interval: 1.5 to 2.8) where a striking correlation between ventricular volume and ARIA frequency was observed (r = 0.86, p = 6.22×10−7).

Conclusion

These findings reveal the potential for anti‐Aβ therapies to compromise long‐term brain health by accelerating brain atrophy and provide new insight into the adverse impact of ARIA. Six recommendations emerge from these findings.
Use of visual aids for improving communication between researchers and research participants living with dementia
Authors: Haroon Muhammad
Published: December 2023

Background

Research shows that pictures enhance the comprehensibility of written information. To ensure vulnerable groups are protected, ethical conduct of research requires collection of informed consent, ensuring research participants have a clear understanding of the research topic. For complex research, consent forms and participant information sheets can be lengthy, text‐heavy, and difficult to interpret, creating comprehension difficulties. For people living with dementia and associated cognitive impairment, such difficulties are magnified. The purpose of our study was to assess the preferences of people with dementia for written or pictorial information when providing informed consent.

Method

A consent process was undertaken as part of a broader research design involving people living with dementia and their care‐partners in focus groups and online interviews. Consent was obtained at the beginning of each session, providing a choice between written and pictorial research information, i.e., consent form and participant information sheet. Text‐based research information was summarized into short sentences. Simplistic illustrations were created based on those sentences which acted as descriptions of the visuals (see Image 1 and Image 2). Both text and picture‐based versions were shared with research participants when first recruited for completion and collection at the focus group or interview. Preference was ascertained by noting the choice of format.

Focus groups were conducted in person in Wynnum Library, Brisbane and interviews were conducted online.

Result

Three people living with dementia and three care‐partners participated in focus groups. Four people living with dementia and two care‐partners participated in online interviews.

All people living with dementia demonstrated a preference for the picture‐based versions, while care‐partners had mixed responses. All participants felt that the multimodal approach was considerate of the needs of people living with dementia.

Conclusion

Our findings suggest the majority of people living with dementia would prefer research information documents in a multimodal format, although the finding is not generalizable due to a small sample size. Whether this preference is due to its visual appeal or its ability to simplify the information is unclear and warrants further investigation. Larger studies may improve generalizability to broader populations.