bluuebunny/crossref_metadata_2025 huggingface dataset:
Acceptance of using digital technologies to aid the timely detection of dementia: perspectives from Boston University Alzheimer’s Disease Research Centre
Authors: Beswick Emily , Wilson Sarah , Popp Zachary T , Rahman Salman , Khan Raiyan R , Tolley Clare , Low Spencer , Slight Sarah
Published: January 2025

Background

Using digital technologies to detect the early signs of dementia‐causing diseases could improve the timely detection of these diseases. To support this approach, we explored users' perspectives on the acceptability of using a variety of digital technologies.

Method

A sub‐group of participants from Boston University’s Alzheimer’s Disease Research Centre were recruited. Participants used up to nine study technologies (active smartphone apps (n = 3), passive apps (n = 2), wrist worn activity monitor (n = 2), EEG headband (n = 1), Oximeter ring (n = 1)) for two weeks, every three‐months, over a year. Semi‐structured interviews were conducted after the first two weeks. A framework thematic analysis approach was applied to the interview transcripts, assisted by N‐Vivo (QSR, version 14.23.2). The Technology Acceptance Model(1) aided in refining key themes.

Result

Twenty‐four individuals were interviewed: 13 with mild cognitive impairment (MCI) and 11 without cognitive impairments. Three key themes emerged; perceived usefulness, intention to use and enjoyment of use. Participants were excited about the possibility of using digital technologies to remotely monitor their brain health, but some raised concerns that this could reduce personal interaction with their healthcare professional. Participants with pre‐existing health conditions, questioned the accuracy of the technology. For example, a participant wondered what effect an oxygen mask used for sleep apnoea would have on the data collected from the oximeter ring, reducing their perceived usefulness of the devices. Many participants using seven or more devices reflected on the burden of using multiple devices, finding it was challenging to familiarise themselves with them and then remember to use them all. Participants with MCI enjoyed the cognitive stimulation they felt after using the gamified cognitive tasks in the active smartphone apps, whereas participants without cognitive impairment wanted more variety to improve engagement.

Conclusion

Results highlight the acceptability of a variety of digital technologies for the timely detection of dementia‐causing diseases and discussed the burden of using multiple devices. Future research should explore how pre‐existing health conditions could affect the accuracy of digital technologies to improve real world applicability. References • Davis FD. Perceived usefulness, perceived ease of use, and user acceptance of information technology. MIS quarterly. 1989 Sep 1:319‐40.
The impact of caregiver tele‐health support and education intervention on the relationship between caregiver grief and quality‐of‐life
Authors: Gothard Sarah , Mooney Aimee , Tupper Emily , Lindauer Allison
Published: January 2025

Background

Current research around caregiving for person’s with dementia (PWD) has historically emphasized caregiver burden. This leaves a gap of knowledge around other contributors to caregiving’s long‐term effects, including grief. The current analysis explores the relationship between caregiver grief and quality‐of‐life.

Method

The Tele‐STELLA study is a multi‐component, telehealth‐based intervention that teaches caregivers strategies to manage upsetting behaviors related to dementia in 8 weekly, 1‐hour sessions with professionals. The caregivers in this analysis (n = 138) cared for a family member with moderate to late‐stage dementia. A multilinear analysis was used to explore the relationship between grief and quality‐of‐life for 138 caregivers of PWD. Caregivers were women (73.2%) and white (87.0%), with 82.6% reporting financial security. On average, caregivers were engaged in their roles for 4.64 years (SD 3.69); 87.0% of the PWDs were in the moderate stage of dementia. Pre and post questionnaires queried caregivers about frequency of problematic behaviors and their reactions to the behaviors, grief, and household quality‐of‐life.

Result

Of the 138 caregivers who started the 8‐week intervention, 98 (71%) completed both pre/post self‐reported data. Scatterplot visualization demonstrated a linear negative relationship between grief/quality‐of‐life at both pre and post intervention timepoints. Controlling for sex and care recipient dementia severity, a multilinear regression was performed and showed, at alpha 0.05, a significant negative relationship between quality‐of‐life and grief (p‐value: 0.00, B1: ‐0.17) at the pre‐intervention timepoint. Post‐intervention analysis of the same model showed the magnitude of the B1 coefficient of grief changed to ‐0.22 and an increased significance (p‐value: 0.00).

Conclusion

This analysis found that grief in dementia caregiving had a strong negative relationship with quality‐of‐life and that this relationship became stronger after intervention. This may be due to caregivers' increased awareness of grief, or to the progressive nature of dementia over the 8‐week intervention period, but still highlights grief’s impact on caregiver quality‐of‐life. Future longitudinal studies will be necessary to evaluate if grief can serve as a predictor of quality‐of‐life and long‐term health outcomes for caregivers, and how best to leverage that knowledge for interventions in this population.
APOE‐ε4 associations with smartphone‐based cognitive markers
Authors: Rosická Anna M , Fittipaldi Sol , Gallagher Eoghan , Hanlon Anna K , Ibáñez Agustín , Bridgeman Katie , Muniz‐Terrera Graciela , Ritchie Karen , Ritchie Craig W , O'Brien John T , Koychev Ivan , Lawlor Brian , Naci Lorina , Gillan Claire M
Published: January 2025

Background

Smartphone‐based assessments are a promising tool for early detection of cognitive decline in midlife. Previous research has shown such cognitive markers can be sensitive to a range of potentially modifiable dementia risk factors even in healthy adults. However, their sensitivity to genetic risk factors like APOE‐e4 is likely to differ by cognitive domain, with evidence of strong negative effects on wayfinding tasks but mixed for other domains. We investigated the associations between a set of previously validated smartphone‐based cognitive markers and APOE‐e4.

Method

N = 87 cognitively unimpaired, APOE‐genotyped participants (aged 44‐67, 57.5% female) of the PREVENT study completed a self‐administered module in the smartphone application Neureka, including gamified cognitive tasks and memory self‐evaluation (completion rates: 81%–99%). Controlling for age, gender, education, and parental history of dementia, we compared APOE‐e4 carriers (n = 35) with non‐carriers in their performance on five cognitive measures: model‐based planning, visual working memory, processing speed (∼Trails A), cognitive flexibility (∼Trails B), and subjective memory problems. We conducted receiver operating characteristic (ROC) analysis to assess if APOE‐e4 status can be predicted from norm‐adjusted cognitive scores, i.e., the difference between observed cognitive performance and what we would predict for given demographics based on an additional benchmark sample (N = 3,376, aged 18‐84, 65% female).

Result

In univariate analyses, APOE‐e4 carriers did not significantly differ from non‐carriers in their demographic characteristics or cognitive scores except for visual working memory, which was better in carriers (t(63.226) = 2.245; p = .028). After controlling for covariates, APOE‐e4 status was not significantly linked to, which was better in APOE‐e4 carriers (ß[bootstrapped 95% CI] = ‐0.29[‐0.53,‐0.06]; t = ‐2.30; p = .025). In ROC‐analysis, norm‐adjusted visual working memory scores modestly differentiated between carriers and non‐carriers (AUC(SE) = .648(0.067); bootstrapped 95% CIs = 0.515–0.774).

Conclusion

The non‐significant associations between APOE‐e4 and most cognitive markers suggest limited sensitivity to genetic risk. Interestingly, APOE‐e4 carriers outperformed non‐carriers in visual working memory, which could be due to antagonistic pleiotropy effects, but needs to be replicated in larger samples. The current study shows limited evidence for the clinical utility of our cognitive markers as indicators of genetic risk in middle‐aged cognitively unimpaired adults.
A Brief Digital Neuropsychological Protocol – II: Using Artificial Intelligence to Assess Verbal Serial List Learning Recognition Latency
Authors: Libon David J. , Swenson Rodney , Tobyne Sean E , Price Catherine C. , Lamar Melissa , Cosentino Stephanie , Banks Russell , Jannati Ali , Showalter John , Bates David , Pascual‐Leone Alvaro
Published: January 2025

Background

Digital neuropsychological assessment easily captures behavior previously not obtainable by traditional pencil‐and‐paper tests. Verbal serial list learning tests are commonly used to assess for putative neurogenerative syndromes. Recognition test performance is often expressed compiling simple ‘yes/ no' responses, but fail to assess process metrics such as the latency to respond to individual recognition test items.

Method

Memory clinic patients were assessed with the a digital neuropsychological protocol where cluster analysis of traditional metrics classified patients into normal (nl = 23), amnestic MCI (aMCI = 17), dysexecutive MCI (dMCI = 23), and dementia (dem = 14) groups. Verbal episodic memory was assessed with a 6‐word Philadelphia (repeatable) Verbal Learning Test. P(r)VLT delayed recognition memory was assessed using a forced multiple‐choice format where the iPad both displayed and verbally administered six trials containing the target word, a prototypic semantic foil (e.g., “apple”) and a generic semantic foil (e.g., “pear”). The patient was asked to touch the word that was part of the original word list as quickly as possible.

Result

aMCI and dementia groups endorsed more recognition foils that other groups (Table 1; dementia > all groups, p< 0.001; aMCI > dMCI & nl groups, p< 0.001). Serial list learning recognition latency was slower for aMCI versus dMCI and nl groups; p< 0.005); and dementia versus dMCI and nl groups (p< 0.001). Regression analysis (dv = recognition latency; block 1 = age, education, sex; block 2 = recognition prototypic & generic foils) was significant (R2 = 0.463, p< 0.001); and found slower recognition latency was associated with greater numbers of prototypic recognition foils (beta = 0.551; p< 0.001). Regression analysis (dv = recognition latency; block 1 = age, education, sex; block 2 = all free recall cluster responses, all free recall extra‐list intrusion errors) also found slower recognition latency was associated with fewer semantic cluster responses (beta = ‐0.252, p< 0.021), but greater numbers of extra‐list intrusion errors (beta = 0.266, p< 0.017).

Conclusion

When brought to scale, automated analysis of recognition latency along with other serial list learning process metrics could help identify early, emergent neurodegenerative illness.
A Brief Digital Neuropsychological Protocol: III ‐ Using Artificial Intelligence to Measure Semantic Memory with the ‘Animal’ Fluency Test
Authors: Libon David J. , Swenson Rodney , Tobyne Sean , Price Catherine C. , Lamar Melissa , Cosentino Stephanie , Banks Russell , Jannati Ali , Showalter John , Bates David , Pascual‐Leone Alvaro
Published: January 2025

Background

Semantic memory refers to knowledge of attributes associated with common objects. Quantifying the strength of semantic association between successive ‘animal' fluency responses can be challenging. The current research assessed between‐group differences for ‘animal' fluency total output and selected verbal serial list learning, episodic memory measures.

Method

Memory clinic patients were assessed with a digital neuropsychological protocol. Cluster analysis classified patients into normal (nl = 23), amnestic MCI (aMCI = 17), dysexecutive MCI (dMCI = 23), and dementia (dementia = 14) groups. During the protocol, patients were given 60secs to provide animal exemplars. Memory was assessed with the P(r)VLT, a 6‐word verbal serial list learning test. Using artificial intelligence assisted scoring all ‘animal' fluency and P(r)VLT outcome variables including the ‘animal' Association Index (AI), where the mean number of shared attributes between successive responses were automatically tallied.

Result

The nl group generated more animal exemplars than all other groups (p< 0.001; Table 1). aMCI and dMCI patients generated more responses than dementia patients (p< 0.043, both analyses). NL and dMCI patients produced a higher, more semantically connected, ‘animal' AI than dementia patients (nl > dem; p< 0.025, both analyses). Regression analysis (dv = ‘animal’ AI; block 1 = age, education, sex; block 2 = recognition prototypic & generic foils) was significant (R2 = 0.145, p< 0.023); and found that a reduced, more impaired ‘animal' AI was associated with increasing numbers of P(r)VLT prototypic recognition foils (beta = ‐0.276; p< 0.024). Regression analysis (dv = ‘animal’ AI; block 1 = age, education, sex; block 2 = P(r)VLT semantic cluster responses, P(r)VLT extra‐list intrusion errors) was not significant.

Conclusion

In addition to commonly used outcome measures such as total ‘animal' responses, this digital neuropsychological protocol scores a number of process variables, including the ‘animal' AI. The association between reduced ‘animal' AI and greater numbers of list learning prototypic recognition foils suggests combined episodic memory and semantic‐related impairment in selected patients. When brought to scale, automated analysis of neuropsychological process variables may aide in identifying emergent neurodegenerative illness.
Media Contribution to Dementia Awareness in Recruitment and Retention of Alzheimer’s Disease Diversity Genetic Cohorts‐ Alzheimer’s disease Sequencing Project in Africa
Authors: Farombi Temitope Hannah , Arulogun Oyedunni , Nichols Michelle , Olorunsogbon Olorunyomi F , Kumolu Timilehin , Ogunronbi Mayowa , Sanni Taofeek Adedayo , Mutiso Victoria , Uthman Muhammed , Sule Abdullateef , Assey Emmanuel , Mwombeki Innocent , Onoria Joy , Onunka Godspower Chibuke , Tagoe Benedict , Melkamu Selem K , Adigwe Ifeoma , Ogunyemi Adedoyin O , Gyabaah Solomon , Byrd Goldie S. , Ogunniyi Adesola , Pericak‐Vance Margaret A , Akinyemi Rufus O.
Published: January 2025

Background

The escalating prevalence of dementia in Africa, propelled by rapidly ageing population, necessitates innovative approaches to raise awareness and address associated challenges. The prevalent misconception of dementia as a result of witchcraft or wizardry is a challenge, and the media acts as a key agent in dispelling such myths. By reaching divers audiences, the media reinforces the notion that dementia is not confined to Africa alone but it is a global concern. It also aids in overcoming the shame and stigma associated with dementia, encouraging individuals to seek consultation.

Method

A comprehensive analysis of media initiatives used by the African Dementia Consortium (AfDC) during the World Alzheimer’s Month and subsequently was conducted. Digital Platforms (Instagram, LinkedIn, Facebook), print and traditional media (publications, journals, newspaper, radio and television stations) were examined for their effectiveness in achieving recruitment objectives, destigmatizing and promoting early diagnosis. Quality tools, such as cameras and recorders, were utilized to capture relevant information, while the outcome was evaluated based on their impact on target audience assessed by greater participation.

Result

Media Platforms have proven instrumental in recruitment efforts by disseminating information that reaches diverse demographic groups in Africa. Through compelling visual and textual content, the media has played a key role in destigmatizing dementia, challenging prevalent misconceptions, and fostering a more inclusive understanding of the condition. In addition, media initiatives have contributed significantly to the promotion of early diagnosis by disseminating educational content that empowers individuals to recognize early signs and seek timely medical intervention.

Conclusion

Both the digital and traditional media play vital roles in visually and textually representing dementia, correcting misconceptions, and fostering understanding. Allocating increased resources to media initiatives hold immense benefit for Africa, contributing to a more positive perspective on dementia and dispelling negative attitudes.
A longitudinal real‐world study in patients with Alzheimer’s Disease dementia using frequent multi‐domain digital measurements performed at‐home on the Cumulus Neuroassessment Platform: usability and feasibility findings
Authors: Diggin Shannon , Alexander‐Sefre Azar , Murphy Brian , Nolan Hugh , Rowe James B , Rueda‐Delgado Laura M , Buick Alison R
Published: January 2025

Background

Many outcome measures used in AD clinical trials require clinic visits and are paper based, making them infrequent and burdensome ‘snapshots', subject to rater bias. A consortium of 10 pharma companies came together with Cumulus Neuroscience to design a solution for frequent, objective, real‐world measurement across a range of domains. We present a study that examined the feasibility of asking patients with mild dementia to use the neuroassessment platform repeatedly at home for one year.

Method

Seven UK sites recruited Alzheimer’s type mild dementia patients (n = 59, ACE‐III scores >60 and = 88) and a matched cohort of controls (n = 60). Participants had 2 weeks of at‐home familiarisation to become comfortable with the 8 assessments presented on a mobile tablet and EEG headsets, one for wake and another for sleep. A staggered longitudinal protocol followed (Figure 1), with burst sampling tapering to periodic sampling over the year. Benchmark paper‐based assessments (including ADAS‐Cog) and self‐reported usability were collected at months 0, 6 and 12. Additionally, plasma was collected at months 6 and 12 for later biomarker analysis.

Result

Preliminary results are available, with <1% expected at‐home sessions still outstanding (last patient out is scheduled for March 2024). Feedback collected at baseline (Figure 2) showed differences in technology usage. Patients felt they required more technology support than controls (49% vs 17%). Nonetheless, they were successful in using the study technology at home on a regular basis and maintained a high level of adherence to the protocol (Figure 3). Overall compliance was 72.9% for dementia, 87.5% for controls and was highest in the latter stages of the study during periodic sampling (Stage 4: 80.1% dementia, 92.6% controls). System Usability Scale results indicated controls rated usability higher (63.8) than dementia participants (54.5) at baseline, increasing for both groups by Week 26 (71.8 controls; 62.2 dementia).

Conclusion

With appropriate technology design, and provision of training and support, patients with Alzheimer’s disease dementia are capable and willing to provide repeated, real‐world samples of a broad range of objective digital endpoints for clinical research.
Assessing a Digital Lifestyle Intervention to Reduce Dementia Risk in Older Adults
Authors: Bunyan Maria , Irving Jessica , Barnett Jennifer H , Kawadler Jamie , Bauermeister Sarah , Vassilev Philip , Gallacher John , Koychev Ivan
Published: January 2025

Background

An estimated ∼40% of dementia cases are due to modifiable risk factors which can be targeted in lifestyle interventions. Effective interventions employ face‐to‐face delivery, making them resource‐intensive and burdensome. Digital interventions offer scalability, accessibility and cost‐effectiveness. Engagement and efficacy of digital interventions are unknown, as is whether the ‘human component' of these interventions must be retained.

Method

The Five Lives app is a digital health solution that combines a CE‐marked dementia risk assessment with a digital coaching programme (DC) to facilitate behaviour changes which could lead to eventual reduced dementia risk. Three groups were compared: DC‐only, DC and access to brief 1‐to‐1 virtual clinician services (DC+VC) and no intervention (control). The study spanned 12 weeks and participants (n = 154) were aged 50‐69 with normal cognition. A lifestyle score was conducted at baseline and exit, which scores participants on behaviour relating to sleep, physical activity, diet, stress & mood and mental stimulation. Engagement was measured as the total number of app activities (brain games, articles, quizzes and lifestyle log) completed during the intervention period.

Result

Participant engagement was high (mean participant activities = 35/week). There was a significantly greater change in lifestyle score between intervention group (DC‐only and DC+VC pooled) and control (F(1,81) = 3.10, p = 0.049), and a trend for significance for a greater change in DC‐only versus control (F(1,24) = 3.96, p = 0.058). The change in lifestyle score between DC‐only and DC+VC was not significant, nor was the difference in app engagement. Total engagement was not predictive of lifestyle score change.

Conclusion

Participant engagement indicates the intervention is feasible in older adults. Results suggest the Five Lives app is a promising tool to facilitate behaviour change to potentially reduce dementia risk, and the VC does not provide significant additional benefits. This study provides initial data to warrant further development of DC interventions to reduce dementia risk. Future analyses should investigate which participants respond best to the intervention, barriers to change, and how engagement interplays with sustained dementia‐targeted lifestyle change.
Evaluating Sociodemographic Bias in an Artificial Intelligence Algorithm to Detect Cognitive Impairment in Electronic Health Records
Authors: Magdamo Colin G. , He Yignan , Dickson John R , Tyagi Tanish , Westover M. Brandon , Mukerji Shibani , Ritchie Christine S , Hyman Bradley T. T , Blacker Deborah , Das Sudeshna
Published: January 2025

Background

Underdiagnosis of Alzheimer’s disease and related dementias (ADRD) leads to lost opportunities for timely intervention, increased healthcare costs, and underestimation of the true burden of disease. To address this problem, we developed an AI algorithm, Decipher‐AI (DEtection of Cognitive Impairment PHenotypes in EHR), to screen primary care patients for undiagnosed cognitive impairment (CI). We evaluated performance across sociodemographic groups using 3 years of EHR data before the first diagnosis or most recent visit.

Method

Decipher‐AI employs a two‐level hierarchical model, consisting of a large language model (LLM) to generate latent representations from unstructured clinical text and a patient‐level model that combines these representations with structured EHR data to predict the probability of CI (AUC: 0.98, 95% CI: 0.94, 1.00). Decipher‐AI was evaluated on a test set comprising 22,000 Mass General Brigham primary care patients aged 65 years or older. The selection process involved stratified random sampling across distinct racial/ethnic strata to ensure representation of diverse sociodemographic factors (Table 1). Cognitive status labels were determined based on the presence of dementia‐related diagnosis codes, while sociodemographic status was measured using the Area Deprivation Index (ADI).

Result

The AUC on the validation dataset was 0.80 [95% CI: 0.79, 0.81]; sensitivity was 0.75 [0.74, 0.77] and specificity 0.68 [0.67, 0.69], at the threshold of maximum accuracy. There were no significant differences in AUCs across sex or race/ethnic subgroups, but AUC was lower for patients under 75 years. (Figure 1A). Notably, Decipher‐AI exhibited diminished performance in patients from more disadvantaged neighborhoods (Figure 1B). Further analysis revealed that these disparities were associated with fewer encounters, outpatient visits, and notes containing cognition‐related keywords in patients from disadvantaged neighborhoods (Table 2).

Conclusion

Our study highlights the potential of Decipher‐AI for screening undiagnosed cognitive impairment in primary care. Nevertheless, disparities in algorithm performance underscore the importance of addressing sociodemographic inequities in EHR data. In the future, systematic tailored screening in primary care via standardized questionnaires coupled with AI‐assisted chart reviews, has the potential to address the underdiagnosis of ADRD in an equitable manner.
Biological Factors Influencing [18F]MK6240 and [18F]FTP Correlation in Target Regions
Authors: Tissot Cécile , Tsai Hsin‐Yeh , Therriault Joseph , Tudorascu Dana , Rahmouni Nesrine , Servaes Stijn , Stevenson Jenna , Lussier Firoza Z , Pezzoli Stefania , Ziontz Jacob , Gordon Brian A. , Pascual Belen , Lowe Val J. , Soleimani‐Meigooni David N. , Oh Hwamee , Klunk William E , Rosa‐Neto Pedro , Jagust William J. , Pascoal Tharick Ali , Baker Suzanne L.
Published: January 2025

Background

The association between [18F]Flortaucipir (FTP) and [18F]MK6240, two commonly used tau‐PET tracers in Alzheimer’s disease (AD), varies due to distinct binding properties and off‐target signal regions. Our study aims to elucidate the biological factors influencing this association and evaluate the applicability of a common equation across different on‐target regions.

Method

113 individuals from the HEAD dataset (11 young, 58 cognitively unimpaired elderly, and 44 cognitively impaired) underwent [18F]MK6240, [18F]FTP and Aß‐PET scans. Images were processed using the inferior cerebellar grey (CG) as the reference region, with subjects categorized by Aß status. Stepwise linear fitting identified off‐target (OFF) regions impacting tracer associations within the whole cortex, Braak and temporal‐meta regions of interest (ROIs). OFF regions included were a composite mask (pallidum, putamen, caudate ‐ PPC) to address collinearity in subcortical nuclei, as well as the region with the greatest partial volume effects (PVE) on the ROI (meninges, choroid plexus, and the hotspot medial to entorhinal cortices (EC)). Akaike information criteria (AIC) analyses tested linear models with various off‐target regions.

Result

PPC and PVE regions influenced tracer association in on‐target regions. PPC binding is associated with age. PPC and meninges retention, along with Aß status interaction, demonstrated the best model fit for the whole cortex (Figure 1). Weighting factors derived from the whole cortex model were applied to Braak regions and temporal meta‐ROI. Braak III‐VI and temporal‐meta ROI showed optimal models including OFF regions and Aß status interaction (Figure 2). Forcing the whole equation gave optimal results. For Braak I (EC), adding the OFF covariates only was the best model. For Braak II (hippocampus), the best model included OFF regions and the interaction with Aß status (Figure 2). Forcing the whole cortex equation onto Braak I and Braak II yielded suboptimal fits.

Conclusion

Harmonizing tau‐PET tracers involves considering significant covariates. Integrating meningeal and age‐related off‐target regions enhances [18F]MK6240 and [18F]FTP association in on‐target regions, further improved by Aß status inclusion. While the whole cortex model may not suit early ROI, it proves effective for Braak III and beyond. Creating an equation for tracer translation necessitates incorporating meningeal and subnuclei off‐target retention.
Imaging the impact of early and late life risk factors on the brain: a comparison
Authors: Gordon Brian A.
Published: January 2025

Background

Alzheimer disease (AD) is a chronic progressive neurodegenerative disorder that presents with cognitive dysfunction, memory loss, language difficulties, emotion dysregulation, and the eventual loss of motor function and death. Magnetic resonance imaging (MRI) shows early atrophy in the medial temporal lobes, which then spreads to the posterior temporal lobe, parietal lobe, and finally the frontal lobe with relative sparing of the sensorimotor cortex. Social disadvantage has been shown to have potentially additive impacts on aging trajectories. Over the first years of life the brain undergoes rapid expansion and maturation. Whereas sensory regions are relatively stable from birth, there is tremendous change in the temporal, parietal, and frontal regions which are responsible for higher order cognitive function. This change is paralleled by the development of motor, language, emotion regulation, and executive function. Early life events such as low birth weight, poverty, and adversity can impact neurodevelopment, including cortical expansion and connectivity. Given this mirroring between regional brain development and degeneration, researchers have hypothesized a “last in first out” mechanism underlying progressive neurodegeneration, but minimum direct comparisons have been performed. longitudinally studies older adults.

Methods

This work brings together unique cohorts spanning the two ends of the lifespan. The Early Life Adversity, Biological Embedding (eLABE) study scans infants scanned longitudinally between birth and age three years of age. The Charles F. and Joann Knight ADRC and ADNI longitudinal follow middle and older‐aged individuals. Structural change is estimated a unique multimodal surface matching (MSM) pipeline that estimates the deformation of pairwise cortical surfaces to estimate cortical expansion or atrophy over time. Analyses will include all children with longitudinal MRI data as well as longitudinal MRI data to characterize healthy aging, individuals who convert to AD, as well as longitudinal change in within individuals with an AD diagnosis.

Results

Preliminary results in each cohort (Figure 1) demonstrate highly similar spatial patterns between early life development and AD related cortical thinning.

Conclusions

Although there has long been speculation that there is a reciprocity between regions that develop in childhood and those vulnerable to age and disease related decline, this work test this theory.
Increasing Amerindian diversity in AD genetics research, A Peruvian perspective
Authors: Cornejo‐Olivas Mario , Illanes‐Manrique Maryenela Z.
Published: January 2025

Amerindian (AI) populations are substantially underrepresented in AD genetic studies. The Alzheimer’s Disease Sequencing Project (ADSP), a global genetic initiative established by the National Institute of Aging (NIA) is supporting regional initiatives in Latin America and its admixed population. Latin America is the largest recently admixed population, with variable Native American, European, and African ancestry proportions, as result of successive settlements and new massive migrations. The Native American population from Latin America are descendants of ancestral Asians who entered America through Beringia 15 000 years ago. By the 14‐15 th century the Native American population was about tens of millions with uneven distribution across the Americas. However, about 90% of the NA populated collapsed due to violence, famine, and infectious diseases. Consequently, the NA from Latin America exhibit lower genetic diversity with higher differences among countries. Peru is the fifth largest country of South America with a complex geography that comprise the Andes mountains, the Amazon jungle, and the Pacific coast. Peru is an emergent economy dealing with governance disparities, centralism in Lima, the capital city, with notable inequities in income distribution. The “modern mestizo “population in Peru concentrates a high proportion (˜70%) of NA ancestry, mostly derived from the ancient pre‐Inca and Inca civilizations. Over the past decade, both local and collaborative efforts, have been contributing to the AD genetic research in the Peruvian populations. A combination of regional research teams and multisource ascertainment approaches allowed the recruitment of 250 AD patients and 400 cognitively unimpaired controls from five different regions across Peru (source: PeADI initiative). The studies performed in the Peruvian cohort have been demonstrating the important role of the Amerindian ancestry in the genetic architecture of AD, including the estimation of APOE4 risk higher than non‐Hispanic Whites and Africans, and the recent identification a novel SORL1 variant in a Peruvian AD family. Despite these significant contributions, performing research in Latin American regions requires strong local brain health programs with community engaged approaches to prevent disparities and contributing to long‐term local capacity building.
Metabolic syndrome and risk of incident dementia in EPIC‐Norfolk: the role of age and exposure duration
Authors: Qureshi Danial , Luben Robert , Hayat Shabina , Talarico Robert , Allen Naomi , Kuzma Elzbieta , Littlejohns Thomas J
Published: January 2025

Background

Metabolic syndrome (MetS) might be a modifiable risk factor for dementia. However, the impact of mid‐life versus late‐life MetS and the duration living with MetS on dementia risk remains underexplored. This study investigated whether the association between MetS and risk of dementia differs across mid‐life versus late‐life, and to explore how duration of MetS influences this risk.

Method

We conducted a prospective study using data from the European Prospective Investigation into Cancer—Norfolk (EPIC‐Norfolk). In full cohort analyses, we studied 20,150 dementia‐free adults aged ≥50 years who attended baseline assessments. Group‐based trajectory analysis was performed on 12,756 participants who attended ≥2 health assessments over 20 years. MetS was defined as the presence of ≥3 of the following: elevated waist‐circumference, triglycerides, blood‐pressure, HbA1c, or reduced HDL‐cholesterol. Incident all‐cause dementia was ascertained using hospital inpatient, death, and mental healthcare records.

Result

The mean (standard deviation [SD]) age of participants was 62.6 (7.5) years, and 54% were female. Over 25 years of follow‐up (mean 18.8 [SD 6.3]), 2,653 participants developed dementia. In the overall cohort (all ages: 50‐79 years), MetS was associated with an increased risk of dementia (Hazard‐Ratio [HR], 1.11, 95% Confidence‐Interval [CI]: 1.01‐1.21). Age‐specific analyses revealed that this risk only remained in those with late mid‐life MetS (age 60‐69: HR, 1.21, 95%CI: 1.05‐1.39) but not in early mid‐life (age 50‐59: HR, 1.12, 95%CI: 0.87‐1.43) or late‐life (age 70‐79: HR, 0.96, 95%CI: 0.81‐1.14). An increasing number of MetS components was also associated with heightened dementia risk, specifically in late mid‐life (P trend = 0.004). Those with a prolonged duration of MetS had a 26% increased risk of developing dementia (HR 1.26, 95%CI: 1.13‐1.40) when compared to those with consistently low MetS. No association was found for increasing MetS (HR, 1.01, 95%CI: 0.88‐1.17).

Conclusion

Late mid‐life MetS was associated with a significantly increased risk of developing dementia. A prolonged duration of living with MetS also elevated dementia risk. These findings provide insights regarding critical periods of dementia risk in the context of MetS, and highlight the importance of not only considering the presence/absence of MetS, but also exposure duration when devising dementia prevention strategies.
Late onset Alzheimer’s Disease mouse model with altered synaptic and behavior phenotypes
Authors: Seth Ankit , Miller Jacob Bradford , Rafiq Ashiq M. , Deak Ferenc
Published: January 2025

Background

Genetically modified mouse models have provided a vital understanding of the Alzheimer’s disease (AD) mechanisms, but these models were generally focused on familial AD and do not recapitulate the late‐onset human AD pathophysiology. To circumvent the complications of existing AD mice models, we are investigating a novel non‐mutant humanized amyloid beta (Aβ) expressing mouse line that expresses the humanized mouse App gene within the Aβ peptide sequence

Method

This study aims to investigate the learning and memory function in this novel human Aβ knock‐in (h‐Aβ KI) mice of different age and sex groups using behavioral tests, neuronal circuitry, and long‐term potentiation experiments.

Result

Behavioral studies revealed age and sex specific phenotype: 12 and 18 months old female h‐Aβ KI mice demonstrated reduced locomotor and exploration activities along with pronounced deficits in the preference for social novelty. h‐Aβ KI mice also showed impaired spatial learning and memory in behavior tests as well as reduced synaptic plasticity in hippocampal CA1 and DG regions. Cultured h‐Aβ KI hippocampal neurons had significantly slower rate of synaptic vesicle release but no difference in average recycling pool sizes compared to wild‐type control neurons in fluorescent FM1‐43 assays. Live imaging of neurons loaded with FM2‐10 dye revealed differences in synaptic release dynamics of readily‐releasable pool between female and male h‐Aβ KI mice with sucrose stimulation. Immunohistology revealed no amyloid deposit at these age and needs further investigation at older ages of this animal model.

Conclusion

Our data demonstrate that expression of wild‐type human Aβ in mice is sufficient to drive synaptic and cognitive changes during aging without plaque deposition.
The Effects of Action Observation Training Combined With Occupation‐Based Intervention through Home Visits on Occupational Performance and Hand Function in Community‐Dwelling Patients with Stroke
Authors: Kim Jong‐Hyeon , Park Jin‐Hyuck
Published: January 2025

Background

Since January 2023, South Korea has launched a pilot program of home‐based rehabilitation services for patients with acute and chronic conditions. However, research on the effectiveness of occupational therapy for homebound stroke patients, aimed at promoting independence and activity participation, is limited. Additionally, previous action observation training studies in home settings often overlooked clients' occupational priorities and meanings. Therefore, this study investigates the effect of combining action observation training with occupational therapy through home visits on occupational performance and hand function in community‐dwelling stroke patients.

Method

In this study, which employed a mixed methods research design, the quantitative component utilized a single‐subject ABA' design, complemented by qualitative narrative interviews. The intervention involved two stroke outpatients, who participated in ten sessions conducted five times a week over two weeks. Each session began with the participants watching edited videos on the researcher’s laptop for 10 minutes in a quiet room, followed by 50 minutes of self‐training using selected equipment and tools, while imitating the actions from the videos. Assessment tools included the Purdue Pegboard Test and Pinch Gauge for evaluating hand function, while occupational performance was measured using the COPM pre‐ and post‐intervention.

Result

First, twol participants showed clinically significant improvements with a score increase of two or more points in occupational performance and satisfaction. Second, twol participants demonstrated an improvement in the assembly task of the Purdue pegboard test during the intervention phase compared to the baseline phase, but this improvement was not maintained during the follow‐up baseline phase. Third, in the Pinch gauge, two participants showed an improvement in the affected side from the baseline to the intervention phase, and this improvement was maintained until the follow‐up baseline phase. However, there were no significant changes observed in the unaffected side. Fourth, qualitative research findings revealed that the participants exhibited an improvement in occupational performance, occupational motivation, occupatioanl patterns, and self‐efficacy.

Conclusion

Action observation training combined with home‐based interventions can be easily implemented at home without significant effort from patients post‐discharge. Therefore, it offers an alternative method for occupational therapy services, serving as a preparatory step before engaging in occupational activities.
A Systematic Review of Interventions Targeting Social Isolation Among Middle‐Aged Adults
Authors: Shin Jiwon , Yang Hyun , Yun Sohyeon , Kim Inhye , An Hyunseo , Park Hae Yean
Published: January 2025

Background

This systematic review aims to examine recent interventions targeting social isolation among middle‐aged adults, identifying trends in intervention types and their effectiveness. It highlights the urgent need for establishing a foundation for social isolation research across all ages.

Method

A comprehensive literature search was conducted using PubMed, EMBASE, and CINAHL databases from January 1, 2014, to January 1, 2024. The search focused on terms related to social isolation and intervention programs. Eight studies were included, primarily randomized controlled trials.

Result

The majority of interventions employed internet‐based methods, reflecting an adaptation to digital health trends. Interventions significantly reduced social isolation, particularly among female participants, and utilized various formats such as online interactions and group discussions. Notably, the use of the UCLA Loneliness Scale, Version 3 (UCLA‐LS‐3) was prevalent for measuring social isolation.

Conclusion

The findings confirm the necessity for ongoing research into diverse and effective social isolation interventions. They serve as crucial evidence supporting the development of future interventions aimed at different age groups to combat social isolation effectively.
Mechanistic Disease Modeling to Inform Potential Strategies for Early Interventions with BACE inhibition
Authors: Stone Julie A , Robey Seth , Kennedy Matthew E. , Duffull Stephen
Published: January 2025

Background

The β‐secretase‐1 inhibitors (BACEi), including verubecestat, were extensively studied in prodromal to moderate AD and demonstrated early cognitive decline (negative effect) at doses achieving >50% inhibition of amyloid production. Questions remain as to whether BACEi may still have utility, if used earlier in disease and at lower levels of inhibition. A mechanistic model of the progression of Alzheimer’s disease was used to predict effects of alternative BACEi therapeutic approaches on disease progression.

Method

The mechanistic model could holistically describe the available clinical data including observational trials and interventional trials with BACE inhibitors, anti‐amyloid mAbs, and anti‐tau antisense oligonucleotides. Varying inhibition levels (15‐ 56%) were simulated to predict amyloid PET, CSF Aβ42, CSF and plasma p‐tau, tau PET response. Delay‐times to BRAAK3‐4 region tau PET SUVr of 1.44 (MK‐6240; or 1.2 FTP) were calculated from simulations of intervention relative to untreated. Simulations of Down’s Syndrome populations (represented by increased production rate of amyloid) tested the impact on the dose and timing of the intervention needed to achieve benefits.

Result

Sporadic AD simulations predicted that NFT progression could be delayed by decade(s) if started very early in disease (amyloid PET of 20‐50 centiloids) with moderate (33‐56%) levels of inhibition maintained for remainder of life. It’s unknown whether these inhibition levels have less cognitive decline than seen previously. Benefits were substantially reduced for later inventions (>60 centiloids), lower levels of inhibition or shorter durations of treatment (<10 years). Predicted biomarker timecourses suggested that separation from placebo within 4‐5 years would be demonstrable for CSF Aβ42 and amyloid PET, but p‐tau and tau PET alterations could take longer, especially for interventions starting at very low plaque loads. Limitations include the limited data from tau‐targeted approaches and on inhibition‐dependencies of the negative cognition effect, which create uncertainties in the predictions.

Conclusion

Mechanistic model‐based simulations suggest that moderate level BACEi interventions very early in the process of amyloid plaque accumulations could lead to substantial delays in progression. The time to differentiation from untreated marker responses was long for tau‐based markers, suggesting that demonstration of effects during a typical trial timeline may be challenging.
Cortical hyperarousal during sleep in mice receiving BACE inhibitors may affect cognitive performance
Authors: Watkins Elyse A , Olker Christopher J , Lin Xuanyi , Song Eun Joo , Kim Sarah , Turek Fred W , Kennedy Matthew E. , Vitaterna Martha H , Vassar Robert J.
Published: January 2025

Background

BACE inhibitors, while effective in lowering amyloid‐beta production, have been associated with mild cognitive worsening in clinical trials. Additional treatment‐related adverse events reported in multiple clinical trials were sleep disturbances and insomnia. The purpose of this study is to determine if sleep disturbances occur in mice receiving BACE inhibitor, if sleep disturbances correlate with cognitive impairment, and the mechanism by which this may occur.

Method

Adult C57BL/6 mice were treated with high dose BACE inhibitor (Merck) or control chow for 12 weeks. At 12 weeks, mice were implanted with a head mount containing electrodes for EEG and EMG monitoring. Sleep was monitored for 48 hours continuously. Cognitive assessments including object location memory, Y‐maze, and Barnes maze were performed. 10 second sleep epochs were manually scored as “wake”, “REM”, and “non‐REM”, based on EEG and EMG, to then train an algorithm to detect and define all remaining epochs. Fast Fourier transforms were performed on all epochs to identify the relative delta, theta, alpha, sigma, beta, and gamma power.

Result

Mice receiving BACE inhibitor chow had altered sleep patterns. This was marked by fewer, longer REM bouts than control mice. Additionally, mice receiving BACE inhibitor had less slow wave non‐REM sleep, marked by a reduction in delta power. Conversely, mice had an increase in the higher frequency beta and gamma waves during non‐REM sleep, suggestive of cortical hyperarousal.

Conclusion

Mice receiving BACE inhibitors for three months had impaired sleep. Longer REM bouts could point to the vivid dreams and disturbed sleep noted in humans. A reduction in the slow wave sleep indicates reduced restorative sleep, which could impair performance on cognitive tests by leading to lethargy and impaired memory consolidation. Furthermore, cortical hyperarousal during non‐REM sleep is prevalent in a number of disorders in humans, including insomnia, anxiety, and post traumatic stress disorder, which could help elucidate an underlying mechanism. This study has implications for the future of clinical trials, because there are commercially available drugs that could restore normal non‐REM sleep and potentially alleviate cognitive worsening.