bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design, Characteristics, and Resources from the Diabetes Prevention Program Outcomes Study (DPPOS) AD/ADRD project
Authors: Luchsinger Jose A. ,   Diabetes Prevention Program Research Group
Published: January 2025

AbstractBackgroundPersons with prediabetes and type 2 diabetes (T2D) are known to have higher risk of cognitive impairment (CI), including age‐related cognitive decline, mild cognitive impairment (MCI), and dementia; however, the characteristics of CI and the determinants and mechanisms in prediabetes and T2D remain unclear. Addressing these gaps is critical since over half of the U.S. population aged 60 years and older, who are at risk for AD/ADRD, have prediabetes or T2D.MethodsThe Diabetes Prevention Program (DPP) was a randomized clinical trial among adults with prediabetes which started in 1996 and demonstrated T2D risk reduction with intensive lifestyle or metformin compared with placebo. The DPP Outcomes Study (DPPOS) is a 25‐center observational follow‐up study. Combined, DPP/DPPOS has followed the original cohort for a mean of 23 (range 21‐25) years with extensive longitudinal phenotyping and a comprehensive data and biospecimen repository. To study AD/ADRD in DPPOS we have implemented (a) the NACC UDS version 3 for the adjudication of MCI and dementia; (b) measurement of plasma biomarkers of amyloid, neurodegeneration, and neuroinflammation; (c) examination of plasma measures of brain insulin signaling via neuron‐derived exosomes; and (d) brain MRI and amyloid PET scanning. Figure 1 describes the constructs of the four interrelated projects of DPPOS‐AD/ADRD. Data and biospecimens will be deposited to relevant repositories and available to researchers.ResultsThe diverse cohort, originally selected to have prediabetes and at high risk of developing T2D, currently includes 1654 participants, 70% of whom have developed T2D of known duration. Forty‐eight percent are non‐White, and 73% are women. The mean age of the cohort in 1996 was 51 years and now 73 years, with 84% ≥65y. We incorporated the standardized NACC UDS protocol for ascertainment of cognitive status with full fidelity beginning in November 2022, including recorded neurologic exams. Brain imaging began in summer 2023, and exosome extraction began in early 2024.ConclusionsState of the art procedures, typically used in AD/ADRD research, have been implemented in a large multi‐center non‐AD/ADRD cohort. The proposed measures will supplement those already gathered and provide novel insight into CI in people with prediabetes and T2D.
Development of tau targeted protein degraders for Alzheimer disease
Authors: Wang Lisha , Kumar Rajnish , Pavlov Pavel F. , Winblad Bengt 
Published: January 2025

AbstractBackgroundAlzheimer disease (AD) is a progressive neurodegenerative disease that is accountable for the leading case of dementia in elder people. Before, only symptomatic treatments are available for AD. Since 2021, two anti‐amyloid antibodies aducanumab and lecanemab have been approved by the US Food and Drug Administration. However, controversies are still around these two antibodies regarding their efficacy, safety, and substantial economic burden. They also have restricted brain delivery and could not pass through intact neurons to target intracellular proteins. There is still an urgent need for effective, easily administered (oral) and low‐cost drugs for AD.The intraneuronal accumulation of tau paired helical filaments (PHFs) is one of the hallmarks of AD brain pathology. Lowered efficiency of degradation pathways, such as ubiquitin proteasome system, further exacerbates tau pathologies. Instead of inhibiting protein aggregation, a class of molecules that promote the degradation of targeted protein is known as proteolysis‐targeting chimeras (PROTACs). Since 2016, PROTACs have been applied to resolve tau pathologies, progressing from being based on peptides to fully synthetic small molecules. This exploration is still at the early stage. Here, we aim to develop novel small‐molecule PROTACs as tau targeted protein degraders for AD treatment.MethodsWe performed global molecular docking of tau binders from a public database (bindingdb.org) into the available PHFs 3D structure and selected top ranked compounds. Together with them, ligands binding to E3 ligase, for instance cereblon (CRBN) and carboxyl terminus of Hsp70 interacting protein (CHIP), were used with different linkers to design synthetically accessible PROTACs. The modelling of ternary complex (tau‐PROTACs‐E3 ligase) are performed to rank designed PROTACs and the highly scored will be synthesised. Protein binding affinities and tau‐reducing effects will be evaluated in different cell models: human neuroblastoma SH‐SY5Y cells and mouse embryonic primary neurons.ResultsWe perform the development of tau targeted protein degraders according to the methods listed above. We selected the top ranked tau binders and designed new PROTACs.ConclusionsThe most potent PROTACs with least off‐target effects will move on to in vivo study and provide pre‐clinical evidence for novel treatment of AD tauopathies.
Can medical comorbidities modify the clinical evolution of mild cognitive impairment and Alzheimer’s dementia?
Authors: Nguyen Catherine Q N , Ma Liwei , Low Yi Ling Clare , Tan Edwin C.K. , Fowler Christopher J , Masters Colin L. , Jin Liang , Pan Yijun ,   AIBL Research Group
Published: January 2025

AbstractBackgroundDespite the health and societal burden that Alzheimer’s disease (AD) has on the elderly population, the underlying cause is not fully understood. Researchers are investigating possible mechanisms, and current studies have suggested that a number of comorbidities increase/decrease the likelihood of AD onset. The aim of the current study was to explore the associations between various comorbidities and AD in older Australians from an epidemiological perspective.MethodThis study used secondary participant data from the Australian Imaging, Biomarker & Lifestyle (AIBL) study (n = 2436) to perform a quantitative analysis. Univariable logistic regression was used to quantify the relationship between comorbidities and mild cognitive impairment (MCI)/AD, represented as odds ratios (ORs). The top 20 comorbidities were investigated as the exposure and based on the participants’ medical histories. MCI and AD were the outcomes of interest (with cognitive unimpairment as the reference) and were based on participants’ cognitive health diagnoses. Selected comorbidity associations with MCI/AD were also analysed via multivariable logistic regression, by stratifying and adjusting for sex, age, education, smoking, drinking and APOE ε4 allele carrier status.ResultFrom the univariable logistic regression, the comorbidities with the strongest odds of developing AD in the AIBL cohort were anxiety, depression, neurological disorders, falls and stroke. Comorbidities with the most reduced odds of developing AD were kidney disease, liver disease and visual defects. These associations remained significant after multivariable logistic regression. When stratified for each covariate, several comorbidity associations observed effect modification from sex and APOE ε4 allele carrier status. When adjusted for all covariates, most of the selected comorbidity associations observed significant confounding. There were moderate similarities between the MCI and AD analyses.ConclusionThis study presents evidence that certain comorbidities appear to modify the clinical evolution of MCI/AD. Further research is needed to identify the mechanisms behind these associations and the potential modifying effect on MCI/AD.
Early amyloid accumulation and APOE‐ε4 are associated with reduced non‐rapid eye movement slow‐wave activity in cognitively unimpaired adults
Authors: Tort‐Colet Núria , Fernández‐Arcos Ana , Stankeviciute Laura , Minguillon Carolina , Hernández Laura , Knezevic Iva , Sánchez‐Benavides Gonzalo , Suarez‐Calvet Marc , Holst Sebastian C , Garces Pilar , Mueggler Thomas , Zetterberg Henrik , Blennow Kaj , Muñoz‐Lopetegui Amaia , Arqueros Aurora , Iranzo Álex , Gispert Juan Domingo , Molinuevo Jose Luis , Grau‐Rivera Oriol 
Published: January 2025

AbstractBackgroundPoor sleep is associated with cognitive decline, and ∼45% of Alzheimer’s disease (AD) patients experience sleep disturbances. Emerging evidence suggests that reduced non‐rapid eye movement (NREM) slow wave sleep (SWS) is linked to amyloid accumulation and APOE ε4‐related genetic vulnerability to AD. Here, we investigate the effects of amyloid and APOE status on SWS, and their interaction, in a cohort of cognitively unimpaired (CU) individuals at higher risk of AD.MethodWe analyzed data from 80 sleep medication free participants (65.26 years old on average, 55% females, Table 1) from the AlfaSleep project, which involves characterization with polysomnography, APOE genotyping, CSF amyloid‐β (Aβ) 40 and Aβ42 (Roche NeuroToolKit), and [18F]flutemetamol‐PET, among other measures. Participants were classified as amyloid positive (A+) using either CSF Aβ 42/40 ratio (<0.071, N = 75), or amyloid PET (>12 Centiloids, N = 5) thresholds for early amyloid deposition.We computed average power spectral densities (PSD) from NREM sleep 30‐s epochs in frontal electroencephalogram channels, and power of slow oscillations (SO), delta and slow wave activity (SWA) as the area under the PSD curve between 0.5‐1Hz, 1‐4Hz and 0.5‐4Hz, respectively. We log‐transformed SWS metrics due to non‐normal distribution. We used linear regression models to test the main effect of amyloid or APOE status on SWS metrics in separated models, and next we entered both in the same model. Finally, we the tested interaction between APOE and amyloid status on SWS metrics. Models were adjusted by age, sex, and apnea‐hypopnea index (AHI).ResultBoth A+ status and APOE‐ε4 carriership were associated with significantly lower power in SO and SWA in separated models (Figure 1A). When combining both in the same model, only the effect of APOE on SO power remained significant, as well as a trend for lower SWA (Figure 1B). Interaction analyses yielded no significance.ConclusionEarly amyloid accumulation and APOE‐ε4 carriership are associated with SWS disruption in CU adults, with APOE‐ε4 carriers probably being particularly vulnerable to SWS disruption. Longitudinal studies spanning younger age individuals are needed to characterize the contribution of APOE‐ε4 to SWS disruption and to test whether preventive interventions targeting SWS could help to reduce AD dementia risk.
Validating the CogSleep Screener in older adults at a memory and cognition clinic
Authors: Kong Shawn Dexiao , Schrire Zoe M , Lin Pinghsiu , Simonetti Simone , Cross Nathan , Mowszowski Loren , Naismith Sharon L , Clinic Healthy Brain Ageing Research 
Published: January 2025

AbstractBackgroundWhile sleep disturbances are prevalent in older people and are linked with poor health and cognitive outcomes, screening for the range of sleep disturbances is inefficient and therefore not ideal nor routine in memory and cognition clinic settings. We aimed to develop and validate a new brief self‐report questionnaire for easy use within memory and cognition clinics.MethodOlder adults (N = 402, mean age 67.3 years, range 50‐86, 63.6% female) were recruited from a memory and cognition research clinic. All participants completed a comprehensive medical, neuropsychological and mental health assessment, alongside self‐report instruments, including existing sleep questionnaires and a new 10‐item sleep questionnaire, the CogSleep Screener. We examined the factor structure, convergent validity, internal consistency, and discriminant validity of this novel questionnaire.ResultUsing exploratory principal component analysis, a 3‐factor solution was generated highlighting the factors of Insomnia, Rapid Eye Movement (REM) Symptoms and Daytime Sleepiness. Each factor was significantly correlated with currently used sleep questionnaires for each subdomain (all Spearman rho>0.3, all p<.001), suggesting good convergent validity. Internal consistency was also good (Crobach’s α = .73). Receiver operating characteristic curves showed good discriminative ability between participants with and without sleep disturbances (all area under curve>0.7, all p<.01).ConclusionThe CogSleep Screener has good psychometric properties in older to elderly adults attending a memory and cognition clinic. The instrument has the potential to be used in memory clinics and other clinical settings to provide quick and accurate screening of sleep disturbances.
Personality as a Factor Underlying Cognitive Reserve
Authors: Coors Annabell , Lee Seonjoo , Habeck Christian G , Stern Yaakov 
Published: January 2025

AbstractBackgroundCognitive reserve is a concept that explains why cognitive performance can be better than would be expected given the level of brain pathology. In this project, we investigated whether certain personality traits are a factor underlying cognitive reserve. If so, individuals with these personality traits would show better cognition and less cognitive decline than would be expected given their level of age‐related brain changes.MethodThe cross‐sectional analyses were based on 399 healthy adults aged 19‐80 and the longitudinal analyses were based on 273 individuals. The mean follow‐up time was 5 years (SD = 0.7 years). The International Personality Item Pool questionnaire was used to assess the BIG5 personality traits openness, conscientiousness, extraversion, agreeableness, and neuroticism. Each cognitive domain (perceptual speed, memory, fluid reasoning, and vocabulary) was measured with up to 6 tasks. Cognitive domain‐specific brain status variables, derived from 77 structural brain measures using elastic net regularization, explained up to 43.1% of variance in cognitive performance.ResultHigher openness was associated with higher fluid reasoning and better vocabulary after adjusting for the cognitive domain‐specific brain status variables, age, and sex. Additionally, lower brain status was only associated with increased decline in perceptual speed among individuals with low openness. In contrast, in individuals with high openness, brain status was almost unrelated to change in perceptual speed.ConclusionHigh openness increases cognitive reserve and should be promoted across the lifespan.
Racial differences in blood pressure variability in the SPRINT trial
Authors: Sible Isabel , Nation Daniel A. 
Published: January 2025

AbstractBackgroundBlood pressure (BP) management is an accessible therapeutic target for dementia prevention. BP variability (BPV) is a newer aspect of BP control recently associated with cognitive decline, dementia and Alzheimer’s disease (AD), independent of traditionally targeted mean BP levels. Most of this work has relied on largely non‐Hispanic White study samples in observational cohorts. It remains unclear what role BPV may play in dementia‐related racial/ethnic health disparities. We examined whether BPV differed by race in the SPRINT BP clinical trial.MethodIn this post hoc analysis of the SPRINT trial, 8034 participants (median (SD) 67 (9.3) years; 34.8% female; 28.6% Black; 58.9% White; 10.8% Hispanic; 1.7% Other) underwent 4 BP measurements over a 9‐month period after treatment randomization (standard [<140 mmHg systolic target] vs intensive [<120 mmHg systolic target] BP lowering). Visit‐to‐visit systolic BPV was calculated as variability independent of mean. Racial groups (Black vs White vs Hispanic vs Other) were compared on BPV using ANCOVA models adjusted for age, sex, mean BP over the same 9‐month period, and number of antihypertensive medications used. Analyses were stratified by standard vs intensive treatment group.ResultUnder standard BP lowering treatment, systolic BPV significantly differed by race (F
3,3969 = 10.11, p < .001). When compared to Hispanic participants (mean (SD) 8.96 (1.1) mmHg), systolic BPV was higher in Black (9.26 (1.0) mmHg; .30 mmHg difference; p < .001), White (9.20 (1.0) mmHg; .24 mmHg difference; p < .001), and Other (9.31 (.9) mmHg; .35 mmHg difference; p = .01) participants. Racial groups did not significantly differ on systolic BPV under intensive BP treatment (F
3,3978 = 1.41, p = .24).ConclusionAlthough the SPRINT trial found no racial differences in treatment effects on cardiovascular benefits/risks, our findings suggest BPV differs by race, particularly under standard BP treatment. BPV is an emerging risk factor for dementia that may require unique treatment approaches beyond traditional lowering strategies. Findings could have therapeutic implications for patient‐centered care strategies aimed at reducing dementia risk and enhance our broader understanding of health disparities in vascular health relevant to AD risk.
Accelerating randomized clinical trials in Alzheimer’s Disease using generative machine learning model forecasts of progression
Authors: Yakubu Amin , Bogert Jennifer , Zhuang Run , Wittenberg Gayle , Pozniak Christine , Zhang Yi , Kusiak Coco , Turner Michelle , Hansen Bryan , Walsh Jonathan R. 
Published: January 2025

AbstractBackgroundPivotal Alzheimer’s Disease (AD) trials typically require thousands of participants, resulting in long enrollment timelines and substantial costs. We leverage deep learning predictive models to create prognostic scores (forecasted control outcome) of trial participants and in combination with a linear statistical model to increase statistical power in randomized clinical trials (RCT). This is a straightforward extension of the traditional RCT analysis, allowing for ease of use in any clinical program. We demonstrate the application of these methods retrospectively on 3 pivotal Phase III clinical trials in mild‐to‐moderate AD (NCT00236431, NCT00574132, and NCT00575055).MethodA probabilistic deep learning model was trained on the trajectories of nearly 7000 participants who had varying degrees of cognitive impairment, ranging from mild cognitive impairment (MCI) to moderate AD. These trajectories were collected observational studies and the control arms of RCTs. This trained model was used to forecast the control outcomes of participants in the three trials retrospectively, by entering their individual trial baseline data. The resultant forecasts are known as prognostic scores and represent comprehensive predictions across a broad range of AD outcomes.We evaluated the potential reduction in estimated variance and how this could translate to required sample size by incorporating the prognostic score as a covariate in the primary linear statistical model of each study, analyzing the 11‐component Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog11) and the Clinical Dementia Rating Sum‐of‐Boxes (CDR‐SB) endpoints as applicable.ResultPrognostic scores have the potential to decrease estimated variance between 5% to 10% and placebo arm sample size between 7% and 17% in the 3 studies when comparing standard + prognostic score vs. standard adjustment.ConclusionPrognostic scores have the potential to increase the statistical power in clinical trials; this would enable a reduced number of subjects required to detect a significant treatment effect. Potential sample size reduction during trial planning must be carefully estimated using independent validation studies to reduce the risk of under‐powering the trial.
Exploring Agency in Dementia: Care Staff Perspectives and Recommendations
Authors: Immonen Annikka 
Published: January 2025

AbstractBackgroundMy dissertation focused on the cultural and historical images of agency in person with dementia. In this partial study I examined care staff, who were also in a caregiver role, and their perceptions of how neurocognitive disorders (NCDs) change agency of a person. This role enabled for them to observe the entire disease process.MethodsThe research utilized data from a survey of care staff (n = 191) and Finnish dementia care textbooks spanning 1985 to 2019 (77 books). The theoretical framework consisted of communicative (Holzkamp), dynamic (Thomas and Znaniecki, Jyrkämä), and embodied (Kontos) agency of a person with dementia.ResultsBefore the onset of illness, care staff depicted their loved ones as social, cheerful, and purposefully active individuals with various possibilities for activities and skills to lead unique lives. The narratives of agency emphasized purposeful and intentional activity, as well as physical engagement.As neurocognitive disorders progressed, care staff observed a decline in agency, particularly linked to cognitive impairment. The narratives highlighted loss of abilities, memory, and social agency. Embodied agency was underemphasized in the narratives. The non‐verbal body language of persons with dementia was weakly presented. Agency was interpreted through the lens of spoken language and cognitive functioning.ConclusionIn both textbooks and accounts from care staff, the non‐verbal body language of people with dementia was inadequately portrayed.To optimally fulfil the agency of people with dementia, the study recommends actively observing their embodied agency and assessing their needs based on these observations. In response to the research findings, a remote learning course is currently under development to assist care staff in recognizing and supporting embodied agency of people with dementia.
Cognitive impairment and dementia in a nationally representative sample of older adults receiving care for incident TBI
Authors: Kornblith Erica S , Diaz‐Ramirez L. Grisell , Yaffe Kristine , Boscardin W John , Gardner Raquel C. 
Published: January 2025

AbstractBackgroundCognitive problems are thought to increase vulnerability to geriatric traumatic brain injury (TBI) due to increased fall risk, but little is known about prevalence of cognitive impairment and Alzheimer’s disease and related dementias (ADRD) among elders who receive treatment for a TBI.MethodEnrollees 65 and older in the nationally representative Health and Retirement Study (HRS) who consented to link survey data to Medicare claims and without a TBI prior to enrollment were studied. We used claims 2000‐2018 to obtain incident TBI diagnoses, defined using inpatient and outpatient International Classification of Disease (ICD) 9 and 10 codes received the same day as an emergency room (ER) visit code and a computed tomography (CT) scan code. Sociodemographic and health factors were defined at baseline interview. Baseline cognition was defined using Langa‐Weir Dementia Probability, a predictive model that classifies each respondent as ADRD; cognitive impairment, no dementia (CIND); or normal cognition.ResultOf respondents who experienced incident TBI (n = 797), 74% were classified as normal cognition, 19% as CIND and 7.1% ADRD at baseline. In the no‐TBI group (n = 8442), 68% had normal cognition, 23% CIND, and 10% ADRD (p<0.01). In sensitivity analyses considering TBI ± ER treatment and/or CT, results were similar. However, in multivariate models examining association of incident TBI with baseline sociodemographic, medical, and cognitive characteristics, neither CIND nor ADRD were associated with TBI status (p’s = 0.30 and 0.51, respectively). Instead, Black race (p<0.01), male sex (p = 0.02), higher education (p = 0,01), lung disease (p<0.01), higher neighborhood socioeconomic status (SES, p<0.01), and older age (p<0.01) were associated with membership in the no‐TBI group.ConclusionOur results suggest prevalence of baseline cognitive impairment and dementia is lower among elders treated for an incident TBI during study follow‐up, compared to the no‐TBI group. CIND/ADRD may protect against TBI through reduced activity or increased support with daily tasks. Alternatively, elders with CIND/ADRD may have reduced health care access or utilization. Moreover, demographic and contextual factors like age, gender, education, and neighborhood SES appear to be more meaningful predictors of incident TBI in this sample, vs. baseline cognition.