bluuebunny/crossref_metadata_2025_split huggingface dataset:
Annual Wellness Visits and Early Dementia Diagnosis Among Older Adults Receiving Medicare Benefits
Authors: Tzeng Huey‐Ming , Raji Mukaila A , Shan Yong , Cram Peter , Fang Kuo Yong‐ 
Published: January 2025

AbstractBackgroundEarly recognition of cognitive impairment (CI) and timely diagnoses of mild CI (MCI) and Alzheimer’s Disease and Related Dementia (ADRD) are key to optimal dementia care. No previous research has examined the effects of Medicare annual wellness visits (AWVs) on early CI recognition among Medicare beneficiaries. Here, we assessed the association between incident diagnosis at MCI, moderate or severe ADRD stages in 2017‐2020, and having a Medicare AWV in the three years prior to diagnosis.MethodThis population‐based, case‐control study used 100% Texas fee‐for‐service Medicare data from 2014 to 2020; population: Medicare beneficiaries diagnosed with incident MCI or ADRD from 2017 to 2020. The exposure is Medicare AWVs. The primary outcome is MCI, moderate or severe ADRD status by ICD‐9‐CM and ICD‐10‐CM codes. We performed a multinomial logistic regression model to examine the association.ResultMedicare beneficiaries (n = 197,356) who had an AWV were 23‐66% more likely to be diagnosed at the MCI stage and 8‐30% more likely to be diagnosed at the moderate ADRD stage compared to diagnoses at the severe ADRD stage relative to those who did not have an AWV. There was a dose‐response relationship; as the number of AWV visits in the three years increased, the magnitude of the likelihood of early diagnosis increased.ConclusionThis study suggests that receipt of a Medicare AWV is associated with increased identification of early CI.
Factors associated with sarcopenia in older people with Alzheimer’s disease: a cohort study in a public outpatient clinic from the South of Brazil
Authors: Nakakogue Lindsey Mitie , Cabrera Marcos Aparecido Sarria , Zanchetta Clara Spinosa , Obata Renan Hayami 
Published: January 2025

AbstractBackgroundThe association of Alzheimer’s disease (AD) and sarcopenia diagnoses is quite common, but frequently sarcopenia is underdiagnosed in this population and it may be contributing to the worsening of functionality in the person with AD.MethodFifty‐five adults over age 60 from a public outpatient clinic in Londrina – Parana‐ Brazil diagnosed with Alzheimer’s disease were followed during the years 2022 and 2023. They were subjected to a sociodemographic questionnaire, BMI assessment, cognitive assessment using the MMSE, functionality assessment using the Katz Index and to a sarcopenia screening test SARC‐F +CC. They were evaluated at the beginning, after 4 and 8 months.ResultOf the fifty‐five older patients evaluated, 60% were female, 47.3% were between 70 and 79 years old, 43.6% had less than 4 years of schooling, 98.2% had mild Alzheimer’s (CDR I) and 25.5% had a BMI < 22 kg/m 2 in the beginning of the assessment. Only 18.2% were smokers, but few practiced physical activity regularly (21.8%). The majority had a diagnosis of Arterial Hypertension (69.1%). Almost half used five or more medications regularly (43.6%) and 36.4% used some medication with anorectic potential. Regarding the treatment of Alzheimer’s disease, 54.5% were using donepezil. Of the 55 older patients analyzed, 15 (27.3%) had probable sarcopenia at the end of 8 months of follow‐up. There was no association between the diagnosis of sarcopenia and gender, but the older the age, the greater the risk of sarcopenia, a risk of 1.091 (1.018‐ 1.170, p = 0.013). There was an association between the reduction in calf circumference and sarcopenia, with a CC < 33‐34cm risk of 9.391 (2.973‐29.664, p<0.001). In relation to patients without sarcopenia, those with probable sarcopenia had a reduction in BMI (p = 0.051). Older patients with probable sarcopenia had more falls, a risk of 1.744 (1.239‐2.456) and worsened functionality, a risk of 1.465 (1.078‐1.991) compared to older patients without sarcopenia (95% CI, p<0.001).ConclusionThe incidence of sarcopenia in older people with Alzheimer’s disease is high and should be investigated during the follow‐up of every older person to prevent negative outcomes such as falls and loss of functionality.
Net Benefit of Lecanemab and Anticoagulants: Results from a Simulation Model
Authors: Shah Sachin J , Dinger Tai , Blacker Deborah , Greenberg Steven M. , Newhouse Joseph , Lykken Jacquelyn M , Pandya Ankur , Hsu John , Hyle Emily P 
Published: January 2025

AbstractBackgroundIn CLARITY‐AD, lecanemab both slowed cognitive decline and increased intracranial hemorrhages (ICHs), particularly among participants concurrently using anticoagulants. The Alzheimer’s Association’s expert guidance is to avoid co‐prescribing; however, CMS and FDA do not restrict or warn against co‐prescribing. We used a microsimulation model to quantify the potential benefits and harms of co‐prescribing lecanemab and apixaban in people with atrial fibrillation (AF) experiencing mild cognitive impairment or early Alzheimer’s.MethodsWe developed a microsimulation model to estimate the health and cognition‐related quality of life among persons 65‐90 years with AF and cognitive impairment. We compared four strategies over 18 months in a cohort of 100,000 people: apixaban alone, lecanemab and apixaban, lecanemab alone, and neither. We populated the cohort using the national Health and Retirement Study‐AF cohort. Monthly model outcomes included ICH, ischemic stroke, cognitive impairment, quality‐adjusted life months (QALMs), and survival. Increased ICH risk was a key input: a trial‐reported 2.02‐fold increase for lecanemab alone, a 2.21‐fold increase for apixaban alone (anticoagulant literature), and a trial‐reported 9.92‐fold increase for lecanemab and anticoagulants together. We assigned quality‐of‐life estimates and mortality rates for people with cognitive impairment, stroke, and ICH. Background mortality rates increased with cognitive decline and following a stroke or ICH event.ResultsOver 18 months, apixaban alone would result in more QALMs (12.39 vs. 12.16), fewer ICH events (1,841 vs. 8,769), fewer deaths (17,652 vs. 21,199), but more cognitive decline (CDR‐SB increase from baseline 1.42 vs. 1.01) compared to apixaban and lecanemab together (Table 2). In the 65 to 74‐year‐old age group, lecanemab and apixaban could be preferred (QALM 13.27 vs. 13.28) given the benefits of slowed cognitive decline but at the risk of 1,424 more ICH events/100,000 treated persons (Table 2). This finding is sensitive to the lecanemab‐apixaban interaction on ICH risk (Figure).ConclusionThese model‐based results support apixaban alone as the preferred strategy for people with cognitive impairment and AF. Improved estimates of the lecanemab‐anticoagulant interaction are critical to identifying the preferred strategy for people aged 65‐74 years. These findings support the Alzheimer’s Association’s expert guidance to avoid co‐prescribing lecanemab and anticoagulants.
Impact of APOE4 dementia risk as a function of age in under‐represented groups using data from the All of Us Research program
Authors: Ghisays Valentina , Khajouei Ehsan , Piras Ignazio , Goradia Dhruman D. , Malek‐Ahmadi Michael H. , Chen Yinghua , Naymik Marcus , Saner Don , Su Yi , Huentelman Matthew J. , Karnes Jason H , Reiman Eric M. 
Published: January 2025

AbstractBackgroundRecent studies have raised the possibility that APOE4 has a smaller impact on the risk for Alzheimer’s disease(AD) in non‐Hispanic Black(NHB) and Hispanic than non‐Hispanic White(NHW) individuals. Confirming that possibility in real‐world cohorts could have major implications for research and care in under‐represented groups(URGs). We used electronic health record (EHR) data from All of Us (AoU) to compare prevalence of all‐cause dementia in these URGs and the impact of APOE4 carriage and allelic dose on dementia hazard ratios.MethodsWe used EHR data from 10,045 Hispanic‐White, 14,937 NHB, and 60,388 NHW ages 60+ to characterize the risk of converting to a diagnosis of dementia in APOE4 homozygotes(HM), heterozygotes(HT), combined carriers, and non‐carriers(NC) using Cox hazards‐ratio(HR) and 95%CIs. We used genomic data to extract genotypes and all ICD‐9 codes related to dementia diagnosis or associated drug prescriptions to identify cases and controls.ResultsResults showed that APOE4 increased dementia risk significantly in all groups but varied in race and ethnicity by allelic frequency. In NHB individuals, APOE4 carriers had a significant increased risk (HR 1.25, 95%CI 1.00‐1.57, p = 0.04), while we failed to detect differences in HM and HTs. Hispanic carriers and HTs also exhibited significant risk (HR 1.54, 95%CI 1.24‐1.90; HR 1.52, 95%CI 1.22‐1.88, p<0.0001; respectively) but failed to detect differences in HMs. In NHW, risk increased significantly with APOE4 copy (HT: HR 1.42, 95%CI 1.28‐1.58; HM: HR 3.70, 95%CI 2.92‐4.68; combined carriers: HR 1.55, 95%CI 1.40‐1.72, p<0.0001). Compared to NHW, Hispanic and NHB groups had 2.4x and 1.6x higher risk (HR 2.44, 95%CI 2.19‐2.72; HR 1.55, 95%CI 1.38‐1.75, p<0.0001).ConclusionUsing diagnostic codes in a large number of AoU participants, we observed greater risk of dementia in URGs and trends to support APOE4 allelic dose effects overall and greater effects in NHWs. Limitations in detecting APOE4 allelic dose effects or interactions with these URGs could be related to sample size, accuracy to characterize AD cases and controls in EHR datasets, and any inaccuracies/biases in clinical diagnosis. This study provides support to further characterize prevalence of AD and non‐AD dementias and impact of APOE4 on AD dementia risk using plasma pTau217 as an AD endophenotype.
Psychometric Properties of the Korean Version of the Motivation to Change Lifestyle and Health Behaviors for Dementia Risk Reduction Scale in Middle‐Aged and Older Adults
Authors: An Hyunseo , Yun Sohyeon , Kim Inhye , Shin Jiwon , Yang Hyun , Park Hae Yean 
Published: January 2025

AbstractBackgroundDespite Korea’s efforts to promote dementia‐prevention lifestyles and health behaviors, adherence among older adults is low. This underscores the importance of identifying factors, “beliefs, and attitudes” that influence lifestyle and health behavior changes to reduce dementia risk. The effectiveness of the scale used to measure these changes has been proven in different cultural contexts, but its suitability for the Korean population has yet to be investigated. Therefore, this study aimed to translate and validate the Motivation to Change Lifestyle and Health Behaviors for Dementia Risk Reduction (MCLHB‐DRR) scale in Korean middle‐aged and older adults.MethodThis study recruited a community‐living sample of Korean adults aged 50 years and older from an online panel. Content validity and construct validity were examined to determine the scale’s validity. Internal consistency and test‐retest reliability were examined to determine its reliability. Test‐retest reliability was evaluated by readministering the MCLHB‐DRR scale to 50 individuals within three weeks of the initial application.ResultA total of 270 participants completed the questionnaire. Content validity was determined by professors and researchers in occupational therapy. Item 8 was removed from the Korean version after most experts agreed that it did not align with Korean cultural perceptions of dementia’s perceived severity. The confirmatory factor analysis of the 26‐item scale showed a good model fit (χ2/df = 1.845, comparative fit index = 0.939, Tucker–Lewis index = 0.929, root mean square error of approximation = 0.056). Cronbach’s alpha values were .821–.900, indicating good internal consistency. No significant test‐retest score differences were identified between the groups.ConclusionThese results indicated that the MCLHB‐DRR scale is valid and reliable for the Korean population to assess beliefs and attitudes toward lifestyle changes to reduce dementia risk. Its validation in the Korean context aids in developing lifestyle interventions for dementia prevention and provides foundational data for comparing lifestyle change motivations across countries.
Intracerebroventricular injection of autologous, Wnt‐activated, adipose‐derived stem cells for the treatment of Alzheimer’s Disease: Experience with the first patient of a “First in Human” Phase 1 FDA trial
Authors: Duma Christopher M. , Keirstead Hans , Nistor Gabriel , Lynn Robert , Buxton Jessica J. , Farmer Sawyer H. , Chung Karlyssa , Harris Ashley 
Published: January 2025

AbstractBackgroundIt has been more than 20 years for a new treatment for Alzheimer’s Disease (AD) to emerge. This treatment has recently been in the form of a monoclonal antibody targeting the end‐products of neuronal death. We are testing the safety of a novel approach using activated stem cells injected directly into the ventricles of the brain.MethodAfter animal testing, we received FDA clearance for a 3 + 3, Phase 1 trial in 9 patients using escalating doses of the test product. The first patient was screened for age less than 80 years, FAST stage 4 or 5, having a Mini Mental Status Exam (MMSE) between 10 and 20, as well as exhibiting brain PET and CSF AD markers. The patient underwent a 3‐step process of liposuction, Ommaya reservoir implantation, and injection following cell selection and expansion based on Wnt expression in the lab (the test product). The patient was admitted to the hospital 43 days after initial lipoaspirate cell expansion and Wnt expression selection, for the injection, and observed overnight. Five ml. of the test product containing 2M cells was injected. Vital signs (VS) and clinical examinations were performed per protocol. CSF analysis, MMSE, amyloid PET and MRI imaging will be performed at regular intervals post‐injection for 1 year.ResultThere were no adverse events following any of the first 2 steps in the patient’s procedures. The injection process required 3 minutes to perform, without anesthetic. This was well‐tolerated with no immediate or remote headache, nausea, vomiting or change in VS up to 5 weeks post‐injection as of this publication.ConclusionThis “first in human” trial of intracerebroventricular injection of Wnt‐expressing, adipose‐derived stem cells appears well‐tolerated and safe for our first injected patient with a minimum of 5 weeks followup. Our intention is to submit parallel Phase 2 trials to the FDA using this Phase 1 safety data, for treatment of patients with AD, MS‐P, Parkinson’s Disease, CTE, and ALS.
OVERTURE Phase 2 Study time‐savings analysis using composite measures of function and cognition
Authors: Kern Ralph , Haaland Benjamin A , Nicodemus‐Johnson Jessie , Dickson Samuel P. , Kuang ZD , Houser Celine , Hajos Mihaly , Vaughan Brent , Hendrix Suzanne B. 
Published: January 2025

AbstractBackgroundThe OVERTURE I (NCT03556280) randomized controlled trial (RCT) evaluated Cognito’s non‐invasive device (SpectrisTM) in mild‐moderate Alzheimer’s disease (AD). Composite measures, such as combined statistical tests (CSTs) and iADRS, combine the joint evolution of function and cognition over time in the population of interest when calculating the combined treatment effect. We estimated time savings of active treatment vs. sham treatment using prespecified ADCS‐ADL and MMSE outcomes, as well as post‐hoc iADRS and CST outcomes using data obtained from the RCT.MethodThe OVERTURE I phase 2 clinical trial (NCT03555280) compared one‐hour, daily, at‐home, active vs. sham treatment for six months (2:1 randomization). We evaluated the ADCS‐ADL and MMSE based on a bivariate linear model for 6‐month change from baseline with correlation structure accommodating a correlation between individual patient change from baseline measures for ADCS‐ADL and MMSE. iADRS was analyzed as described (Wessels et al 2015). The CST is computed based on averages of least squares means for ADL and MMSE as well as treatment effects on each endpoint.Result135 participants were screened, 74 were randomized and 53 completed (20 sham, 33 active) the RCT. Safety, tolerability and adherence was confirmed in the RCT, and no serious treatment‐related adverse events or ARIA were observed. Active vs. sham treatment resulted in significant reductions in disease progression over 6 months of treatment (mean difference, 95% CI) in ADCS‐ADL 8.31, 2.85‐13.77; MMSE 2.21, 0.39‐4.04; CST 5.26, 2.17‐8.36; and iADRS 6.65, 0.41‐12.89. Corresponding time savings (months, % time savings) in ADCS‐ADL (5.02, 84%); MMSE (4.56, 76%); CST (4.92, 82%); and iADRS (3.63, 60%) were observed.ConclusionThe OVERTURE I RCT demonstrated that non‐invasive at‐home (SpectrisTM) treatment meaningfully reduced the decline in ADCS‐ADL, MMSE, CST and iADRS over 6 months compared to sham treatment and was associated with 60‐84% time savings. These outcomes will be further evaluated in the ongoing HOPE pivotal trial in mild‐moderate AD (NCT05637801).
High‐frequency assessment methods to detect subtle change in cognitive worsening
Authors: Aschenbrenner Andrew J. 
Published: January 2025

AbstractBackgroundSeveral trials using BACE inhibitors have stopped for futility, and in some cases, evidence of progressive cognitive worsening, particularly early in treatment. As new trials are launched, evaluations of acute cognitive decline need to be made at the individual level, so that treatment can be stopped or adjusted if there is evidence of sufficient cognitive decline. To this end, it is essential to adopt assessment methodologies that can monitor cognitive safety and provide benchmarks against which to compare acute change. A cognitive safety monitoring system in this context must be psychometrically reliable, sensitive to change, and tolerable by participants. We examine the suitability of a high‐frequency, remote cognitive assessment study (Ambulatory Research in Cognition [ARC]) for this purpose. Its sensitivity can be established by administering controlled cognitive challenges, such as 24‐hour sleep restriction. Consistent cognitive change that exceeds this magnitude can serve as an early warning of adverse cognitive effects.MethodTo date, ARC has enrolled and continuously followed ∼350 healthy and very mildly impaired older adults using brief cognitive tests across three domains. Tests were administered four times daily for one week and repeated at six‐month intervals. Adherence and reliability of these tests have previously been shown to be excellent. We compared performance on the cognitive tests at the beginning and end of the day as a proxy for sleep restriction.ResultsAverage response time at the start of the day was 3.4 seconds (SD = 1.12) and at the end of the day response time was 3.6 seconds (SD = 1.1). This difference was marginally significant based on a paired samples t‐test (p = 0.07, Cohen’s d = 0.19).ConclusionRemote, high‐frequency cognitive assessment is feasible and tolerable by healthy and impaired participants. More importantly, this assessment methodology affords the ability to measure variability and can detect even subtle cognitive deficits associated with sleep restriction. In our presentation, we will expand on our methods for developing the construct of cognitive safety and provide additional details on how this system could be used in upcoming BACE inhibitor secondary prevention trials.
Study design considerations for strategies in early interventions in Alzheimer’s disease
Authors: Dickson Samuel P. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) treatments targeting disease modification face a development paradox: the cascade of events that lead to AD may already have irreversible consequences at diagnosis, so the most treatable patients won’t progress enough to show significance at a sample size or timeframe that most sponsors can afford. Though monoclonal antibodies (mABs) have seen some recent success, the limitations of mABs have led many to consider designs that either build on the success of mABs, or start earlier in disease progression by pursuing secondary prevention for subclinical patients, or primary prevention. We present statistical considerations for these designs with enrichment strategies.MethodWe use AD risk by age and ApoE genotype and other historic data to estimate event rates and sample sizes for primary and secondary prevention studies and for studies of combination treatment with mABs. We consider both event‐based and continuous‐endpoint analyses for biomarkers or clinical outcomes. We assume a 30% reduction in events for treatment. The primary population targets ages 65 to 85, but can be enriched by targeting later ages or alternative demographics like the Down syndrome (DS) population.ResultA 1.3% base event rate is anticipated in primary prevention studies. For 80% power this may require more than 20,000 participants over 5 years and close to 30,000 when accounting for 30% dropout. Enrichment by raising the minimum age by 10 years or including only ApoE4 carriers or participants with DS reduces sample size requirements by half. Using a continuous biomarker outcome will also reduce sample size to approximately 10,000 to 15,000 participants. Secondary prevention study sample sizes may be reduced to 1,000 to 6,000 subjects over a two‐year treatment period, while combination studies may have 500 to 2,000 subjects. A digital assessment that reduced variability 30% would reduce sample size by half.ConclusionEarly intervention and combination treatment studies may require larger sample sizes than have been used in most AD clinical trials, but the recent successes of mABs and the potential gains in safety and efficacy may justify the additional resources.
1,5‐anhydroglucitol predicts the risk and possible mechanisms of Alzheimer’s disease
Authors: An Dinghao , Xu Yun 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is associated with abnormal glucose tolerance. However, the contributing factors are unknown. We aim to find markers of Alzheimer’s disease in association with abnormal glucose tolerance.MethodUsing genome‐wide association data, we screened out the association between the latest AD dataset and 50,044 datasets to find indicators of glucose tolerance that may be related to AD. Then we implemented a bidirectional MR analysis to evaluate the genetic relation between them and AD. According to the expression levels in brain tissue, we identified the hub genes. Then, we conducted enrichment analysis by combining hub genes and AD drug targets interaction analysis to evaluate the possible pathways. Moreover, we performed a mediation analysis to assess whether blood glucose‐related indicators and diseases are mediators between the two.ResultAfter a thorough screening, we found 1,5‐anhydroglucitol, a blood glucose monitoring indicator, could act as a genetically determined risk factor for AD. (ivw: OR = 1.006, 95%CI:1.000‐1.012, p = 0.049; ivw fe: OR = 1.006, 95%CI:1.002‐1.010, p = 0.007). However, we did not find any blood glucose‐related indicators and diseases that could act as a mediating factor. Through genetic annotation of SNP and based on their expression levels in brain tissue and cells, only MGAM and RAB3GAP1 may act as hub target genes, while SI cannot be a target. Hub gene self‐interaction and AD drug target interaction analyses suggest the presence of reported AD‐related genes. Functional and signaling dual pathway analyses suggest the possible mechanism between 1,5‐anhydroglucitol and AD.ConclusionWe found that 1,5‐anhydroglucitol, a potential marker of glucose tolerance, may be a risk factor for Alzheimer’s disease. We also discovered a potential new target gene for AD: RAB3GAP1 and evaluated possible pathways between 1,5‐anhydroglucitol and AD. Anyway, our findings contribute to the understanding of pathogenesis and yield novel potential therapeutic targets of AD.