bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between education and multimodal neuroimaging in men and women across the lifespan
Authors: Gonneaud Julie , TURPIN Anne‐Laure , Vivien Denis , la Sayette Vincent De , Chételat Gael
Published: January 2025

Background

Education has been associated with reserve mechanisms and lower dementia risk, but the literature shows inconsistent results on the association between education and brain outcomes across the lifespan. Considering that both dementia risk and education are likely to differ between sexes, our study aims at understanding the association between education and brain outcomes across the lifespan and whether it differs by sex.

Method

In 207 healthy individuals (110women) aged 19‐84 years old (47.98±18.75), we investigated the association between years of education and multimodal neuroimaging (structural‐MRI, FDG‐PET, Florbetapir‐PET) and how this association was modulated by age and sex. Analyses were restricted to regions involved in Alzheimer’s disease and/or reserve mechanisms (hippocampal volume, temporoparietal metabolism, neocortical amyloid, anterior and posterior cingulate cortices [ACC/PCC] for each modality).

Result

There was no main effect of years of education on neuroimaging (ps>.09) nor interaction between education and the other variables. However, exploratory interactions conducted within young (18‐40), middle‐aged (40‐60) and older (60+yo) groups separately showed that, only in the older group, sex interacted with education on ACC volume, revealing that education was associated with greater volume only in older women (Figure; pinteraction = .006). Complementary analyses conducted in an independent and larger sample of older adults (n = 135, 83women, >65yo) in whom lifestyle was assessed retrospectively, suggest that midlife and late‐late‐life mental engagement, more than early‐life engagement (reflecting mainly education), are related to greater brain outcomes in late‐life (ACC volume, PCC amyloid burden, ACC metabolism). We assessed the moderative effect of sex on these associations and found that the association between grey matter volume and occupation (midlife engagement) was mainly driven by women (pinteraction = .02). The interaction between early‐life engagement and sex on ACC volume highlighted in the main cohort was replicated, yet at a trend‐level (pinteraction = .08).

Conclusion

Our study suggests that education is not strongly associated with age‐related differences in structure, metabolism or amyloid burden. Older women with higher levels of education, however, showed higher ACC volumes. These results suggest that education could promote brain reserve in late life in a sex‐dependent manner. Future studies should investigate the mechanisms behind these differences in brain reserve.
Improving Memory and Cognition by Enhancing Mitochondrial function and Biogenesis
Authors: Nour Dalia , Mostafa Mai , Ismail Fatma , Hanafi Rasha , AbdelKader Reham M.
Published: January 2025

Background

Alzheimer’s disease (AD) treatment remains to be a challenge; this is due to the fact that the pathogenesis of the disease is very complicated and not well understood. Unquestionable is the fact that the pathological hallmarks of AD are accumulation of amyloid plaques, neurofibrillary tangles and mitochondrial dysfunction all leading to neuronal cell death. Mitochondrial dysfunction plays an important role in AD. Previous studies demonstrated reduced mitochondria number in hippocampal neurons in brains from AD patients, emphasizing the role of mitochondrial biogenesis in AD. They showed significant changes in proteins levels in AD brain tissues compared to controls, demonstrating reduced mitochondrial biogenesis leading to mitochondrial dysfunction. TIn this study our aim was test natural isolated compounds (Licochalcone(LicoA) and pyrroloquinoline quinone(PQQ)) with potential effect on mitochondrial biogenesis on memory and cognition in a neuroinflammatory mouse model.

Method

A new GC/MS analysis method was developed and validated for detection of PQQ and LicoA in brain tissue. Mice were treated with either PQQ or LicoA in a neuroinflammatory mouse model. Memory was tested using object recognition and Y‐Maze tests. Brains were extracted from treated mice and levels of PQQ and LicoA were determined. Furthermore mRNA levels and proteins involved in mitochondrial biogenesis and function were determined using RT‐qPCR and ELISA.

Result

For the first time we were able to develop a method for determination of PQQ and LicoA in brain tissue of mice. Interstingly both PQQ and LicoA were found to cross the blood brain barrier. Both PQQ and LicoA enhanced memory and cognition. Moreover, both PQQ an and LicoA increased the mRNA levels and the levels of proteins involved in the mitochondrial biogenesis pathway such as PGC‐1α, NRF‐1, ND1 and ATP levels.

Conclusion

Isolated natural phenolic compounds such as PQQ and LicoA levels were determined in brain tissues of mice after peripheral adminstration. These compounds enhanced memory and cognitive function and thier mechanism of action involves enhancing mitochondrial biogenesis and function. Therefore, enhancing mitochondrial biogenesis may represent a new era for treatment of AD.
Exploring sex‐specific accelerated hippocampal atrophy across AD stages beyond APOE‐ε4 assessment in genetic risk evaluation
Authors: Evans Tavia E , Vilor‐Tejedor Natalia , Rodrigo Albert , Genius Patricia , Rodríguez‐Fernández Blanca , Anastasi Federica , Navarro Arcadi , Adams Hieab H.H. , Gispert Juan Domingo
Published: January 2025

Background

Current evidence suggests that hippocampal subfields have partially different genetic architecture and may improve the sensitivity of the detection of Alzheimer’s disease (AD). In this study, we investigated whether genetic predisposition to AD contributes to the accelerated rate of hippocampal volume atrophy across sex and AD stages and how this contribution is specifically driven by functional variants located in the APOE gene.

Methods

The study comprised 1,051 participants from ADNI cohort (75.2 yo; 42.3% women), with complete demographic, genetic, and magnetic resonance imaging scans at baseline and every 6 months for a total of 96 months (Controls (amyloid negative), CUN = 363; mild cognitive impairment, MCIN = 474, AD patients, ADN = 214). Hippocampal subfields were extracted using the longitudinal processing method within FreeSurfer (v6.0). Genetic predisposition to AD was assessed through polygenic scoring with and without considering the APOE región. Effects of polygenicity of plasma APOE, functional APOE brain eQTLs and CSF pQTL were also considered. Linear mixed‐effect models with random‐ time slope and intercept for individuals were used to investigate the association between genetic predisposition to AD and hippocampal subfields volumetric trajectories over time. Models were adjusted by age, sex, AD disease status, years of education and total hippocampal volume. Disease and sex status‐specific trajectories dependent on genetics predisposition were assessed by including an interaction term.

Results

Significant hippocampal subfield volume reductions were observed, with more pronounced atrophy in MCI and AD participants [Figure 1A]. High genetic predisposition to AD was associated with accelerated atrophy in various subfields [Figure 1B]. MCI individuals with high genetic predisposition showed more severe atrophy in several subfields, with sex‐related differences observed, particularly in women [Figure 2]. Notably, these effects were non‐significant when excluding APOE variants. Further functional analyses pinpointed CSF pQTLS of the APOE gene and APOE‐e4 carriership status as primary drivers [Figure 3].

Conclusions

Our findings underscore the significance of genetic predisposition, especially functional APOE variants, in understanding AD progression and sex‐specific trajectories. The results reveal varying atrophy patterns across disease stages, offering crucial insights for refining AD detection and tailoring interventions for more effective management.
Predicting Individual’s Cognitive Performance Through Multi‐Omics Blood Data Using Hierarchical Input Neural Network ‐ HINN
Authors: Vashishath Yashu , Beaver Sarah , Bozdag Serdar , Saeed Fahad
Published: January 2025

Introduction

Detecting declines in cognitive function is a critical global health concern, highlighting the need for timely identification to implement effective intervention strategies. This study investigates the potential of blood‐based biomarkers as accurate and non‐invasive measures of cognitive function. We developed a novel deep learning architecture that integrates multi‐omics data by considering their relationship. Specifically, we integrated single nucleotide polymorphisms (SNPs), gene expression, and DNA methylation data to predict cognitive test scores.

Methods

A novel computational architecture called Hierarchical Input Neural Network (HINN) (Figure 1) was developed to integrate multi‐omics datasets. In this study, HINN had three input layers receiving SNPs, DNA Methylation, and gene expression data, respectively. First, we conducted multiple GWAS runs to identify significant SNPs associated with cognitive scores based on different cognitive tests and found 373 SNPs across these runs. We identified 13037 DNA methylation sites proximal to these SNPs and 455 genes associated with these probes.

Results

We observed that MAE of the HINN model for MMSE, MoCA, ADAS11, and RAVLT‐I was 2.28, 2.98, 4.54, and 8.88, respectively. Similarly, MSE of the same model for MMSE, MoCA, ADAS11, and RAVLT‐I was 10.41, 17.16, 45.30, and 135.59, respectively. We compared our model with the other baseline models, namely L1‐regularized, support vector machine, random forest, and deep neural network. We also compared HINN with the pathway guided deep neural network in which all omics data were fed to single layer, which was connected based on biological processes relationship. The HINN model showed improvement of 2.98% to 9.81% for MAE and 3.99% to 12.3% for MSE in comparison to all other models (Figure 2).

Conclusion

The findings derived from the HINN model highlight its efficacy in detecting novel biomarkers for cognitive assessment. Through the hierarchical input approach, we outperformed baseline methods to predict cognitive score. Notably, our method is characterized by its independence from assumptions and subjective scoring, ensuring the robustness and reliability of predictions across diverse cognitive measures. The versatility of our model, capable of predicting multiple cognitive metrics, amplifies its utility and confidence in biological studies targeting cognitive assessment.
Development, Validation, and Clinical Utility of the Janssen plasma p‐tau 217+tau Simoa assay
Authors: Triana‐Baltzer Gallen
Published: January 2025

Background

Over the last two decades the Alzheimer’s biomarker field has progressed dramatically, beginning with the identification of specific analytes in CSF that track with autopsy‐confirmed AD, progressing to development of specific PET tracers and CSF assays to monitor brain amyloid and tau burden up to 20 years before symptoms, and now delivery of highly accurate, sensitive, and precise assays for measuring specific Abeta and pTau species in plasma.

Method

Here we present on the development, validation, and clinical utility of Janssen’s plasma p217+tau Simoa assay. The assay was initially created for CSF in 2017 and used as a pharmacodynamic marker in the Ph1 posdinemab trials, demonstrating substantial dose dependent reduction in CSF p217+tau. Translation of the assay to plasma required several key modifications, to enable quantification of the much lower levels in the periphery (∼1% of CSF levels) and avoid substantial negative interference in plasma (Triana‐Baltzer 2021).

Result

Over the past four years the Janssen plasma p217+tau assay has been evaluated in >10 large clinical cohorts, where it has consistently demonstrated high accuracy in MCI/AD populations for identifying brain amyloid or tau status (by CSF or PET; AUCs 0.85‐0.95; e.g. Dore 2022) as well as cognitive decline (Fig. 1, Feizpour 2023; Saloner 2023). Cutoff concentrations and specificity/sensitivity parameters appear conserved when transitioning from symptomatic to cognitively unimpaired populations (Dore 2022), however more work is needed to confirm this. Preliminary data indicates age, creatinine, BMI, sex and/or race may impact p217 concentrations (Fig. 2, Pichet‐Binette 2023), however more work is needed.

In late 2023 the assay was validated at Quanterix as a Lab Developed Test (LDT) in CAP/CLIA environment for global diagnostic availability. This test, marketed as Lucent AD p217, was evaluated in two large cohorts (n = 352 and 521, MCI/AD) against amyloid status (PET or CSF). The assay captured 100% of samples in the linear range and employs a 2‐cutoff approach for identifying subjects with low/intermediate/high risk of amyloid positivity (ala Brum 2023), with observed 90.3% sensitivity, 91.3% specificity for identifying low and high‐risk groups

Conclusion

To accelerate clinical trials the assay is currently being used as a prescreening tool in multiple Janssen‐sponsored Ph2 trials.
Neurodegeneration and acute neuronal injury drastically skew the p‐tau217/non‐p217 ratio in both CSF and plasma regardless of analytical technique – a mass spectrometry and Simoa study
Authors: Blennow Kaj
Published: January 2025

Background

Plasma p‐tau217 shows high promise as an AD biomarker. In some mass spectrometry (MS) studies, the ratio between p‐tau217 and the corresponding non‐phospho peptide tau212‐221 (p‐tau217/T217) was suggested to increase accuracy to detect AD‐type tau phosphorylation. However, disorders with rapid neurodegeneration or acute neuronal injury, are known to have increased neurodegeneration biomarkers e.g., total tau [T‐tau] and brain‐derived tau [BD‐tau]. Since both T‐tau and BD‐tau contain the T217 peptide sequence, it is likely that T217 also would increase, and the ratio thus be affected, but CSF/plasma p‐tau217/T217 has not been studied in these conditions.

Method

CSF and plasma p‐tau217, T217 and p‐tau217/T217 measured by Simoa and/or MS; T‐tau and BD‐tau by Simoa. Neurodegeneration cohorts (n>300) included CSF and plasma from controls, AD and sporadic Creutzfeldt‐Jakob disease (CJD). Plasma samples from acute neuronal injury cohorts (n>500) included traumatic brain injury (TBI) and cardiac arrest with brain hypoxia (Simoa analyses) plus ischemic stroke (MS and Simoa).

Result

Both p‐tau217 and the p‐tau217/T217 ratio markedly increased in AD, in CSF around 400% and in plasma around 280% of mean control levels. All neurodegeneration biomarkers increased dramatically in CJD (e.g. 1400% for CSF T217 by MS) and with acute brain injury (e.g. 600% increase in TBI for plasma BD‐tau). Changes were similar when measured by MS or Simoa, and CSF T217 by MS also correlated tightly with T‐tau by Lumipulse (r = 0.99). Consequently, in both CSF and plasma, the p‐tau217/T217 ratio was drastically skewed in rapidly progressive dementias (e.g., 16% of control levels in CSF in CJD) and in acute brain conditions, with marked reductions in p‐tau217 ratios in CSF and plasma, regardless of analytical technique.

Conclusion

Non‐phosphorylated tau variants (T‐tau, BD‐tau and T217) all markedly increase in dementias with rapid neurodegeneration and with acute brain injury and thereby drastically skew the p‐tau217/T217 ratio. This will be an important consideration for applications in clinical routine where patients with mixed pathologies are common. Therefore, plasma p‐tau217 alone may be preferred, as also supported by recent studies (Montoliu‐Gaya, Acta Neuropathol 2024;147:5) showing similar performance to identify AD for plasma p‐tau217/T217 and p‐tau217 by itself.
Computational Modeling and Simulation of the Cerebrospinal Flow and Drug Delivery
Authors: Montoya Gustavo , Teli Jaykumar Vishwanath , Kadamus Christopher , Lin Kathleen , Eddy Kaitlyn , Curry Eli , Blankenship Keith , Anumba Nmachi , Sharma Rakesh , Sharma Vijay Kumar , Ghosh Ujjal Bhanu , R Prasanth , Corrales Carlos , Sheikh Imran , Mariano Dean , DeMaria Christopher , Roy Kaushambi , Sirkar Rhea , Katuin Joseph , Subramony Anand
Published: January 2025

Background

The spinal intrathecal space, characterized by a complex three‐dimensional (3D) fluid‐filled geometry with varying levels of anatomic intricacy, plays a pivotal role in drug administration strategies targeting the central nervous system (CNS). Lumbar injections into this space represent a clinically used approach for delivering therapeutics directly to the brain, bypassing critical barriers such as the blood‐brain and blood‐cerebrospinal fluid barriers. A nuanced understanding of CSF dynamics is vital for comprehending physiological states of the CNS for drug delivery.

Method

The CSF’s dynamic nature enables the dispersion of solutes throughout the brain and ventricular system. In order to optimize CSF drug delivery strategies, a profound comprehension of the intrathecal anatomy coupled with insights into the physiology of CSF generation, absorption, and flow, is imperative. The application of quantitative modeling tools, such as Computational Fluid Dynamics (CFD), yields critical insights into the impact of CSF fluid dynamics on drug dispersion and efficiency. CFD modeling provides a granular analysis of CSF flow field, surpassing the capabilities of Magnetic Resonance Imaging (MRI) or invasive methodologies.

Result

Eli Lilly’s initiative in developing a CSF model aimed to predict drug distribution patterns mediated by cerebrospinal flow within the intrathecal space. This model sought to simulate prototypical CSF flow to ascertain the time required for a specified drug mass to reach the brain following lumbar intrathecal injection. Additionally, it aimed to assess the subsequent distribution of the drug within the brain, across a diverse patient demographic. This approach is instrumental in fine‐tuning drug delivery protocols, customizing delivery methods to particular drugs, avoiding off‐target drug effects, and ensuring maximum efficiency and efficacy for direct CNS treatments.

Conclusion

Through this computational methodology, we have demonstrated the feasibility of obtaining validation data for the CFD simulations using several imaging methodologies and techniques. Furthermore, we have been able to build these complex models and use them to inform in vivo studies. We have also been able to demonstrate that it is possible to build comparable NHP and human models from the fluid dynamics perspective.
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

Background

Early 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.

Method

This 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.

Result

Medicare 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.

Conclusion

This 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

Background

The 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.

Method

Fifty‐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.

Result

Of 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).

Conclusion

The 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

Background

In 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.

Methods

We 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.

Results

Over 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).

Conclusion

These 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

Background

Recent 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.

Methods

We 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.

Results

Results 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).

Conclusion

Using 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

Background

Despite 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.

Method

This 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.

Result

A 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.

Conclusion

These 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

Background

It 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.

Method

After 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.

Result

There 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.

Conclusion

This “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

Background

The 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.

Method

The 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.

Result

135 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.

Conclusion

The 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

Background

Several 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.

Method

To 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.

Results

Average 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).

Conclusion

Remote, 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

Background

Alzheimer’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.

Method

We 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.

Result

A 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.

Conclusion

Early 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

Background

Alzheimer’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.

Method

Using 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.

Result

After 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.

Conclusion

We 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.
Aggregation Trumps Phosphorylation in Tau‐mediated Toxicity
Authors: Cooper Amber , Richardson Brad , Zhang Yongrui , Moreno Miguel Ramírez , Batchelor Ben , Price Ray , Skoulakis Efthimios M. C. , Allan Douglas , Mudher Amritpal
Published: January 2025

Background

Disease‐modifying therapies for tauopathies like Alzheimer’s disease have targeted Tau hyperphosphorylation and aggregation, as both pathological changes are implicated in Tau‐mediated toxicity. However, the interplay between Tau hyperphosphorylation and aggregation, and their relative contribution towards overall Tau toxicity is not entirely understood.

Method

Leveraging the genetic tractability of Drosophila, we generated novel transgenic lines designed to manipulate Tau phosphorylation and aggregation to address these questions and unpick the relationship between these pathological changes. Tau accumulation and neurodegenerative phenotypes were visualised and quantified using Confocal and super resolution (Structured Illumination Microscopy, SIM) microscopy. Changes in total and phosphorylated Tau in Drosophila brain homogenates were also quantified by western blot analysis.

Result

We report profound neurodegeneration following expression of phospho‐mimicking human Tau, indicative that phosphorylation is a key driver of Tau toxicity in tauopathies. However, when Tau is rendered unable to aggregate, through deletion of a known aggregation motif, Tau toxicity was completely abolished even in the presence of phospho‐mimicking mutations. To phenocopy the neuroprotective effects of genetically suppressing aggregation, a peptide inhibitor that targets the same aggregation‐promoting motif, was also efficacious in significantly reducing Tau phenotypes throughout the lifespan of Tau expressing flies.

Conclusion

Our data demonstrates that Tau phosphorylation mediates neurodegeneration through a mechanism gated via Tau aggregation such that if hyperphosphorylated Tau cannot aggregate, it is no longer toxic. These results should inform the next generation of Tau therapeutics as suppression of Tau aggregation may have profound disease‐modifying potential without the need to clear pathogenic phosphorylated species. Funded by Alzheimer’s Society of Canada and Mike & Valeria Rosenbloom Foundation Research Award: Award Number: AWD‐019542 ALZSOCCA 2020o.
Link Prediction of Cortical Atrophy in Alzheimer’s Disease using Morphometric Correlation Networks
Authors: Luo Tiffany , Wang Chencai , Ellingson Benjamin M. , Cankurtaran Ceylan Z.
Published: January 2025

Background

Predictive biomarkers characterizing disease progression are called for in the context of emerging treatments for Alzheimer’s disease. We implemented a link prediction model on morphometric correlation networks(MCN) generated from structural MRI.

Method

High‐resolution T1MPRAGE images were retrospectively collected at two timepoints (interval 2.6 ± 1.2 years) for each of the 32 AD patients (AD)(mean age 74.6 ± 6.8, 14F/18M) and age‐matched cognitively normal controls (CN)(n = 32, mean age 75.0 ± 6.3, 16F/16M) from Alzheimer’s Disease Neuroimaging Initiative database. Images were processed using Freesurfer(version7.2) cortical reconstruction pipeline followed by cortical volume quantification. Whole‐brain surface‐based analyses (set at p < 0.05 and FDR < 0.05) were performed to identify regions showing significant differences between CN and AD, and significant atrophy between two timepoints across AD followed by computation of interregional correlations of cortical volume changes. Topological robustness of the MCNs for both timepoints were quantified to assess the network robustness of AD in response to the removal of predominant nodes. The MCN was used to build a link prediction model. Graph embedding was implemented to learn and extract features of each node in the MCN, and the light gradient boosting machine algorithm was applied to classify the cortical changes as atrophy. The AUC(area under the receiver operating characteristic curve) was used to evaluate the model’s performance.

Result

AD showed widespread cortical volume reduction. When examining the longitudinal cortical atrophy, the left superior temporal gyrus (STGl,p = 0.0108), precuneus (p = 0.0262), inferior(IPLl, p = 0.0019) and superior parietal lobule (SPLl,p = 0.0007), lingual gyrus(LGl,p = 0.0004); the right lateral occipital cortex (LOCr,p = 0.0168) and hippocampus(HCP r,p<0.0001); and bilateral supramarginal gyri(SMGl,p = 0.0227; r,p = 0.0181) showed significant volume loss (Fig. 1) and were identified as predominant nodes in the MCN that led the co‐atrophy as AD progressed (Fig. 2). With AD progression, robustness was weaker and removal of predominant nodes significantly reduced network resilience. The link prediction model predicted the cortical atrophy pattern in AD with AUC of 0.97 (Fig. 3).

Conclusion

We successfully implemented a model to predict progression of cortical atrophy and identified atrophy‐leading brain regions in AD. Future clinical translation of our approach can serve as an imaging biomarker.