bluuebunny/crossref_metadata_2025 huggingface dataset:
Systemic exposures of gantenerumab: An integrated population pharmacokinetics (popPK) analysis across multiple clinical studies
Authors: Schwab Dietmar , Jolivet Sebastien , Gibiansky Leonid , Lott Dominik
Published: December 2023

Background

Characterization of gantenerumab systemic exposure is important to inform dose selection and understand the factors that influence pharmacokinetics (PK), such as participant‐ or study‐specific characteristics, and the safety and efficacy of gantenerumab treatment.

Method

Gantenerumab systemic PK following subcutaneous administration was investigated in multiple clinical studies, including single‐dose studies in healthy participants with dense PK sampling and multiple‐dose studies in participants living with AD (pwAD) with sparse PK sampling. An integrated population PK (popPK) analysis was conducted across six single‐dose studies in healthy participants and seven multiple‐dose studies in pwAD using nonlinear mixed‐effects modelling in NONMEM v7.2. The studies in pwAD included GRADUATE I and II (NCT03444870; NCT03443973), GRADUATION (NCT04592341), and the legacy studies SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) including their open‐label extensions. In total, 23,200 observations from 3,053 participants were available for analysis. Covariate assessments included demographic characteristics, laboratory values, disease status, concomitant medication, and study‐specific factors.

Result

A robust popPK model was established incorporating data from multiple clinical studies with diverse titration and dosing regimens. Main factors identified as influencing exposure were body weight, serum albumin, drug substance generation, and Asian race. Moderate variability at steady‐state (AUCss) was observed, as determined by a coefficient of variation of 22.4% in clearance. Steady‐state exposure in the GRADUATE and GRADUATION studies was slightly higher than expected and within a comparable range versus the legacy studies (see figure). Dosing frequency had no impact on average plasma exposure and a minor impact on minimum and maximum plasma concentrations at steady‐state. The ratio of the plasma concentration–time profile for dosing every week and every 2 weeks was within a 0.8 to 1.25 margin. Low immunogenicity was observed, with 4.8% of the GRADUATE participants being ADA‐positive. The impact of ADAs on exposure was small.

Conclusion

Systemic exposure of gantenerumab was well characterized in a popPK analysis. Participants in the GRADUATE, GRADUATION and legacy studies had comparable exposures, with a minor impact of dosing frequency. The lower amyloid removal reported in the GRADUATE studies versus the legacy studies cannot be explained by differences in PK.
Associations of physical activity with cerebrospinal fluid biomarkers of neurodegeneration, neuroinflammation, and Alzheimer’s disease
Authors: Planalp Elizabeth M. , Van Hulle Carol A. , Bendlin Barbara B , Blennow Kaj , Carboni Margherita , Carlsson Cynthia M , Engelman Corinne D. , Kollmorgen Gwendlyn , Ma Yue , Okonkwo Ozioma , Johnson Sterling C , Zetterberg Henrik , Merten Natascha
Published: December 2023

Background

Alzheimer’s disease (AD) and related dementias are public health concerns often with long preclinical phases. Thus, intervention and prevention methods in midlife could prove efficacious. Cerebrospinal fluid (CSF) biomarkers can change early in the disease process and have been utilized for dementia diagnostics. Multiple health‐related lifestyle factors have been associated with risk for AD, yet existing research on lifestyle factors has focused on clinical outcomes such as cognitive decline, mild cognitive impairment and/or AD dementia; their associations with early changes in CSF are less understood. Our aim was to determine whether physical activity (PA), a modifiable lifestyle factor, is associated with biomarkers for neurodegeneration, glial activation, and inflammation.

Method

Participants were N = 204 cognitively unimpaired adults (aged 45–80 years) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center, two on‐going, longitudinal studies of preclinical AD. PA was defined as the weekly metabolic equivalent (MET), calculated by scoring amount and intensity of mild, moderate, and vigorous exercises per week (range 0–79 METS). We assessed CSF biomarkers using robust exploratory prototype assays from the NeuroToolKit research platform (Roche Diagnostics International, Switzerland). Participants also completed demographic and health questionnaires (Table 1). We used linear regression models to assess associations between PA and CSF biomarkers, adjusting for age at biomarker assessment, sex, education, and chronic health conditions (diabetes, hypertension, cardiovascular disease).

Result

Preliminary results showed that participants who engage in more PA had higher CSF S100B concentrations, a pro‐inflammatory calcium‐binding protein (standardized b change per MET = 0.0013, 95% confidence interval: 0.0003–0.0023; p = .01). No other PA‐biomarker associations were significant.

Conclusion

Higher PA was significantly associated with higher CSF concentration of S100B, a marker of (astro‐)glial activation. Future studies will need to examine whether PA is associated with higher S100B in individuals along the disease continuum of AD, and whether this is reflected in the blood. Longer follow‐ups may be needed to determine associations of PA with other biomarkers, where we had limited variation in this primarily healthy study cohort.
Atrophy of Brodmann Area 36 differentiates age‐related subjective memory decline from cognitively normal older adults and is associated with NPTX2
Authors: Corona‐Long Caitlin A , Chang Elizabeth , Speck Caroline L , Gallagher Michela , Bakker Arnold
Published: December 2023

Background

Advancing age is associated with changes in cognitive functions, particularly memory, although there are significant individual differences between subjects. While some older adults experience minimal cognitive decline, others exhibit more pronounced deterioration that can progress to Alzheimer’s disease dementia (AD). Some older individuals report subjective memory complaints (SMC) despite normal scores on objective memory assessments. Longitudinal studies suggest that SMC may be predictive of AD dementia and precedes the onset of mild cognitive impairment (MCI) by around 15 years. However, given large individual differences and biases towards reporting complaints, objective measures are needed to identify those individuals who are on a trajectory of decline relevant to AD.

Method

In the current study cognitively normal older adults, older adults with SMC, and patients with MCI were recruited from the ADRC and the community to complete neuropsychological assessment, an MRI scan and a lumbar puncture to assess what measures are associated with self‐reported SMC. Structural MRI scans were analyzed using the Automated Segmentation of Hippocampal Subfields (ASHS) pipeline. Cerebrospinal fluid (CSF) was analyzed using standard methods to obtain fluid biomarkers associated with AD.

Result

Consistent with previous reports, entorhinal cortex volume significantly differed between cognitively normal older adults and patients with MCI. However, entorhinal cortex volume did not differentiate between controls and SMC subjects. Instead, volume of Brodmann area (BA) 36 was significantly different between control participants and SMC subjects as well as between controls and patients with MCI. Furthermore, volume of the right BA35 and BA36 was moderately correlated with neuronal pentraxin‐2 (NPTX2), a marker of synaptic integrity that is reduced in AD. Volume of the right BA36 was additionally correlated with measures of cognition including the Mini‐Mental Status Exam and objective measures of memory function.

Conclusion

Together these findings show that particularly atrophy of BA36 may provide an objective measure differentiating between cognitively normal older adults and those with SMC, and in identifying the early stages of AD prior to a diagnosis of aMCI.
Cross‐sectional associations between amyloid and tau PET and cognitive performance in Black adults without dementia: Preliminary results from the African Americans Fighting Alzheimer’s in Mid‐life study
Authors: Ennis Gilda E. , Langhough Rebecca E , Cody Karly Alex , Zuelsdorff Megan , Bouges Shenikqua , Carter Fabu P. , James Taryn T. , Salazar Hector , Betthauser Tobey J , Asthana Sanjay , Johnson Sterling C , Bendlin Barbara B , Gleason Carey E.
Published: December 2023

Background

Few studies have examined amyloid and tau and cognitive performance in samples solely comprised of African American (AA) adults. The African Americans Fighting Alzheimer’s in Mid‐life (AA‐FAIM) study (n = 293 active AA participants) is currently collecting amyloid and tau positron emission tomography (PET) scans. Preliminary cross‐sectional associations between amyloid and tau PET and cognitive performance are presented here.

Method

N = 55 adults without dementia had amyloid and/or tau PET (n = 48 had amyloid PET; n = 47 had tau PET; n = 40 had both scans). 11C‐Pittsburgh Compound B (PiB) PET quantified cortical β‐amyloid. 18F‐MK‐6240 PET measured tau in entorhinal cortex (EC), medial temporal lobe (MTL), and temporal lobe meta‐ROI. Amyloid and tau PET positivity cut‐points were derived from prior research. Cognitive assessment included immediate and delayed recall (RAVLT) and Trails B. Linear regression tested associations between amyloid and tau PET and cognition.

Results

In those with both amyloid and tau PET, seven (17.5%) were amyloid and EC tau PET positive (Table 1). Increased amyloid PET DVR and amyloid PET positivity were significantly related to increased tau PET SUVR in models unadjusted and adjusted for age and sex (Figure 1). In the combined sample (n = 40), neither amyloid nor tau PET was significantly related to cognition in models adjusted for age, education, and prior‐test‐exposure (or remote testing when recall was analyzed) (p‐values>.06). In the tau PET sample (n = 47), increased tau in EC and MTL was significantly related to worse immediate recall in adjusted models; in contrast, amyloid was not significantly related to cognition (Table 2) in the amyloid PET sample (n = 48). Associations between PET and cognition were similar following removal of n = 4 MCI participants.

Conclusions

Preliminary results in this small sample suggest that elevated brain tau is related to verbal‐learning and recall in a sample of AAs without dementia; results related to amyloid did not reach statistical significance. A larger sample size is needed to increase the statistical power to detect associations and improve the precision and comparability of tau and amyloid parameter estimates. Recruitment of more participants for longitudinal PET and cognitive testing is planned to refine characterization of AD‐related change in the AA‐FAIM cohort.
The effects of type 2 diabetes on prefrontal cortex‐dependent cognitive function in older African American APOE‐ε4 carriers
Authors: Napoleon Darian A. , Gills Joshua L. , Osiecka Zuzanna , Malin Steven K. , Fausto Bernadette A. , Gluck Mark A.
Published: December 2023

Background

Alzheimer’s disease (AD) is a leading cause of death in the United States and disproportionately impacts African Americans. AD has recently been characterized as “type 3 diabetes” due to evidence that hyperglycemia impairs cognitive function. Individuals with the Apolipoprotein ε4 (APOE ε4) allele may also have triple the risk of Alzheimer’s disease. However, few data exist examining the effects of hyperglycemia on working memory and the moderating effects of AD genetic risk. Therefore, this study examined the effect of untreated diabetes (non‐medicated) on prefrontal cortex‐dependent cognitive performance in older African Americans.

Method

Ninety older cognitively healthy African Americans (60‐91y, 78% female) were recruited for this cross‐sectional study. HbA1c was used to define untreated type 2 diabetes (>6.5%; no glucose‐lowering medications), prediabetes (5.7%‐6.4%), and normoglycemia (<5.7%). Saliva samples were also collected for APOE genotyping, and all participants underwent a cognitive assessment consisting of the Digit Span test (a measure of working memory). Body mass index (BMI) and estimated aerobic fitness (VO2 max) were also determined. Participants were classified as non‐diabetic (ND) or diabetic (D). ANCOVA was used to examine group differences (with and without stratification by APOE status) in Digit Span performance with age, sex, education, depressive symptomology, BMI, and estimated VO2 max as covariates.

Result

There was no difference across groups in age (ND: 71.4±6.8 vs. D: 70.1±4.7), BMI (ND: 31.0±8.7 vs. D: 32.4±7.4), VO2 max (ND: 12.9±2.0 vs. D: 12.6±1.8), or education status (ND: 13.9±2.2 vs. D: 13.0±2.5) across groups (p > 0.05). People with diabetes demonstrated worse pre‐frontal cortex‐dependent performance (D: 18.7±1.6 vs. ND: 22.4±0.61, p = 0.039) than those without diabetes. Moreover, individuals with diabetes and the APOE ε4 genotype performed significantly worse on the Digit Span assessment than those with diabetes and without the risk allele (16.50±0.71 vs. 21.4±6.7, p = 0.044).

Conclusion

These results suggest that untreated people with type 2 diabetes are characterized by reduced working memory which is exacerbated by AD genetic risk. This result is independent of aerobic fitness and BMI, suggesting that interventions focused on pathologies related to hyperglycemia may be needed to improve cognition in older African American adults.
Examining the Effects of Hospitalization in ADNI Subjects: Characterizing Changes in Cognition and Glucose Metabolism Associated with Inpatient Hospital Stays
Authors: Struble Helen , Liu Stephen S. , Silverman Daniel H.
Published: December 2023

Background

Risk of inpatient hospitalization and dementia both increase with age, though no study has attempted to characterize lasting changes in regional brain metabolism occurring after inpatient hospitalization.

Method

We screened adverse events reported to the Alzheimer’s Disease Neuroimaging Initiative (ADNI), identifying subjects with minimum one‐night hospitalizations and two pre‐ and two post‐hospitalization ADNI visits. 523 visits from 133 subjects were included in neuropsychological analysis, with 55 subjects hospitalized for major surgery. An analogous “event date” was set in demographically matched control subjects using the median elapsed time from first visit to hospitalization; 352 visits from 88 controls were included. Memory and executive function composite scores were used to calculate pre‐ and post‐event cognitive trajectories. Pre‐ and post‐event FDG‐PET images were acquired and quantitatively examined using standardized volume of interest (sVOI) analysis. Students t‐tests were used to determine the difference in pre‐ and post‐event trajectories within groups and between groups.

Result

Within‐group analysis of inpatient subjects revealed significantly declined trajectory of memory and executive function after hospitalization (p<0.001, p = 0.02), though the difference in pre‐ and post‐event trajectory did not differ significantly from the control group. There was no significant difference in change in trajectory between subjects with surgical and non‐surgical hospitalizations. To prevent the dilution of metabolic alterations that may begin on one‐side, the sVOI with the greatest decline between post‐ and pre‐event trajectory was chosen for all bilateral volumes. Within the inpatient group, significant decline in metabolic trajectory after hospitalization was observed in the inferior lateral anterior and medial anterior temporal volumes (p<0.005, p<0.0005). This change in metabolic trajectory in the anterior temporal volumes after hospitalization was not significantly different between surgical and non‐surgical subjects. Finally, the decline in trajectory observed in the inferior lateral and medial anterior temporal volumes in the inpatient group was significantly greater than the control group (p = 0.05, p = 0.005), in which no significant decline in trajectory was observed.

Conclusion

Inpatient hospitalization is associated with accelerated decline in metabolic trajectory after discharge in two anterior temporal volumes, regardless of whether the hospitalization was associated with a major surgery.
Overcoming Recruitment Challenges and Increasing Representation and Diversity of Participation in Early MCI Clinical Trials: The MIND Study Experience
Authors: Lewandowski Agnes , Newhouse Paul A , Aisen Paul S. S , Ismail Andalib , Andrews Patricia , Brody Mark , Goldstein Mark , Li Clara , Mintzer Jacobo E , Scharre Douglas W. , Szigeti Kinga , Turner R. Scott , Raman Rema
Published: December 2023

Background

The MIND (Memory Improvement with Nicotine Dosing) study is an ongoing trial to determine whether long‐term transdermal nicotine treatment results in sustained cognitive improvement and attenuation of cognitive decline in patients with MCI. To improve the demographic representation of screened and randomized study participants, the MIND Study Underrepresented Group (URG) Recruitment and Retention (R&R) Initiative was established.

Method

The goal was to increase the screenings and randomizations of participants who self‐report as belonging to an underrepresented race or ethnic group or report a low educational attainment level (high school completion or less). Key elements of the initiative comprised of: (a) financial support of site infrastructure, (b) centralized support with culturally relevant recruitment materials, (c) monthly meetings to secure best practices, and (d) dissemination of successful strategies. Measurement of success included overall screening and randomization rates, as well as qualitative and quantitative metrics reported by initiative sites.

Result

Nine sites (25% of active study sites) participated in this initiative from March 2022‐February 2023. The first three months required development of site‐specific recruitment plans, goal setting, and needs assessments. During this year, we observed an increase in URG screenings (21.3%) and randomizations (33.3%) (Table 1). Similar increases were observed in race and ethnicity (25.4% and 44% respectively) as well as low educational attainment (21.2% and 31.6% respectively) groups. This initiative improved the overall URG monthly screening from 2.23/month prior to the initiative to 2.42/month during the initiative and the monthly randomization rate from 0.93/month to 1.58/month. Site‐reported data on the pre‐screening activity indicated that the main reasons for pre‐screen fails were participants either not belonging to an URG (56%) or not meeting MCI criteria (20%). Concerns around study burden, study partner availability and nicotine were reported in less than 10% of the pre‐screened individuals.

Conclusion

This initiative successfully increased the representation of screened and randomized MIND Study participants with respect to self‐reported race, ethnicity, and educational level. Initial success suggests that a multifaceted approach coordinated through close collaborations between sites and the central coordinating center are necessary to screen and randomize representative populations in early MCI trials.
Reliability of VPA Learning Over Repeat Exposures Across an Extended Interval Using Automated Remote Method
Authors: Kaula Alexander J , Taptiklis Nick , Cormack Francesca K
Published: December 2023

Background

The current study examined the test‐retest reliability of a newly developed Learning Over Repeat Exposures (LORE) paradigm using Verbal Paired‐Associates. This LORE paradigm involves the acquisition of a set of 8 verbal paired associates over a 5‐day “burst”. In this investigation, two bursts, separated by a nine‐month interval, were compared to assess the stability of novel learning outcome measures, such as the learning slope (between day 1 and the day of max performance) and first overnight forgetting.

Method

An opportunistically recruited sample of 14 participants (out of an initial pilot study of N = 20) completed the VPA‐LORE task using the Cambridge Cognition ‘NeuroVocalix’ platform, which employs text‐to‐speech and automated speech recognition technology to remotely administer and score the task, enabling its potential use at scale. The task structure consists of an immediate recall following presentation on the first day of a burst, and a single recall attempt followed by a presentation on subsequent days. As with the pilot study, neither floor nor ceiling effects were observed, and performance was in the expected range.

Result

The observed moderate to strong correlations between the two bursts revealed good reliability for the measures examined: learning slope from day 1 to day of max score, r
s = .815, first day immediate recall, r
s = .736, max pairs learned, r
s = .707, and day 1 forgetting r
s = .702. In total, participants missed only a few visits, with six missing sessions out of a total of 140 sessions, representing 4.3% of all sessions. The retention of 14 participants from the original pilot study also highlights the feasibility and acceptability of this method.

Conclusion

These results suggest that the VPA‐LORE paradigm, delivered via the NeuroVocalix platform, is a stable and reliable assessment tool even when considering extended intervals between bursts and accounting for missing data. The novel learning measures derived from the VPA‐LORE paradigm provide valuable insights into learning processes and could further enhance cognitive assessment. Future research could explore the applicability of the paradigm for clinical populations and longitudinal studies in cognitive assessment.
Early loss of astrocyte p38alpha MAPK has sexually dimorphic impacts on measures of neuronal excitability and cytokines in aged mice
Authors: Gant John C , Coleman Meggie J. , Davis Verda A , Norris Christopher M. , Van Eldik Linda J. J. , Braun David J
Published: December 2023

Background

The p38alpha MAPK (p38) signaling pathway is ubiquitously expressed in the brain where it plays central roles in neuroinflammation, metabolism, synaptic development and communication, and modulation of blood brain barrier integrity. Its activity in astrocytes has largely been described as immunomodulatory; however, it has also recently been reported to contribute to long term depression and associated behaviors. Astrocytes are also known to be important to healthy brain aging and neuroprotection, but the specific involvement of astrocytic p38 signaling is unclear. We therefore used conditional KO mice to determine how the loss of p38 in astrocytes early in adulthood (3 months) affects synaptic function and cytokine expression phenotypes in later life (20+ months).

Method

Mice were bred homozygous for floxed p38, heterozygous for a Rosa reporter, and with or without tamoxifen‐inducible Cre recombinase under control of the astrocyte aldh1l1 promoter. When animals were about 3 months of age they were placed on tamoxifen diet (400 ppm) for 4 weeks, after which they were returned to standard chow and allowed to age until 20‐24 months prior to undergoing electrophysiological endpoints or collection of brain tissue for biochemical analyses. Electrically evoked field excitatory post synaptic potentials (fEPSPs) were recorded in hippocampal CA1 stratum radiatum in acutely prepared brain slices and cytokines from the whole hippocampus were measured from a subset of mice that did not undergo electrophysiological recordings.

Result

Males and females showed baseline differences in measures of I/O, fiber volley amplitude, early vs. late potentiation, and paired pulse facilitation. Additionally, knockout of astrocyte p38 generally had opposite effects on these parameters in males and females. Interestingly, the pattern of hippocampal IL‐1β cytokine levels mirrored these differences.

Conclusion

These data indicate that there may be qualitative differences in male versus female brain aging that are differentially impacted by astrocyte p38 signaling. The implications of these findings are currently being explored to determine the underlying mechanisms for these sexually dimorphic effects and further determine what functional differences may exist for hippocampal‐dependent behaviors.
Inter‐network connectivity of early Aβ and tau‐seeded functional networks is associated with longitudinal tau accumulation in at‐risk cognitively normal older adults
Authors: Fonseca Corrina S. , Harrison Theresa M. , Adams Jenna N. , Ziontz Jacob , Jagust William J.
Published: December 2023

Background

Functional connectivity (FC) between networks may be related to Aβ and tau interactions in preclinical Alzheimer’s disease (AD). Here, we investigated associations between inter‐network FC of early Aβ and tau‐seeded networks, APOEe4, global Aβ, and longitudinal tau accumulation in cognitively healthy older adults (OA).

Method

Voxel‐wise PiB‐PET and FTP‐PET OA images were ordered by increasing pathology burden and iteratively compared to a reference set of young adult (YA) PET images. Peak voxels of the earliest significant differences were matched to Brainnetome ROIs and used to construct separate Aβ and tau‐seeded networks within a group average YA FC matrix (Figure 1). Next, the average inter‐network FC between all node pairs between the networks was calculated in OA (n = 60; aged 77.6±5.5). Longitudinal FTP slopes of the entorhinal cortex (EC) and inferior temporal gyrus (ITG) were estimated using linear mixed effects models. Linear regression was used to assess relationships between baseline inter‐network FC, APOEe4 status, baseline global PiB, and both a prior ROI and voxel‐wise FTP slopes.

Result

In all OA, inter‐network FC was not associated with baseline global PIB (t(58) = ‐0.23, p = 0.82), EC FTP slope (t(58) = 0.49, p = 0.63), or ITG FTP slope (t(58) = ‐1.45, p = 0.15). There was a significant interaction between baseline global PiB status and inter‐network FC where FC was negatively associated with ITG FTP slope in PiB+ participants (t(56) = ‐2.01, p = 0.04; Figure 2A). There was also a significant interaction between APOEe4 status and inter‐network FC in predicting ITG FTP slope with a negative relationship only in e4 carriers (t(56) = ‐3.19, p = 0.003; Figure 2B). Voxel‐wise analyses revealed significant negative relationships between inter‐network FC and FTP slope in the left fusiform gyrus and ITG in PiB+ participants and e4 carriers, respectively (Figure 2C‐D).

Conclusion

Lower baseline inter‐network FC of early Aβ and tau‐seeded networks was associated with greater longitudinal tau accumulation outside of the medial temporal lobe (MTL) in cognitively normal OA with higher AD risk (i.e., elevated Aβ or APOEe4). Our results suggest that this network disruption is associated with faster rates of tau accumulation outside of the MTL, possibly reflecting a later stage in the preclinical progression to AD.
Classification of amyloid‐positivity using memory scores in subjects with early‐onset Alzheimer’s disease
Authors: Bushnell Justin , Hammers Dustin B. , Apostolova Liana G. , Kramer Joel H. , Carrillo Maria C. , Dickerson Brad C. , Rabinovici Gil D. , Clark David G.
Published: December 2023

Background

The Rey Auditory Verbal Learning Test (RAVLT) is a common neuropsychological test for characterizing episodic memory deficits. Performance of the RAVLT has been described in numerous presentations of cognitive impairment. However, there is limited research for analyzing the predictive value of RAVLT scores. We examine the ability of the RAVLT to classify individuals with early‐onset cognitive impairment in terms of amyloid positivity.

Method

We transcribed RAVLT recordings from 214 cognitively impaired subjects in the Longitudinal Early‐Onset Alzheimer’s Disease Study (LEADS). Each RAVLT test consists of eight tasks: five learning trials, an interference list, short delay free recall, and long delay free recall. Subjects were stratified by amyloid positivity (EOAD vs. EOnonAD). We calculated traditional and novel scores based on counts (raw score, primacy, recency) and timings (stopping time and speed). To split the data into training and test sets, we selected subjects such that Cohen’s D was below 0.05 between nuisance covariates (age and education) and included similar proportions of each sex. Due to the imbalance of classes in the data set, we generated 1,000 equal‐sized bootstrap samples of cases and controls (n = 200) and fit a random forest classifier for each sample. Subjects in the test set were classified by majority vote. This classification process was applied to three different sets of RAVLT variables for comparing performance.

Result

With raw scores and demographics alone, we achieved AUC of 0.839. We obtained an AUC of 0.841 using variables with possible utility identified in previous work. The best model used only speed scores and demographic variables, with an AUC of 0.858.

Conclusion

We marginally improved the classification accuracy of amyloid‐positive subjects over raw scores alone. Further work is needed to determine the utility of novel scores in predicting biomarker positivity.
Prediction of future dementia for MCI patients using a novel multimodal machine learning framework
Authors: Cirincione Andrew Joseph , Lynch Kirsten M , Choupan Jeiran , Varghese Bino , Sheikh‐Bahaei Nasim , Pandey Gaurav
Published: December 2023

Background

Prediction of future dementia for patients with mild cognitive impairment (MCI) is a significant clinical goal, so that the identified cases can benefit from treatments. Currently, the clinical standard for diagnosing dementia utilizes multimodal data like cognitive tests, MRI and PET scans, and other biomarkers. However, efficiently and objectively analyzing these complex, diverse data can be difficult in the clinical setting, contributing to high rates of underdiagnosis or misdiagnosis of dementia at early stages. Machine learning (ML) offers a potentially more efficient and objective methodology to aid the prediction of future dementia for MCI patients from these multimodal data.

Method

e recently developed Ensemble Integration (EI), an ML framework to advance predictive modeling from multimodal data by leveraging complementarity among the data modalities (Li et al, Bioinformatics Advances, 2022). In the current work, we conducted the first assessment of EI’s ability to predict the future development of dementia among MCI patients using multimodal data from The Alzheimer’s Disease Prediction of Longitudinal Evolution (TADPOLE) challenge (Marinescu et al, Predictive Intelligence in Medicine, 2019) (Table 1). We developed an EI‐based predictive model of dementia from data of 672 MCI patients collected at their first visit (baseline), and rigorously evaluated this model and benchmark methods on baseline data from two separate test sets (Figure 1).

Result

For predicting the future development of dementia among MCI patients, the EI‐based model performed better on two test sets (AUROC = 0.77/0.78, sensitivity = 0.71/0.75, specificity = 0.74/0.75) than the more commonly used XGBoost (AUROC = 0.66/0.67, sensitivity = 0.59/0.63, specificity = 0.73/0.71) and deep learning (AUROC = 0.63/0.64, sensitivity = 0.78/0.62, specificity = 0.41/0.55) approaches. This model also suggested MRI‐derived measurements of the cortical thickness, surface area and volume of regions in the thalamus and parahippocampus to be predictive of this outcome (Table 2).

Conclusion

EI is an effective framework for predicting if an MCI patient will develop dementia in the future, as well as identifying neuroanatomical features that may be associated with this progression.
A novel analytic approach to examine the relationship between APOE4 allele status and CSF complement‐related proteins and signaling pathways
Authors: Orenduff Melissa , Sykes David , Cooter Mary , Morshed Nader , Stevens Beth , Lucas Joseph E. , Lutz Michael W , Berger Miles
Published: December 2023

Background

The mechanisms by which the APOE4 allele contributes to AD risk are unclear. Here, we tested the hypothesis that in cognitively normal adults, APOE4 allele is associated with a decrease in complement‐related proteins and downregulation of complement‐related pathways.

Method

Untargeted LC‐MS/MS proteomics was conducted on CSF samples (n = 118) from APOE3/3, APOE3/4 and APOE4/4 individuals over age 60, with groups matched on age and sex. We developed a novel analytic approach (which we term “up/down analysis”) based on the directional consistency of the β‐coefficients from a linear model for the intensities of peptides mapping to a given protein with respect to APOE4 carrier status (APOE4‐/ APOE4+). The analysis involves two steps: 1) The direction of the beta‐coefficient (positive/up or negative/down) for the level of each peptide (the outcome variable) due to APOE4 carrier status was derived from linear regression models adjusting for age, sex, and study. 2) These β‐coefficients were tallied for all peptides from a given protein (i.e. number of positive/up versus negative/down β‐coefficients). We then tested the probability under a binomial distribution that the distribution of up versus down peptides from each protein would be as, or more extreme than what we found, with a = 0.05. Pathway enrichment analysis (using p‐values from binomial tests) was conducted using GAGE and functional annotations based on KEGG. We used Benjamini‐Hochberg for multiple comparison correction.

Result

We found 158 proteins for which the direction of peptide intensity was consistently up (+β‐coefficient) or down (‐β‐coefficient) with respect to APOE4 status beyond what would be expected by chance. Of these 158 proteins, 37 were from the complement pathway. Pathway enrichment analysis further supports the role of the complement system; as the top differentially expressed pathway (FDR <0.05) was related to complement signaling.

Conclusion

Our results suggest that APOE4 carriers have lower CSF levels of key complement cascade proteins, which has previously been viewed as an indicator of complement activation. These results may provide insights into the mechanisms by which APOE4 and associated complement‐related proteins and signaling pathways ultimately contribute to increased AD risk.
Protective effects of mitochondrial genome abundance on Alzheimer’s Disease: a Mendelian randomization study
Authors: Alvarez Brian D , Molina Carmen Romero , Wilkins Heather M , Pa Judy , Swerdlow Russell H , Goate Alison , Andrews Shea J
Published: December 2023

Background

Mitochondrial DNA copy number (mtDNAcn) is a surrogate measure of mitochondrial function that is associated with higher cognitive performance and reduced risk of AD neuropathology. Here, we use two‐sample Mendelian randomization (MR) to estimate the causal association of blood‐based mtDNAcn on AD/dementia while controlling for latent confounders, sample overlap, and testing bidirectional effects.

Method

GWAS Summary statistics of mtDNAcn were procured from three separate studies using various bioinformatic methods to estimate mtDNAcn; microarray, whole exome sequencing (WES), and whole genome sequencing (WGS) datasets using the UK Biobank (UKBB) and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Longchamps et al., 2021. uses quantitative PCR (CHARGE) and WES, WGS (UKBB). Hagg et al., 2021 use microarray approximation, as well as WGS and qPCR. Chong et al., 2022 employ the novel AutoMitoC in addition to WES data (UKBB). Kunkle et al., 2019 employed late‐onset clinical AD cases/controls (n = 94,437), and Bellenguez et al., 2022 (n = 487,511) used AD/dementia from clinical and proxy cases/controls. MR estimates the causal association between mtDNAcn and AD and AD/dementia using IVW analysis, and MR Egger, Weighted Mode, and Weighted Median as sensitivity analysis. Latent Heritable Confounder‐MR (LHC‐MR) was used to investigate bidirectional effects in the presence of sample overlap between the mtDNAcn datasets and AD/Dementia.

Result

There were no significant causal associations of mtDNAcn on AD or AD/dementia using univariate MR analysis. However, using LHC‐MR, higher genetically predicted mtDNAcn was causally associated with AD/dementia using all three mtDNAcn datasets (OR [95%CI]: Chong = 0.84 [0.78, 0.90], p < 0.001; Longchamps = 0.89 [0.82, 0.96], p = 0.003; Hagg = 0.84 [0.78, 0.91], p < 0.001). In the reverse direction, genetic liability for AD/dementia was causally associated with higher mtDNAcn levels (β [SE]: 0.10 [0.05], p = 0.017).

Conclusion

Higher blood‐based mtDNAcn was causally associated with reduced risk of AD, with limited evidence to suggest a bidirectional effect. Discrepancies between univariate MR results and LHC‐MR may be explained by the increased power and the inclusion of a latent confounder.
Disentangling the causal effects of education and participation bias on Alzheimer’s disease using Mendelian Randomization
Authors: Chatterjee Aadrita
Published: December 2023

Background

Higher education has been associated with reduced risk of Alzheimer’s Disease (AD) based on previous epidemiological research. However, the relationship between education and AD could be influenced by participation bias whereby people with higher education may be more likely to be enrolled in studies. In this study, we use two‐sample Mendelian randomization (MR) to investigate the potential effects of education and participation bias on AD and further investigate their relationship.

Method

Genome‐wide association summary (GWAS) statistics were obtained from GWAS’s of educational attainment (n = 1,100,000), participation in an optional mental health questionnaire (MHQ) of the UK Biobank (n = 451,036) and AD (n = 94,437). Independent genome‐wide significant (r2 = 0.001, 10Mb window, p<5×10−8) single nucleotide polymorphisms (SNPs) were extracted from the exposure summary statistics and harmonized with the outcome SNPs. Inverse variance weighted (IVW) meta‐analysis was the primary MR method and sensitivity analyses included MR Egger, Weighted Median and Weighted mode. Cochran’s Q statistic was used to test for heterogeneity, MR Egger intercept for pleiotropy, and radial MR to identify outliers.

Result

Genetically predicted higher educational attainment was causally associated with a reduced risk of AD (IVW OR [95% CI]: 0.691 [0.548, 0.832], p = 3.29e‐07). Similarly, participation in the MHQ was also associated with a reduction in AD risk (IVW OR [95% CI]: 0.987 [0.975, 0.998], p = 0.031]. Our analysis showed no evidence of heterogeneity or pleiotropy and radial MR analysis did not identify any significant outliers, indicating that our univariate MR analyses were robust.

Conclusion

Univariant MR analyses indicated that education and participation were both associated with a reduced risk of AD. However, further investigation using multivariable MR is necessary to fully evaluate their independent effects on AD through multiple clumping and proxy variant identification steps. This will allow us to see if the protective effect of education on AD is mediated by participation bias.
Comparison Among Different Modeling Methods on the Mini‐Mental State Examination
Authors: Wu Xian , Fardo David W. , Katsumata Yuriko
Published: December 2023

Background

The Mini‐Mental State Examination (MMSE) is commonly used in clinical and research settings. It is recognized that MMSE is not sensitive to detect cognitive impairment 1. One of the potential reasons may come from an inappropriate statistical model. MMSE raw scores do not follow a normal distribution which is an inherent assumption in a linear regression model. Previous studies either ignored the normality assumption or used MMSE transformed scores 2. Tobit modeling explicitly handles ceiling effects by making best use of ceiling data information for estimation 3. In this study, we compared three different modeling methods to investigate associations between risk factors (we chose hypertension here) at baseline and change in MMSE scores over time.

Method

46,513 participants in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) were included in this study. Hypertension was defined if they met one of the following criteria: (1) systolic blood pressure (BP) ≥ 140 or diastolic BP ≥ 90; (2) self‐reported or clinician‐assessed hypertension; and (3) current use of any type of antihypertensive medication. We compared three modeling methods in all participants and three subgroups: normal cognition (NC); mild cognitive impairment (MCI); and dementia. The three models were: (1) MEM: mixed‐effect modeling on MMSE raw scores; (2) Transformed: MEM on transformed MMSE scores with square root of (30‐MMSE); and (3) Tobit: mixed‐effect Tobit modeling on MMSE raw scores.

Result

MMSE score distributions were left‐skewed in all participants and three subgroups, particularly in the NC group (Figure 1). Hypertension at baseline was associated with change in MMSE scores over time in all participants, whereas discrepancy in associations existed across three subgroups. Smallest standard errors, Akaike information criterion (AIC), and Bayesian Information Criteria (BIC) values were generated by Tobit models (see Table 1 for results from regression and model comparison).

Conclusion

Based on results from the model comparison, Tobit models were superior across all participants and three subgroups. Moreover, results from Tobit regression modeling can be interpreted as the ways that we explain results from multiple linear regression. In the future, we will apply Tobit models to discover associations between different risk factors and cognitive functions.
The “microbiome‐gut‐brain axis” in Alzheimer’s disease and its role in neurocognitive decline
Authors: Loew Ethan B , Sallis Benjamin , Tracy Matthew , Haran John P , McCormick Beth
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive neurocognitive disease characterized by amyloid beta plaques and neurofibrillary tangles in the brain along with inflammation both in the brain and systemically. This has led to the theory of microbial communities or infections as being causative in the development of neuroinflammation as well as immunosenescence and inflamm‐aging seen in AD. Our own research has demonstrated a decreased abundance of anti‐inflammatory taxa and an increased abundance of pro‐inflammatory taxa in the gut microbiome of AD patients. However, it is unclear how the AD microbiome exerts effects on the central nervous system.

Method

We have performed gut microbiome profiling, analysis of immune cell populations in serum, blood cytokine profiling, and cognitive assessments of AD older adults at 90‐day intervals.

Result

In our early data collected from this ongoing study we have observed changes in B‐cell populations with an increased abundance of class‐switched B‐cells in older adults with greater levels of cognitive impairment (Spearman R = 0.33, p = 0.001). We have further demonstrated that fecal transfer of the microbiome of older adults with AD into mice promotes B‐cell class‐switching when compared with cognitively impaired older adults without AD (Percent total B‐cells, AD 75.12 (SD 10.41) vs ND 50.02 (SD 11.90) p<0.016). Additionally, we have discovered a loss of phytoestrogen‐metabolizing bacteria such as Adlercreutzia equolifaciens among AD older adults with rapidly progressing dementia. Phytoestrogens have been previously identified in protecting the intestinal epithelium from oxidative stress and epithelial permeability. Our work suggests that that the phytoestrogen (s)‐equol, produced by A. equolifaciens, confers resistance to epithelial damage in the setting of oxidative stress and bacterial lipopolysaccharide.

Conclusion

We propose that Adlercreutzia equolifaciens and similar phytoestrogen‐metabolizing bacteria will better maintain epithelial homeostasis in the setting of inflammation while a gain of pro‐inflammatory taxa in AD leads to intestinal barrier disruption. This leads to increased antigen presentation, immune cell dysregulation, and ultimately cognitive decline. This continuing work aims to further establish the connection between AD related neurocognitive decline, the microbiome, and immune system.
Generation and screening of mouse models of ADRD with multiple genetic manipulations to model dementia with mixed brain pathologies
Authors: MacDonald Bethany , Kaur Harpreet , Tooley Andrew , Zuberi Aamir , Lutz Cathleen , O'Connell Kristen MS , Dunn Amy R , Kaczorowski Catherine C.
Published: December 2023

Background

Alzheimer’s disease‐related dementias (ADRD) encompass a wide range of neurodegenerative diseases including Alzheimer’s disease, vascular dementia, frontotemporal dementia (FTD), Lewy body dementia (LBD), and mixed dementia [1‐4]. ADRDs are distinguished by the presence of pathologies including amyloid, tau, TDP‐43 inclusions, alpha‐synuclein aggregates, cerebral amyloid angiopathy, and/or hippocampal sclerosis [4‐9]. Consequently, the heterogeneity of ADRDs presents challenges for animal modeling of disease mechanisms. Our laboratory has demonstrated that genetic diversity in disease modeling is critical to recapitulate the molecular and cognitive features of AD [1,9, 10]. Here, we introduce multiple genetic manipulations to develop novel translational models of ADRD.

Method

Precision models of ADRD on multiple genetic backgrounds were generated via combinatorial CRISPR editing to knock‐in human disease‐causing mutations onto the C57BL/6J (B6) strain and crossed to either B6, DBA/2J (D2), FVB, or WSB to generate a set of 20 unique ADRD models (Fig.1). The effect of homozygous mutations were evaluated on the B6 background. Each model was assessed using a high‐capacity multi‐domain go/no‐go screen to prioritize candidate strains for future ADRD modeling of drug discovery, preclinical testing, and disease pathology.

Result

Assays included frailty, open field, y‐maze, rotarod, and contextual fear conditioning. Models with one or more late‐onset behavioral deficits (12 mo) were a “go”; whereas, early behavioral deficits (6 and 9 mo), aggression, high attrition, and low fecundity and additional factors were considered unsuitable (“no‐go”). We identified several promising models of ADRD that exhibited late‐onset frailty and motor deficits as function of mutation burden and genetic background (e.g., App/Psen1/Tardbp/Mapt on the D2 background). The FVB background strain exhibited early frailty deficits (6 mo), and thus considered unsuitable (“no‐go”). The WSB background strain exhibited reserve across multiple frailty and behavioral assays up to 12 mo.

Conclusion

Our results demonstrate that combining ADRD mutations in genetically distinct backgrounds is a promising strategy to generate new mouse models that better model the human mid and late‐life onset of deficits associated with ADRD. The resulting model(s) will be translationally relevant and provide important insight into disease mechanisms for the future of ADRD research and drug discoveries.