bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiomics Blood Test for Increasing Asymptomatic AD Patients Proportion in Preventive Clinical Trials
Authors: Souchet Benoit , Michaïl Alkéos , Heuillet Maud , Dupuy‐Gayral Aude , Haudebourg Eloi , Pech Catherine , Berthemy Antoine , Billoir Baptiste , Autelitano François , Fortea Juan , Fowler Christopher J , Jayadev Suman , Lleo Alberto , Masters Colin L , Mouton‐Liger Francois , Paquet Claire , Braudeau Jerome
Published: December 2023

Background

With the first positive phase III trials for anti‐amyloid approaches in MCI participants, the drug evaluation during the asymptomatic Alzheimer’s disease (AD) stage is now more relevant than ever. Currently, cognitively unimpaired participants are included in preventive trials based on risk factors such as amyloid positivity. The lifetime risks for an individual without cognitive impairment does not exceed 30% for a 65‐year‐old with amyloidosis alone (Brookmeyer et al., 2018). Based on this risk factor, most participants included will never develop AD and therefore will not respond to anti‐AD therapies. There is a need to develop new biomarkers with high specificity predicting which individuals in the cognitively unimpaired population will exhibit AD symptoms and which will not to conduct effective preventive clinical trials.

Method

Targeted mass spectrometry assays were developed for 81 blood biomarkers (45 proteins and 36 metabolites) pre‐identified in AAV‐AD rats (Audrain et al. 2018). 287 participants were collected in plasma at baseline and followed clinically from 1 to 18 years. Participants’ diagnosis (AD, or Healthy Controls) was established at the last clinical visit based on reference diagnosis standard. 73.9% of participants had available amyloid status, 42.9% were determined as amyloid positive. Predictive machine learning models for asymptomatic AD participants (n = 48, followed for an average of 6.1 years) among individuals without cognitive decline (HC, n = 239, followed for an average of 4.6 years) was developed. The training dataset (70%) aimed to select the biomarkers subset, train the algorithm, and define the cut‐off. External test dataset (30%) aimed to validate in blind the locked predictive model.

Result

With 20 blood biomarkers and 2 covariates (age and gender), the model predicted asymptomatic AD (n = 16) from HC participants (n = 72) with 81.9% specificity and 56.3% sensitivity during external validation (AUROC = 69.1%, p = 0.02). When current amyloid tests (CSF or PET) and this predictive ML model were applied in series, and participants positive for both were predicted as asymptomatic AD, 90.9% specificity and 54.5% sensitivity were achieved.

Conclusion

Multiomics blood peripheral biomarkers predict asymptomatic AD patients among cognitively unimpaired individuals with high specificity. This could constitute an additional tool for the inclusion of participants in preventive clinical trials.
Atrophy of hypothalamic subunits in Alzheimer’s disease
Authors: Quattrini Giulia , Saglia Silvia , Agosta Federica , Bagattini Chiara , Bulgari Martina , Canu Elisa , Delai Mara , Ferrari Elisabetta , Filippi Massimo , Fracassi Claudia , Pievani Michela , Bortoletto Marta , Marizzoni Moira
Published: December 2023

Background

Non‐cognitive deficits (e.g., sleep‐cycle and neuroendocrine alterations) are commonly observed in Alzheimer’s disease (AD) and are suggestive of hypothalamic (HPT) dysfunctions (Ishii and Iadecola., 2015). However, studies on the HPT involvement in the early stages of the disease are limited. Here, we compared the volumes of HPT and its subunits in cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD.

Method

Twenty‐nine cognitively unimpaired (CU), 21 MCI, and 21 AD participants were enrolled and underwent 3T MRI and neuropsychological exams. 3D T1‐weighted images were processed using the standard FreeSurfer v7.2 pipeline, and the newly released tool for the automated segmentation of HPT and its subunits (Billot et al., 2020). After normalization to the total intracranial volume, whole and subunits HTP volumes were compared among groups using the Kruskall‐Wallis test with Dunn‐Bonferroni correction.

Result

MCI and AD showed lower left (p<.001) and right (p = .013) whole HPT volume than CU. Furthermore, lower volumes were detected in both the hemisphere for the anterior (p<.011) and posterior (p<.001) subunits in AD, and for right anterior posterior (p = .025) and for the superior tubular (p = .045) subunits in MCI, as compared with CU. No HPT differences were observed between AD and MCI patients.

Conclusion

Posterior HPT subunit atrophy was detectable since MCI stage and increased according to the disease progression. These results suggest a possible involvement of hypothalamus in early AD phases.
Donanemab in Early Symptomatic Alzheimer’s Disease: Efficacy and Safety in TRAILBLAZER‐ALZ 2, a Phase 3 Randomized Clinical Trial
Authors: Mintun Mark , Ritchie Craig W , Solomon Paul , Sims John R. , Salloway Stephen , Hansson Oskar , Apostolova Liana G. , Zimmer Jennifer A. , Evans Cynthia D. , Lu Ming , Ardayfio Paul A , Sparks JonDavid , Wessels Alette M , Shcherbinin Sergey , Wang Hong , Nery Emel Serap Monkul , Collins Emily C. , Dennehy Ellen B , Brooks Dawn A. , Skovronsky Daniel M.
Published: December 2023

Background

In TRAILBLAZER‐ALZ, donanemab cleared brain amyloid plaques and significantly slowed disease progression in early symptomatic Alzheimer’s disease (AD).

Methods

TRAILBLAZER‐ALZ 2 (NCT04437511), a multicenter, randomized, double‐blind, placebo‐controlled trial, enrolled participants with early symptomatic AD and amyloid and tau pathology by positron‐emission tomography. The study randomized participants with low/medium‐tau (n = 1182) and high‐tau (n = 552) pathology (missing tau category, n = 2). Participants (randomized 1:1) received donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks (w) for 72w. Donanemab participants meeting amyloid clearance treatment completion criteria at 24w or 52w were switched to placebo in a blinded procedure.

The primary outcomes were change in Integrated AD Rating Scale (iADRS) score from baseline at 76w in either the low/medium‐tau or combined (low/medium‐tau and high‐tau) populations. Statistical testing allocated most power (80% alpha spend) to low/medium‐tau population outcomes, with the remainder for combined population outcomes, which included clinical and biomarker assessments.

Results

In the low/medium‐tau population, change in iADRS score at 76w was ‐6.02 with donanemab and ‐9.27 with placebo (difference, 3.25; 95% CI, 1.88 to 4.62; P<0.001), representing a 35.1% slowing of disease progression. Change in Clinical Dementia Rating Scale (CDR) – Sum of Boxes, the key secondary outcome, was 1.20 with donanemab and 1.88 with placebo (difference, ‐0.67; 95% CI ‐0.95 to ‐0.40; P<0.001), representing a 36.0% slowing. Participants receiving donanemab experienced a 38.6% lower risk of progressing to the next disease stage versus placebo over 76w (CDR‐Global score, Hazard Ratio = 0.61; P<0.001). Amyloid clearance at 24w, 52w and 76w was achieved in 34.2%, 71.3% and 80.1% of donanemab‐treated participants, respectively. Plasma P‐tau217 was significantly reduced by 39.3% from baseline with donanemab and increased by 8.4% with placebo at 76w (P<0.001). Significant, positive results across all clinical endpoints were also observed in the combined population. The incidence of serious adverse events was 17.4% (donanemab) and 15.8% (placebo), with three deaths among patients treated with donanemab who experienced serious ARIA. Adverse events with donanemab included amyloid‐related imaging abnormalities (ARIA)‐E (24.0%, 6.1% symptomatic); ARIA‐H (31.4%); and infusion‐related reactions (8.7%).

Conclusion

Donanemab treatment significantly slowed clinical progression at 76w and had a safety profile consistent with earlier studies.
How do professionals working in the field of dementia care define quality of nursing home care and how do they believe warm technology contributes to this?
Authors: Bernaards Claire M , Westenbrink Lizan , de Vries Marijke , Coolen Celeste
Published: December 2023

Background

Warm technology (WT) aims to improve quality of life of people living with dementia by supporting and enhancing human potential, social connectedness, dignity and self‐reliance. However, how care researchers and dementia care professionals think about the relationship between WT and quality of care (QOC) in nursing homes (NHs) is unknown. Also, there is a lack of international consensus on the definition of QOC in NHs. The goal of this project was to explore how care researchers and dementia care professionals define the concept QOC in NHs and how they believe WT contributes to this. The Tovertafel, a research based technology that activates nursing home residents with dementia by projecting interactive games on a surface, served as an example for WT in this study.

Method

Semi‐structured (online) interviews were held in England, Ireland, Canada, United States of America and the Netherlands with 9 researchers and 11 care managers, 6 activity coordinators and 3 specialized nurses working in dementia care units of NHs. All care professionals had access to a Tovertafel. The interview guide was based on three existing multidimensional quality of nursing home care frameworks. To analyze the interviews, a thematic analysis was employed by means of open, axial, and selective coding using ATLAS.Ti.

Results

Most research and care professionals made a clear distinction between the clinical domains of QOC (e.g. providing effective and safe care) and the social domains of QOC (e.g. building relationships, trust, and providing person centered care) in NHs. According to the interviewees, the Tovertafel contributes to several social domains of QOC by: 1. supporting care professionals in the provision of person centered care and gaining trust from residents, 2. improving work pleasure of dementia care professionals, 3. creating a safe, pleasant and homelike environment, 4. increasing family involvement, and 5. increasing (non‐verbal) communication. The interviewees reported fewer and more indirect effects on the clinical domains of QOC in NHs. The results were comparable between countries.

Conclusion

Warm technology, such as the Tovertafel, seems to have a positive effect on QOC in NHs, primarily by having a positive impact on several social QOC domains.
Circulating brain‐enriched microRNAs as peripheral biomarkers of neurodegeneration
Authors: Mireskandari Alidad , Kumar Gyanendra , Kunwar Arzu , Ablordeppey Kenny K , Kiefer Michael , Wolk David A. , Sheinerman Kira S. , Umansky Samuil R.
Published: December 2023

Background

Minimally invasive diagnostic tools are needed to better characterize heterogeneous groups of patients with mild cognitive impairment (MCI), pre‐MCI, and dementia. At DiamiR, we developed an approach based on targeted selection and quantitative analysis of microRNAs enriched in specific brain regions, present in synapses, and detectable in blood plasma. microRNAs are short, non‐coding regulatory molecules whose levels change in disease.

Method

Concentrations of 24 brain‐enriched and inflammation‐associated microRNAs (Table 1) were analyzed in plasma samples of 200 study participants with the following clinical diagnoses at the time of blood draw: 76 cognitively unimpaired (CU), 85 MCI, and 39 Alzheimer’s disease (AD). The demographic characteristics and clinical data of the study participants are summarized in Table 2. The plasma samples were collected at the Penn Alzheimer’s Disease Research Center (ADRC). Based on amyloid status (Abeta+/‐), APOE genotype (APOE4 +/‐), and sex, each sample was assigned to a specific subgroup. RNA from plasma samples was isolated using the MagMAX mirVana kit (ThermoFisher). microRNA concentrations were measured by qPCR using custom plates (Qiagen) pre‐plated with lyophilized miRCURY LNA‐based primers for a 24‐microRNA panel. Differentiation of subgroups by microRNA pairs and their combinations (classifiers) was evaluated using a proprietary software program developed at DiamiR.

Result

Using the ratio between two microRNAs as a biomarker (“pair” approach) reduces variability and enhances specificity and sensitivity. Effective microRNA pairs were combined into classifiers. Data on the differentiation of subgroups using one, two, and three microRNA pairs are presented in Table 3.

In line with our prior results, sex‐stratified analysis yielded higher AUC values for females and males as compared to the combined group. Interestingly, microRNAs differ in effective pairs for female and male subgroups. For example, levels of inflammation‐associated miR‐146a were higher in female MCI/AD study participants. However, sex‐stratified groups were relatively small and further assessment is required.

Conclusion

These data support the development of assays based on the analysis of circulating brain‐enriched and inflammation‐associated microRNAs for better characterization of MCI/AD patients and understanding of AD‐associated processes. Further, combining these microRNAs with other factors, such as amyloid and APOE, may enhance a biomarker algorithm.
Evaluating Prevalence of Cognitive Impairment in Older People Living with HIV Served by a Community‐Based Organization in Colorado, USA
Authors: Burk‐Leaver Erin Yvette
Published: December 2023

Background

Older people living with HIV (PLWH) experience unique pathophysiology contributing to accelerated and accentuated aging when compared to older adults living without HIV. Indeed, cognitive dysfunction is a significant age‐related risk exacerbated by HIV. This study investigated prevalence of Mild Cognitive Impairment (MCI) in older PLWH by employing the Montreal Cognitive Assessment (MoCA), which has a high sensitivity for assessing cognitive performance, and its relationship with HIV health, socioeconomic status, and functional aptitude.

Method

A cross‐sectional study was conducted in older PLWH ≥50 years receiving HIV‐related care and services at a Community‐Based Organization (CBO) between June and October 2022. The MoCA English Version (8.1) was used to screen cognitive performance. MCI was defined as MoCA scores 18‐26; 10‐17 for moderate cognitive impairment (MoCI); and ≤9 for dementia. Functional aptitude was measured by participants’ Ryan White Part A Wellness acuity scores (0‐41), where higher scores are indicative of lower functional aptitude.

Result

During the study period, 31 participants were screened; 64.5% were male and 88.9% had virologic suppression. The median age was 60.7 (standard deviation [SD] 6.3) and the median years living with HIV was 23 years (SD 8.9). The median MoCA score was 23 (SD 3.5): 21 (67.7%) with MCI; 3 (9.7%) with MoCI. The median acuity score was 18 (SD 11.9): 21 (SD 11.8) for MCI; 28 (SD 8.5) for MoCI. Multivariable linear regression analysis revealed that a lower MoCA score was associated with lower educational attainment (≤12 years) (r = 0.671, p = 0.0276) and low annual income (r = 0.789, p = 0.0043). A higher acuity score was not significantly associated with MoCA scores.

Conclusion

A majority of older PLWH screened were within range for M/MoCI. Thus, it is both necessary and ethically responsible for CBO’s serving older PLWH to integrate routine cognitive screening to identify early and pre‐symptomatic stages of impairment, providing prompt services to reduce symptoms and improve health outcomes.
Comparison of IVIM MRI measures of brain fluid transport against contrast‐enhanced MRI in the setting of sleep deprivation
Authors: Levendovszky Swati Rane , Vanderweerd Carla , Roberts Mitchell , Singh Tarandeep , Corbellini Alejandro , Jaffe Michael , Lowenkron Jeffrey , Piantino Juan , Lim Miranda , Dagum Paul , Iliff Jeffrey J
Published: December 2023

Background

Glymphatic exchange of interstitial solutes may underlie the observed clinical association between sleep, aging, and Alzheimer’s Disease (AD). Furthermore, glymphatic function is currently primarily measured by contrast‐based (CE) MRI, limiting its clinical utility. In this work we test a wearable device to assess sleep architecture and a diffusion‐based intravoxel incoherent motion (IVIM) protocol to detect sleep‐related changes in the glymphatic system at two sites.

Method

Site 1: We recruited 13 participants (age = 62±3 yrs. old, 4F) and assessed them prior to and following overnight sleep and sleep deprivation. Sleep efficiency, relative slow delta power, N2, N3, and REM durations were measured with the wearable device. Using CE‐MRI, delayed contrast enhancement in the subarachnoid (SASe) was measured at ∼4 hrs after contrast injection to assess brain parenchymal solute clearance during a second recovery sleep opportunity. For contrast‐free MRI, we measured slow subarachnoid CSF flow (D*) in the SAS using IVIM at night and in the morning. Cognitive assessments were conducted in the morning only. Site 2: We conducted an identical sleep/sleep deprivation study (N = 10, age = 54±5 yrs. old, 9F), but without CE MRI. We tested the correlation between SASe and D*. Next, we compared changes in D* between a night of sleep and sleep deprivation and tested associations with sleep parameters.

Result

A. Change in D* after sleep or awake opportunity was significantly associated with SASe (p = 0.05) Greater SAS D* was associated with lesser contrast in the SAS. B. Although not significant, D* reproducibly decreases with sleep deprivation and remains unchanged after sleep. C‐D. Differences in D* during sleep were significantly associated with slow wave spindle number (p = 0.03) and N3 duration (p = 0.04). E.
D* measurement concurrent with PVT administrations showed that while greater D* after staying awake was associated with longer reaction times, greater D* after a night of sleep was associated with shorter reaction times.

Conclusion

With a wearable device, remote sleep assessment was successfully performed. IVIM‐derived D* was associated with CE MRI measures in the SAS providing a non‐invasive alternative to study brain fluid transport. D* showed associations with sleep parameters as well as sleep‐associated cognition.
Update to the comparative analytical performance of plasma Aβ assays and their relationship to amyloid PET
Authors: Zicha Stephen , Saad Ziad S. , Shaw Leslie M. , Bannon Anthony W. , Rubel Carrie E. , Schindler Suzanne E. , Dobler Iwona , Du‐Cuny Lei , Giardina Sarah F. , Kolb Hartmuth C. , Meyers Emily A. , Mordashova Yulia , Raunig David L. , Rosenbaugh Erin G. , Weber Christopher J. , Zhang Hang , Zetterberg Henrik , Potter William Z.
Published: December 2023

Background

A previous comparative analysis of plasma Aβ42/40 immunoassays and mass spectrometry‐based assays conducted in 2021 found that several assays had strong performance in predicting amyloid PET status (Zicha et al., 2022). In the spirit of enabling the National Institute on Aging and the Alzheimer’s Association framework for classifying Alzheimer’s disease (AD) utilizing measures of pathology for amyloid, tau, and neurodegeneration (ATN), we have added to this comparative analysis a newly developed immunoassay on an automated, scalable platform. Robustly validated plasma Aβ assays represent a non‐invasive and cost‐effective alternative to CSF or neuroimaging for early detection of Alzheimer’s disease pathology and screening participants for enrollment into clinical trials.

Method

The project team consists of pharmaceutical industry, patient advocacy, governmental, and academic representatives. The current study utilized an additional aliquot of the same 130 plasma samples provided by ADNI that were previously tested on three immunoassays and three mass spectrometry‐based assays. The statistical analysis plan was performed as published previously to determine if the measurement of plasma Aβ with age and APOE ε4 status performs better than age and APOE ε4 status alone in determining amyloid PET status.

Result

In this sample cohort, the new automated immunoassay with age and APOE genotype had similar prediction of amyloid status compared to mass spectrometry‐based assays, with an ROC AUC of 85.7 (95% CI: 79.1 – 92.4) for the immunoassay and 84.2 (95% CI: 77.0 – 91.3) for the best‐ performing mass spectrometry‐based assay. The Spearman correlation of plasma Aβ42/40 with amyloid PET (florbetapir standardized uptake value ratio) for the new immunoassay was ‐0.567 (p < 0.001) compared to ‐0.536 (p < 0.001) for the best performing mass spectrometry‐based assay. The new immunoassay significantly improved the prediction of amyloid positivity beyond age and APOE ε4 genotype (p = 0.003).

Conclusion

Results from this comparative analysis together with the continued advancement in plasma assay technology identify a potential use for plasma Aβ42/40 measurement in addressing the amyloid component of the ATN framework. Further evaluation of plasma Aβ42/40 in addition to p‐tau in plasma is planned using longitudinal samples to determine the ability of plasma biomarkers to detect amyloidosis.
Becoming Whole with Dementia, Qualitative Data on the Lived Experience of Dementia
Authors: Ware Caitlin
Published: December 2023

Background

The diagnosis of Alzheimer’s is often perceived as catastrophic. Moreover, as the disease progresses, it is assumed that one ‘loses oneself’. Nonetheless, there is certainly more to the story. Some autobiographies of those living with dementia suggest that despite the major anxieties surrounding the loss of memory, the experience of dementia can involve self‐discovery. J. Lacan put forth the idea that the subject is split by language, or divided into ego and subject of the unconscious. Would the growing loss of language in dementia lesson this subjective split?

Method

Qualitative data from 20 autobiographies of persons diagnosed with dementia was analyzed and compared from a psychoanalytic perspective, using Lacan’s concepts of the split subject (1966) and Other jouissance (1973).

Results

We found that although many writers express anxiety and frustration with growing aphasia, they express great insight into their existence. This is described by some as becoming one’s true whole self: “[W]ith dementia stripping away the layers of cognition and emotion, I’m becoming who I really am.” (Bryden, 2005, p.162) “I am never half full or half empty, I am always me.” (Taylor, 2006, p.106) "[T]hat thing we might call ‘personhood’ remains whole in me”. (Raushi, 2001, p.108)

Some express tranquility: “[A]n extraordinary calm has descended over me. A feeling I have never known before. A secret microcosm that is impossible to turn away from.” (Rose, 2003, p.46) “I have never felt as few anxieties and worries in my life”. (Coffin, 2009, p.79)

Notably, some write about mystical experiences, similar to what Lacan describes as Other jouissance; Bryden (2005) and Raushi (2001) cite this Zen paradigm: “Stop thinking and talking about it and there is nothing you will not be able to know.”

Conclusion

There is far more to the story of dementia than that of loss. If language splits the subject, with its growing absence, the subject becomes less divided. This can be expressed in terms of becoming one’s whole true self, great tranquility, and for some, be described as a mystical experience. Where the ego may be lost, the whole subject can be found.
Innovation in direct care worker training: preparing a workforce to provide in‐home care to older adults living with Alzheimer’s disease and related dementias
Authors: Yeh Jarmin , Beld Matthew , Pond Brittney , Neri Mel , Martinez Suzanna , Hollister Brooke , Garcia Andrea , Mauricio Juvenal , Mata‐Pacheco Juliana , Emelle Michelle , Castaneda Moraima , Eldridge Corinne , Ross Leslie
Published: December 2023

Direct care workers who provide in‐home care – such as caregivers hired by consumers of California’s Medicaid‐funded In‐Home Supportive Services (IHSS) program – are well positioned to observe changes in their consumer’s cognition, health, or behaviors to report to family members and healthcare partners, thereby helping to reduce risk of emergency department visits, avoidable hospitalizations, and other adverse outcomes that are disproportionately high among people living with Alzheimer’s disease and related dementias (ADRD) (Alzheimer’s Association, 2023). Despite their vital role in supporting people living with ADRD, direct care workers receive low wages and minimal training or supportive supervision. Strengthening the dementia care workforce is a public health priority; failure to do so will add health, social, and economic burdens to individuals, families, and society (American Public Health Association, 2020). An innovative initiative to bolster the direct care workforce is the IHSS+ADRD Training Project, which provides a 10‐week, instructor‐led, competency‐based, online training in English, Spanish, and Cantonese. The goal is to train 600 IHSS caregivers in Alameda County, California between 2020‐2024. We use a quasi‐experimental, longitudinal design to evaluate outcomes. Pre‐training, post‐training, and 3‐month follow‐up surveys are used to compare changes in IHSS caregivers’ dementia knowledge and self‐efficacy. Administrative records pulled one‐year before and after training are used to compare healthcare utilization patterns of IHSS consumers whose caregiver completed the training. This poster presents updated preliminary results from an analytic sample of 165 IHSS caregivers and consumers for whom we have complete follow‐up data to‐date. Dementia knowledge and self‐efficacy significantly increased at post‐training (p≤ 0.05), with trends suggesting retention at follow‐up. Most IHSS caregivers were very satisfied with the training (83%). Healthcare utilization data followed expected trends given COVID‐19 pandemic protocols in Alameda County. These results reveal promising signs that direct care workers do value training opportunities to better support consumers at home; however, the results need to be further understood in the context of COVID‐19 and the ADRD illness trajectory. Implications include replicating this training to other counties and beyond California to help meet the estimated 1.2 million additional direct care workers needed in the U.S. by 2030 (PHI, 2022).
Alzheimer’s Disease mechanistic pathways were discovered through in silico experiments in causal AI based digital twins
Authors: Sanjay Apoorva Bharthur , Shokeen Deepanshi , Shen Xinyu , Shin So‐Youn , Latourelle Jeanne
Published: December 2023

Background

Beyond a single‐gene‐based approach, pathway‐based approaches have become important in drug development paradigm. Several pathways are known for the pathogenesis of Alzheimer’s disease (AD), but these may be from animal studies or observational human subject studies. Here, we focus on identification of gene pathways with direct causal relationships to AD through Gemini Digital Twins of AD patients.

Method

Two independent and complementary AD Digital Twins were built using an A.I. platform REFSTM [aitiabio.com], based on Bayesian network models of ADNI and ANMerge consortium data which reverse‐engineered the connectivity of ∼59K and ∼35K multi‐modal variables and a wide range of AD‐related outcomes (cognitive, imaging and biomarker) profiled from 317 subjects (Control:MCI:Dementia = 97:191:29) and 199 subjects (Control:MCI:Dementia = 65:63:71), respectively [Fig1]. The average causal effect of each gene (at the blood gene expression level) on each outcome was estimated through in silico counterfactual experiments. Pathway enrichment analyses were performed on metascape.org.

Result

We identified a total of 573 and 300 AD‐driver‐genes from ADNI‐ and ANMerge‐based Digital Twins, of which 41 overlapped (significance‐of‐overlap = 6e‐15). These 41 robustly validated genes, of which 61% were identified by the network as causal mediators of APOE4 genotype, were enriched in several biological processes known for AD such as ‘regulation of RNA splicing’ and ‘macrophage activation’ [Fig2]. The AD‐driver‐genes were also enriched in other interesting pathways in both Digital Twins, such as ‘immune response’ and ‘oxidative stress’. Furthermore, the ADNI‐specific AD‐driver‐genes, representing a sample population with a higher proportion of MCI patients, were related to additional processes such as ‘mitochondrial respiration’ and ‘ribosomal sub‐complexes pathways’, previously known to be involved specifically in early stage AD.

Conclusion

We prioritized several AD‐related pathways for potential drug development identified from causal driver genes discovered and validated in two independent Digital Twins. Some of these pathways are more related to proteopathic biochemical phase of AD, rather than cellular phase, suggesting an area of a potential early intervention. Investigating causal genes from two complementary consortium studies with a different proportion of early vs. late stage AD patients may be a promising approach to identify disease‐stage‐specific and disease‐stage‐common signatures in the pathway‐based drug discovery efforts.
Development of FKBP5 ASOs to mitigate tau pathology
Authors: Gebru Niat T , Hill Shannon E. , Blair Laura J.
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of abnormal protein aggregates, including tau tangles, in the brain. FKBP51 (encoded by FKBP5 gene) is a chaperone protein that regulates tau and has been implicated in AD pathology. FKBP51 overexpression in the brains of tau transgenic mice correlates with increased tau oligomers and neuronal toxicity, whereas siRNA mediated knockdown of FKBP5 decreased tau levels in cell culture models. In this study, we developed antisense oligonucleotides (ASOs) to target FKBP5, in an effort to lower tau levels. We hypothesize that ASOs targeting FKBP5 will reduce FKBP51, which will decrease tau levels and improve tau‐associated deficits.

Method

We designed and synthesized vivo‐morpholino ASOs that specifically bind to and target FKBP5 mRNA degradation. We tested three ASOs in vitro using human neuroglioma and mouse hippocampal neuronal cultures but encountered tissue toxicity when using direct injections into the brains of wild‐type mice. To overcome this, we designed and synthesized locked‐nucleic acid (LNA) GapmeR ASOs targeting regions conserved between human and mouse FKBP5. These have been tested in human neuroglioma and mouse hippocampal neuroblastoma cells lines for their ability to decrease dexamethasone induced FKBP5 upregulation and assessed for toxicity.

Result

Initial screening of vivo morpholino ASOs resulted in 50% ‐ 80% reduction in dexamethasone induced FKBP51 levels at 10 µM. This was further corroborated in mouse primary cortico‐hippocampal neurons where FKBP51 levels were reduced by 50% ‐ 75%, which correlated with significant reduction in total tau levels. However, in vivo pilot studies showed tissue toxicity for our control construct. LNA GapmeR ASOs reduced FKBP51 levels at much lower concentrations (<10 nM) with no apparent toxicity.

Conclusion

Fkbp5 ASOs have shown promising results at decreasing FKBP51 and total tau levels. Future studies will include further testing in vivo for efficacy and safety, followed by studies in tau transgenic mice.
The AI‐based AlphaFold 2 algorithm predicts an open structure for tauC3
Authors: Chain Daniel G , Margolin Richard A
Published: December 2023

Background

TauC3 is an especially noxious C‐terminal tau fragment produced by caspase‐3 cleavage at Asp421. Two decades of accumulating evidence support its importance in the pathogenesis of AD and other tauopathies, notably FTD and PSP. TauC3 promotes aggregation and filament formation, recruits full length tau (FLT) to incipient fibrils, and despite low concentration in AD brain tissue relative to total tau, has been reported to account for substantially all the seeding activity in AD brain extracts. TauC3 has also been shown to slow fast axonal transport (FAT), with deleterious consequences. Although tau’s largely disordered structure prevents analysis by X‐ray crystallography, FRET analysis suggested the existence of a hairpin conformation in which the N‐terminus folds over the C‐terminus close to the MTBR. In this model, Ser432 is the point of closest contact with Pro301. Opening of the hairpin has been hypothesized to 1) make FLT prone to aggregation by exposing the MTBR, and 2) impair FAT by overexposing the phosphatase activating domain near the N‐terminus. We postulated that tauC3 cannot form the hairpin because it lacks Ser432 and thus has an “open” conformation. This would explain tauC3’s substantially increased pathogenicity compared to FLT. The AI‐based tool AlphaFold 2 (AF2) is being used to predict the conformation of many proteins with great accuracy. Applying it to FLT and tauC3 could provide valuable data about the hairpin and whether caspase cleavage alters it.

Method

We tested AF2’s ability to predict the conformation of 4‐repeat FLT and tauC3 from FASTA sequences, aligning the models produced with the MTBR.

Result

AF2 modeling revealed a dramatically different conformation for tauC3 compared to FLT, specifically, an open conformation with the MTBR and N‐terminus far apart (Figure). Interestingly, it also revealed that the entire C‐terminus region of FLT starting at Gln423 is composed of a single α‐helix.

Conclusion

AF2 predictions support the existence of the hairpin conformation for tau and underscore the critical importance of residue 432 in maintaining it. The extended C‐terminus α‐helix may have functional implications. TauC3’s open conformation is consistent with its slowing of FAT and its ability to seed aggregation even at low concentrations.
Relationship between norepinephrine metabolism and plasma markers of tau pathology
Authors: Beckers Elise , Riphagen Joost M. , Ashton Nicholas J. , Janelidze Shorena , Blennow Kaj , Hansson Oskar , Zetterberg Henrik , Jacobs Heidi I.L. , Van Egroo Maxime
Published: December 2023

Background

The brainstem locus coeruleus (LC) constitutes the primary source of norepinephrine (NE) in the central nervous system and has been reported as one of the earliest accumulation sites of hyperphosphorylated tau protein in Alzheimer’s disease (AD). Autopsy and animal studies suggested that this aggregation of hyperphosphorylated tau in the LC is associated with hyperactivity in LC neurons and elevated concentrations of NE metabolites. Here, we investigated whether elevated concentrations of 3‐methoxy‐4‐hydrophenylglycol (MHPG), a NE metabolite measured in the plasma, is associated with plasma phosphorylated tau, a biomarker of AD pathology.

Method

Ninety‐eight cognitively unimpaired participants (age = 59.82 ± 13.13 [30‐84] y, 52 females, Table 1) underwent a blood draw. Plasma MHPG concentrations were measured and adjusted for NE. Levels of total tau, phosphorylated tau at threonine 181 (pTau181) and threonine 231 (pTau231) were quantified by single molecule array (Simoa), while phosphorylated tau at threonine 217 (pTau217) was quantified by the Meso Scale Discovery (MSD) platform. Multiple linear regression models tested for the relationship between MHPG concentrations and plasma levels of tau‐related measures, while controlling for age and sex.

Result

PTau231 and MHPG concentrations were positively correlated (t = 2.26, p = .03, Figure 1). No significant relationships were found between MHPG and other phosphorylated tau biomarkers (all p > .23), but we observed a trend for a positive association with plasma total tau levels (t = 1.88, p = .06).

Conclusion

Consistent with previous CSF studies as well as animal studies, we found that elevated NE metabolism co‐occurs with the earliest events in the phosphorylation cascade of tau proteins, suggesting an important role of a dysregulated NE system early in the AD pathophysiologic cascade. Future work will need to determine the evolution of theses associations as the disease progresses, potential effect modifications by beta‐amyloid and the downstream effects of these processes on cognition and behavior.
U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER): Baseline Characteristics of a Trial Cohort Enriched for Risk of Cognitive Decline
Authors: Whitmer Rachel A.
Published: December 2023

Background

U.S. POINTER is a two‐year clinical trial to evaluate whether lifestyle interventions targeting multiple risk factors protect cognitive function in older adults at increased risk for cognitive decline. We describe the baseline characteristics of the U.S. POINTER clinical trial cohort overall, and before and after changes in risk factor enrichment inclusion criteria.

Method

U.S. POINTER is a Phase 3, multicenter, randomized 2‐year clinical trial of two lifestyle interventions varying in intensity and format, in older adults at increased risk for cognitive decline and dementia. The study closed enrollment with 2111 individuals at 5 sites (North Carolina, Northern California, Chicagoland, Houston, Rhode Island). Eligible participants were sedentary and consumed a suboptimum diet and met other risk enrichment criteria that included first degree family history of memory impairment, and suboptimum cardiovascular health status (meeting specific cut‐points of systolic blood pressure, LDL cholesterol or hemoglobin A1c). 20 months into enrollment, risk enrichment criteria were revised to account for two other factors: older age (70‐79 years), and African American/Black or Native American race or Hispanic/Latine ethnicity.

Result

Mean age at baseline is 68.2 years, 31% represent communities of color, 69% are women, and 30% are not college graduates. 58% reported maternal memory loss, mean systolic blood pressure = 131 mmHg, mean total cholesterol = 193 mg/dl, mean HbA1C = 5.9%, and mean body mass index (BMI) = 29.9 kg/m2. Mean adjusted modified Telephone Interview for Cognitive Status (TICSm) score is = 37.6 (max = 50 pts), Geriatric Depression Score (GDS) is = 1.8, and Short Physical Performance Battery Chair Stand Score (SPBC) is = 3.3. Some baseline characteristics (BMI, total cholesterol, SBBP chair stand) vary by clinical site. The change to risk score enrichment criteria (Table 1) increased representation of participants from communities of color and number of males in the study cohort.

Conclusion

U.S. POINTER successfully enrolled 2111 participants across 5 sites who are at high risk for cognitive decline and dementia, with appropriate representation by groups typically underrepresented in clinical trials, individuals aged 75 or older, and men, with the expansion of risk score enrichment criteria.
Unsupervised Machine Learning Identify Cis‐Regulatory Network Involved in Neurodegeneration
Authors: Goncalves Tassia Mangetti , Xu Jason , Li Daofeng , Gabel Harrison , Wang Ting , Zhao Guoyan
Published: December 2023

Background

Cis‐Regulatory Modules (CRMs) are crucial to ensure the precise spatiotemporal gene expression, but we still lack a complete catalog of mammalian CRMs.

Methods

We developed the Mammalian Regulatory Module Detector (MrMOD), that accurately predicts a comprehensive set of high‐resolution CRMs in mouse and human genomes including enhancers, promoters, silencers, locus control regions, and microRNA regulatory modules not limited to any tissue, cell type, developmental stage, or stimuli. We validated our predictions using 19 orthogonal experimental data sets, including thousands of experimental defined CRMs and millions of putative regulatory elements from multiple databases. Next, we used an unsupervised machine learning method to annotate CRM functions. We scanned the mouse genome for transcription factor binding sites (TFBS) using position weight matrices of known transcription factors (TF) from the CIS‐BP database and obtained TFBS abundance in each CRM for every TF. Unsupervised clustering was performed using Seurat on CRMs from chromosome 17. Each CRM cluster represents a set of CRMs with similar TFBS compositions. Cluster marker genes represent TFs whose binding sites are enriched in the CRM cluster. Genes associated with the CRMs in the cluster represent the putative target genes. Functional enrichment analyses of the TFs and CRM associated genes were performed using ClusterProfiler and disgenet2r.

Results

Seurat identified a total of 43 clusters. In particular, CRM cluster #17 is linked to neurodegeneration based on five supporting evidence: 1) TF marker genes of cluster #17 include TFs known to be involved in neurodegeneration such as Spi1, Yy1, Nr4a2, Nr4a3, and Tfeb. 2) TF marker genes of cluster #17 were significantly enriched for Alzheimer’s Disease, Parkinson’s Disease, Multiple Sclerosis, among others. 3) Genes associated with cluster #17 CRMs were significantly enriched for neurodegeneration: Multiple Sclerosis and neurodegenerative disorders. Gene Ontology Cellular Components terms significantly enriched for synapse, presynapse, axon, and synaptic membrane. 4) Genes associated with cluster #17 CRMs significantly overlap the known TF target genes in the ChIP‐Atlas database defined by human ChIP‐seq experiments. 5) Top TF marker genes of cluster #17 known to activate transcription in neurons cooperatively.

Conclusions

We developed a novel approach to elucidate mechanisms involved in neurodegeneration.
Human microglia, microglial LRRK2, and tau pathogenesis: a complex relationship
Authors: Karabova Maria Kreger , Santambrogio Alessia , Washer Sam J , Metrick Michael M , Caughey Byron , Vendruscolo Michele , James William S. , Cowley Sally A
Published: December 2023

Background

Emerging evidence indicates leucine‐rich repeat kinase 2 (LRRK2) may be involved in tau uptake and spread throughout the brain. Microglia, the brain‐resident phagocytes, become one of the highest LRRK2 expressing cells under inflammatory conditions. Rodent microglia were also shown capable of secreting seeding‐competent tau into the extracellular space. We set out to examine the contribution of human microglia and microglial LRRK2 to tau pathogenesis.

Method

Isogenic LRRK2 wild‐type (WT) and knockout (KO) induced pluripotent stem cell (iPSC) lines, together with Parkinson’s disease (PD) patient‐isolated LRRK2 G2019S‐mutated iPSC lines were differentiated into an in‐vitro model of human microglia, and incubated with in‐house purified, endotoxin‐free, human recombinant 2N4R tau in monomeric or in vitro aggregated form to examine the cellular response.

Result

Microglia internalise recombinant monomeric and aggregated tau by overlapping but distinct mechanisms. RNA‐seq analysis was performed to reveal changes in microglial gene expression upon tau internalisation. We further identified LRP1 as one of the major microglia receptors mediating soluble tau entry, and LRRK2 bona‐fide substrates, Rab8a and Rab10, as the Rab GTPases involved in the downstream LRP1‐tau complex trafficking. The internalised soluble tau is readily degraded but intracellular clearance of tau aggregates is concentration‐ and incubation‐length dependent, and inversely associated with microglial tau secretion. Following tau fibril incubation, the intracellular non‐cleared tau and tau secreted by microglia, shows seeding competency, supporting the role for microglia in tau prion‐like spreading. Finally, we describe the influence of microglial LRRK2 on tau processing. Compared to LRRK2 WT, tau uptake and clearance is accelerated in G2019S microglia. However, tau fibrils processed by G2019S microglia, though reduced in the amount, template pathogenic conformation faster and more consistently onto naive tau substrate.

Conclusion

Collectively, we provide detailed characterisation of the response of human iPSC‐microglia to tau protein in its native and pathogenic form, and show that microglial LRRK2 influences tau processing in a complex way that warrants further investigation.
Discordance in amyloid positivity defined by Visual Reads VR and Centiloids CL
Authors: Charil Arnaud , Nelson Todd , Devanarayan Viswanath , Reilhac Anthonin , Dhadda Shobha , Reyderman Larisa , Irizarry Michael C.
Published: December 2023

Background

Amyloid PET VR is the most common method to determine Aβ pathology in clinical practice. Amyloid positivity by VR or CL cut‐off generally shows a good concordance, however, it is possible to have discordant cases whereby the VR is positive, but CL is below the cut‐off of amyloid positivity, or vice versa. The objective of this analysis was to assess the rate and cause of discordance in defining amyloid pathology using VR and CL in Eisai’s Elenbecestat MissionAD Phase 3 program.

Method

Florbetaben, Florbetapir, and Flutemetamol amyloid PET scans from 3412 participants with MCI due to AD or mild AD dementia were visually read at screening by trained neuroradiologists and quantitated using CLs. VR classification of the amyloid status is based on the higher or equal grey matter (GM) uptake relative to uptake in the white matter (WM) in at least one area, as per manufacturer’s guidance. Quantitatively, amyloid negativity was defined as CL<30. The number of positive cortical regions (SUVR>1.17) was also calculated.

Result

The positivity concordance between VR and CL was 92%, while the negativity concordance was 94.6%. VR+/CL‐ discordance was 8% (n = 1814 VR+, n = 145 CL‐) whereas VR‐/CL+ discordance was 5.4% (n = 1598 VR‐, n = 86 CL+). VR+/CL‐ discordant cases had significantly fewer positive cortical regions than both VR+/CL+ and VR‐/CL+ cases (Figure 1). VR‐/CL+ had a significantly higher WM uptake than both VR‐/CL‐ and VR+/CL‐ cases (Figure 2).

Conclusion

VR+/CL‐ discordant cases show fewer amyloid positive cortical regions, computing CLs results in below cut‐off values due to a dilution effect. These cases are considered VR+ as per manufacturer’s guidelines as they show at least one area of amyloid accumulation. On the other hand, VR‐/CL+ discordant cases result from an increased WM uptake, reducing GM/WM contrast required to determine visual read positivity. VR represents a robust and validated method to determine the presence of amyloid deposition and enables enrolling patients with amyloid beta pathology, as visible on amyloid PET scans, while CLs are optimal for assessing longitudinal changes over time and are a more sensitive measure to assess disease progression.