bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel, efficient and seamless Phase 2A‐2B design to test varoglutamstat in early AD: the VIVA‐MIND study
Authors: Messer Karen , Jacobs Diane M. , Salmon David P. , Qiu Yuqi , Revta Carolyn , Weber Frank , Kuhn‐Wache Kerstin , Leger Gabriel C. , Feldman Howard H.
Published: December 2022

Background

Improved Phase 2 study designs may increase success rates in late stage AD trials. Varoglutamstat (PQ912) is an oral small molecule glutaminyl cyclase inhibitor designed to address several key disease mechanisms. A Phase 2A study (NCT02389413) of 120 early AD patients treated for 12 weeks provided preliminary evidence of safety and tolerability, and effects on working memory, CSF biomarkers, and synaptic function (EEG theta‐power).

Objective

To design a well‐powered, safe, and efficient study of varoglutamstat in early AD incorporating adaptive dose selection in Phase 2A, a futility analysis testing pharmacological, biological and cognitive criteria, and a seamless transition to a larger Phase 2B study investigating longer‐term efficacy and safety.

Methods

An efficient and safe selection rule across 3 descending doses (600mg, 300mg, 150 mg BID) was established using a continuously monitored Pocock safety boundary targeting a set of treatment emergent AE’s of interest. Well‐powered stage‐gate criteria at a planned interim futility analysis included thresholds for target occupancy in plasma, and would detect negative effects on a cognitive composite or absence of benefit on EEG theta‐power. The Phase 2B study was powered to detect an effect size of 0.7 points on the Clinical Dementia Rating – Sum of Boxes score at 18 months, an established approvable endpoint.

Results

The on‐going Phase 2A adaptive dose‐finding trial (NCT03919162) is randomizing 180 subjects with MCI or mild probable AD, initially to 24+ weeks of 600mg varoglutamstat dose or placebo, BID. If the safety boundary is hit, the dose will be discontinued and all subjects titrated down, with similar sequential testing of lower doses as needed. The interim futility analysis will occur when the first 180 randomized subjects have been on study for at least 24 weeks. If this stage‐gate is passed, Phase 2B will enroll 234 additional patients to achieve 414 total patients treated for 72 weeks at full dose of varoglutamstat or placebo.

Conclusion

This novel study design enables adaptive dose selection, an early interim futility analysis, and longer‐term determination of cognitive and functional efficacy, and should support robust proof‐of‐concept for varoglutamstat using a total sample of 414 subjects treated for 72 weeks.
Development and evaluation of Simvastatin based SNEDDS for treatment of Alzheimer’s disease
Authors: Hardeep   , Pandey Narendra Kumar
Published: December 2022

Background

The purpose of this research work to improve solubility and bioavailability of Simvastatin using self nano‐emulsifying drug delivery system (SNEDDS) for treatment the Alzheimer’s disease.

Method

Self emulsifying property of various oils including essential oils was evaluated with suitable surfactants and co‐surfactants. Validation of method for accuracy, repeatability, Interday and intraday precision, ruggedness, and robustness were within the acceptable limits. The liquid SNEDDS was prepared and optimized using ternary phase diagram, thermodynamic, centrifugation and cloud point studies.

Result

The globule size of optimized formulations was less than 200 nm which could be acceptable nanoemulsion size range. The mean droplet size, drug loading, PDI and zeta potential were found to be 141.0 nm, 92.22%, 0.23 and ‐10.13 mV and 153.5nm, 93.89%,0.41 and ‐11.7 mV and 164.26 nm, 95.26%, 0.41 and ‐10.66mV respectively. The best formulations were subjected to FESEM for surface morphology.

Conclusion

Formulation development, and evaluation of simvastatin loaded self nano‐emulsifying drug delivery system (SNEDDS) for treatment the Alzheimer’s disease were carried out.
Machine learning for Alzheimer’s disease classification from genomic tiling variants
Authors: Lee Matthew , Lee Brian N , Zaranek Sarah Wait , Bao Jingxuan , Yang Shu , Jung Sang‐Hyuk , Huang Heng , Saykin Andrew J. , Thompson Paul M , Davatzikos Christos , Kim Dokyoon , Zaranek Alexander Wait , Shen Li ,   for the Alzheimer's Disease Neuroimaging Initiative and the AI4AD Initiative
Published: December 2022

Background

As machine learning (ML) technologies make improving strides, they’ve demonstrated advantageous novelties in the understanding and prediction of Alzheimer’s Disease (AD). Recent efforts in AD research have aimed to capitalize ML for AD genomics. Whole‐genome tiling (WGT) establishes a new representation of whole‐genome sequencing (WGS) data, one that has been brought forth in support of ML and precision medicine.

Method

A comprehensive description, workflow, and publicly available WGT data can be found at https://curii.co/su92l-j7d0g-swtofxa2rct8495. In this work, we analyzed the ADNI WGT data, and first performed quality control, imputation, and one‐hot encoding to each tile and the respective tile variants (Figure 1). Then, using the GWAS result from an independent cohort, we mapped the top ten most significant single‐nucleotide polymorphisms (SNPs) associated with AD, to their respective tiles. Using these tile data, we performed AD classification with an XGBoost algorithm. We then reiterated this process including covariates (age, sex, and ethnicity) with tiling variants. A total of 1,545, subjects (474 cases, 1,071 controls) were studied.

Result

After mapping our 10 most significant SNPs from an independent GWAS study to WGT data. We ended up with 10 different tiles where those 10 tiles encapsulated 356 SNPs. In our comparative analysis we make AD diagnosis classifications using either our 10 tiles of WGT data, our 356 SNPs in WGS data, covariate data (age, sex, and ethnicity), or a combination of genomic data (tiles or SNPs) and covariates. Our results (Figure 2) show that WGT performs comparatively to that of SNPs, indicating the patterns embedded within individual SNPs and those within WGT data have similar discriminative power.

Conclusion

Our pilot investigation on the use of a small set of targeted WGT represented genomic data within the context of ML and AD classification has demonstrated similar performance to the SNP data. These results suggest that despite the differing information encapsulated within WGT data compared to WGS data, we are able to derive comparable results in AD classification. Our study on WGT and its use in AD machine learning shows the potentiality and novelty of WGT, and it warrants probing for further exploration of its maximal use.
Development of Novel Partial Mitochondrial Complex I Inhibitors as a Therapy for Alzheimer Disease.
Authors: Trushin Sergey , Stojakovic Andrea , Chang Su‐Youne , Macura Slobodan , Trushina Eugenia
Published: December 2022

Background

Consistent failure of clinical trials for Alzheimer Disease (AD) emphasizes the necessity to identify novel therapeutic targets for this debilitating condition. We recently identified the mitochondrial complex I (MCI) as a small molecule druggable therapeutic target for AD.

Method

Using rational design and extensive structure‐activity relationship studies, we developed novel classes of partial MCI inhibitors with high selectivity, specificity, safety, and drug‐like properties. Target engagement, selectivity and specificity of new compounds were established using multiple in vitro assays, including surface plasmon resonance (SPR), competitive and direct binding, proteomics and pull down experiments. Using these techniques, we developed new lead compound C458 that was interrogated in in vivo efficacy studies in APP/PS1 mice.

Result

We demonstrated that the new lead C458 directly binds to MCI. A single dose administration of C458 to mice or treatment of primary mouse neurons activates AMPK‐a, Akt, autophagy, Sirtuins 1 and 3, and upregulates PGC‐1a leading to enhanced mitochondrial biogenesis. C458 has excellent oral bioavailability, blood–brain‐barrier penetrance, and was remarkably clean in the 250 kinase and CEREP 44 safety panels. Chronic administration of C458 (25 mg/kg/day in drinking water ad lib) to APP/PS1 mice for 6 months starting at pre‐symptomatic stage did not cause detectable side effects, and resulted in cognitive protection, improved long‐term potentiation, and decreased oxidative stress and inflammation. Furthermore, APP/PS1 mice treated with C458 showed a significant increase in glucose uptake and utilization in the brain detected with a translational in vivo biomarker FDG‐PET, as well as an enhancement of ATP production measured in vivo using 31P NMR.

Conclusion

Mechanistic studies confirmed that C458 treatment triggered mitochondrial stress response augmenting mitochondrial biogenesis, anti‐oxidant signaling, and cellular energetics that ultimately restored energy brain homeostasis, leading to cognitive protection in a mouse model of AD. Our studies demonstrate that modulation of MCI activity using novel specific MCI inhibitors improves bioenergetics in the brain and averts cognitive decline representing novel therapeutic approach for AD.
Fosgonimeton, a novel, small molecule positive modulator of the HGF/MET system is neuroprotective in primary neuron culture
Authors: Reda Sherif , Johnston Jewel , Taylor Robert W , Church Kevin
Published: December 2022

Background

Positive modulation of the hepatocyte growth factor (HGF)/MET system may represent a promising therapeutic strategy for several neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Activation of the HGF/MET system induces neuroprotective effects that counteract neurotoxicity, neuroinflammation, and oxidative stress‐induced damage, all pathological hallmarks of neurodegeneration. Herein, we investigated the in vitro neuroprotective potential of fosgonimeton (ATH‐1017), a novel, small molecule positive modulator of the HGF/MET system that has demonstrated neurotrophic and pro‐cognitive effects in vitro and in vivo. In addition, we assayed several novel compounds with related activity to fosgonimeton to establish the neuroprotective effects of a series of HGF/MET positive modulators.

Method

Mature rat cortical neurons were treated with the active metabolite of fosgonimeton or related HGF/MET positive modulators and subjected to a variety of neurotoxic insults including 1‐methyl‐4‐phenylpryidinium (MPP+), glutamate, lipopolysaccharide (LPS), or hydrogen peroxide (H2O2). Neuronal cell viability was determined using CellTiter Glo luminescence assay to assess relative levels of ATP. Furthermore, the effect of fosgonimeton and other test compounds on mitochondrial membrane potential (MMP) was assessed utilizing a fluorescent MMP dye.

Result

Cortical neurons treated with our HGF/MET positive modulators exhibited significant improvement in cell viability against MPP+ neurotoxicity, glutamate excitotoxicity, LPS‐induced cytotoxicity, and H2O2‐induced oxidative stress. For example, treatment with 1 µM fosgonimeton rescued cell viability against neurological insults with the following percent recoveries: 85% vs. MPP+, 61% vs. glutamate, 93% vs. LPS, and 144% vs. H2O2. Significant improvement in cell viability was also observed at 100 nM, 10 nM, and 1 nM fosgonimeton against all insults, highlighting its potent neuroprotective actions. Furthermore, fosgonimeton treatment led to an increase in mitochondrial membrane potential, suggesting that it may mitigate mitochondrial dysfunction associated with neurodegeneration.

Conclusion

Our data demonstrate the ability of fosgonimeton and related HGF/MET positive modulators to offer protection against several neurological insults that are central to neurodegeneration. The neuroprotective effects of fosgonimeton, in addition to its neurotrophic and pro‐cognitive effects, highlight its therapeutic potential to restore neuronal health and slow or reverse neurodegeneration. Fosgonimeton is currently in clinical trials for Alzheimer’s disease, Parkinson’s disease dementia, and Dementia with Lewy bodies.
Comorbid Pathology in Clinical Trial Participants: Autopsy Findings and Clinical Features
Authors: Jicha Gregory A , Barber Justin M , Abner Erin L , Gold Brian T. , Kryscio Richard J , Schmitt Frederick A. , Van Eldik Linda J , Wilcock Donna M , Nelson Peter T
Published: December 2022

Background

The presence of multiple comorbid pathologic features in late onset dementia has been well documented across cohort studies that incorporate autopsy evaluation. It is likely that such mixed pathology may also be common in Alzheimer’s disease and related dementias (ADRD) clinical trial participants, potentially confounding the results of interventional trials that are designed to target a solitary pathophysiologic mechanism.

Method

The University of Kentucky Alzheimer Disease Research Center autopsy database was screened for participants that had previously engaged in therapeutic interventional trials for Alzheimer’s disease, vascular cognitive impairment and dementia, and/or ADRD prevention trials from 2005 to present. Seventy‐five cases (out of a total n = 546) had engaged in clinical trials for the prevention or treatment of ADRD. Pathologic features studied included b‐amyloid, tau, a‐synuclein, TDP‐43, and cerebrovascular disease using conventional rating scales.

Result

Autopsy cases for those that previously engaged in clinical trials did not differ significantly from those that were trial‐naïve in respect to demographic, genetic (ApoE), or clinical characteristics with the exception of CDR global scores that were lower for past trial participants (p<0.05). Comorbid pathologies were common across study types with a mean of 3 pathologic features/participant, 18% with quadruple misfolded proteinopathy (QMP; Ab, tau, a‐synuclein, & TDP43), and only 34% of MCI/AD trial participants demonstrating a “pure” disease state that was targeted by the study intervention.

Conclusion

In our study, approximately 2 out of 3 ADRD trial participants had comorbid mixed pathologic features. Understanding the heterogeneity of pathologies seen in clinical trial participants may allow improved I/E criteria based on clinical features and the rational use of antemortem biomarkers to stratify the likelihood of mixed comorbid pathology that may be unwanted or may be the target for future interventional strategies. Such insights may also enable improved power analyses and statistical designs that may be able to adjust for the confounds of such mixed pathologic disease states that are common in ADRD clinical trials.
Latent space projection of brain FDG‐PET creates a powerful classifier for neurodegenerative diseases
Authors: Barnard Leland R , Botha Hugo , Corriveau‐Lecavalier Nick , Dicks Ellen , Lee Jeyeon , Min Paul H , Senjem Matthew L. , Gunter Jeffrey L. , Schwarz Christopher G. , Boeve Bradley F. , Knopman David S. , Lowe Val J. , Petersen Ronald C. , Jack Clifford R. , Graff‐Radford Jonathan , Jones David T.
Published: December 2022

Background

Fluorodeoxyglucose positron emission tomography (FDG‐PET) is an established modality for differential diagnosis of dementia. Deriving phenotypic signatures from FDG‐PET via machine learning is challenging due to the high dimensional nature of brain images relative to the generally small number of labeled examples available for training, the class imbalance among those labels, and the cooccurrence of multiple pathologies. In this study, we developed a multi‐class, multi‐label framework to address these challenges.

Method

A database of clinically acquired PET/CT images from 3,000 unique patients was used to develop a latent space model using matrix decomposition. This model was then applied to images from a separate cohort of Mayo Clinic Alzheimer’s Disease Research Center participants (n=1,745) labeled as cognitively unimpaired (CU) (n=1,436) or with the following potentially co‐occurring phenotypes: Alzheimer’s disease (AD) (n=165), Lewy body dementia (DLB) (n=92), behavioral variant frontotemporal dementia (bvFTD) (n=43), semantic (svPPA) (n=10) and logopenic (lvPPA) (n=13) variant PPA, and posterior cortical atrophy (PCA) (n=17). A k‐nearest neighbors classifier that is robust to these imbalanced and overlapping labels was then trained on these examples. The resulting classifier was evaluated by area under receiver‐operator characteristic curve (ROC‐AUC) via leave one out cross validation, using clinical diagnosis as the gold standard.

Result

ROC curves and AUC scores for each phenotype are illustrated in Fig. 1a. Because the classifier is based on a k‐nearest neighbors connectivity matrix, it has a convenient graphical representation, where images are nodes and edges are drawn between an image and its set of nearest neighbors in latent space. A self‐organizing force directed graph constructed in this way is illustrated in Fig 1b, highlighting the strong separation of CU and degenerative images, as well as the segregation of each phenotype within the neurodegenerative region of the graph.

Conclusion

In this study, we developed a machine learning framework for classification of neurodegenerative disease based on k‐nearest neighbor analysis in a low dimensional latent space projection of FDG‐PET images. By leveraging low‐dimensional representations and k‐nearest neighbors analysis, this framework is robust in multi‐class, multi‐label tasks with strong class imbalance and provides a highly interpretable graphical representation.
A novel oral formulation (CoM pat. pend.) of HP‐alpha‐cyclodextrin as a safe (not ototoxic) and convenient (oral) drug against Alzheimer’s disease
Authors: Wittkowski Knut M.
Published: December 2022

Background

There are few, if any, disease‐modifying treatments (DMTs) for AD. HP‐beta‐cyclodextrin (HPβCD) was effective in AD models and ph1/2 trials of overnight IV HPβCD qow showed reduction of CSF tau protein, but also confirmed its risk of cholesterol‐related ototoxicity. As the hearing loss seen in these short (12 wk) trials was only transient (Fig. 1), the FDA accepted INDs for IV HPβCD as a drug against NPC1 (ph3) and AD (ph2).

Method

To avoid ototoxicity and the need for overnight infusion, we conducted a human PK/PD study of a novel (non‐covalent) clathrate of HPαCD and a milk/coconut oil medium‐chain fatty acid (capric acid, C10). HPαCD alone, co‐administered with, and as a clathrate with C10 (2:1 molar) were administered orally before bedtime. HPαCD and phospholipids (PLs) were measured by FPLC in morning urine. We also conducted animal studies in breast cancer and fast progressing neurodegenerative diseases (ALS/HD), where high levels of endocytosis are also known to “derail” the endocytosis‐lysosome‐autophagy (ELA) axis.

Result

IP animal studies had showed HPαCD as more effective than HPβCD in breast cancer (reducing endocytosis and inflammation) While aCDs are reducing obesity in WT animals (and humans), HPaCD increasing bodyweight as a DMT in models of ALS?HD. Clinically, some HPαCD and PLs appeared in morning urine after oral administration as a mixture, but twice as much with the clathrate (Fig. 3).

Conclusion

Intermittent fasting (IF) and the IF mimetic HPαCD (too small to fit cholesterol) are not only effective against ALS, but were previously shown to be at least as effective as HPβCD in lysosomal storage diseases (LSDs, Fig. 4) and more effective in cancer, where endocytosis is also involved, albeit with different manifestations (Ancidoni 2021) (Fig. 5). With the new results showing that (a) the HPαCD clathrate ASD‐005 is
intestinally absorbed
, safe, and has
systemic effects in other ELA axis diseases
and (b) HP‐CDs are
active across the blood‐brain barrier
(Fig. 1), oral HP‐cyclodextrin clathrates are now emerging as more convenient, safer, and often more effective DMTs for AD or, when formulated with the GRAS aCD, as nutraceuticals to improve neurologic and cardiometabolic health in aging (ASD‐NP6).
Single‐cell network biology characterizes cell type gene regulation for drug repurposing and phenotype prediction in Alzheimer’s disease
Authors: Gupta Chirag , Xu Jielin , Jin Ting , Khullar Saniya , Liu Xiaoyu , Alatkar Sayali Anil , Cheng Feixiong , Wang Daifeng
Published: December 2022

Background

Dysregulation of gene expression in Alzheimer’s disease (AD) remains elusive, especially at the cell type level. Gene regulatory network, a key molecular mechanism linking transcription factors (TFs) and regulatory elements to govern target gene expression, can change across cell types in the human brain and thus serve as a model for studying gene dysregulation in AD. However, it is still challenging to understand how cell type networks work abnormally under AD.

Method

To address this, we integrated single‐cell multi‐omics data and predicted the gene regulatory networks in AD and control for four major cell types, excitatory and inhibitory neurons, microglia and oligodendrocytes. Importantly, we applied network biology approaches to analyze the changes of network characteristics across these cell types, and between AD and control.

Result

We found that many hub TFs target different genes between AD and control (rewiring). Also, these cell‐type gene networks show strong hierarchical structures in which top TFs (master regulators) are largely common across cell types, whereas different TFs operate at the middle levels in some cell types (e.g., microglia). The regulatory logics of enriched network motifs (e.g., feed‐forward loops) further uncover cell‐type‐specific TF‐TF cooperativities in gene regulation. The cell type networks are highly modular. Several network modules with cell‐type‐specific expression changes in AD pathology are enriched with AD‐risk genes and putative targets of approved and pending AD drugs, suggesting possible cell‐type genomic medicine in AD. Finally, using the cell type gene regulatory networks, we developed machine learning models to classify and prioritize additional AD genes. We found that top prioritized genes predict AD and clinical phenotypes (e.g., cognitive impairment).

Conclusion

Overall, this single‐cell network biology analysis provides a comprehensive map linking genes, regulatory networks, cell types and drug targets and reveals mechanisms on cell‐type gene dysregulation in AD.
Impact of therapeutic plasma exchange on amyloid plaque load and vascular health in APP/PS1 mice
Authors: Cover Christopher G , Peretin Jenna , Lopez Oscar L. , Vazquez Alberto L
Published: December 2022

Background

Therapeutic plasma exchange (TPE) has been shown to be a beneficial treatment for Alzheimer’s disease (AD) to both humans and mice; however, little is known about TPEs impact on preserving vascular function. Since AD pathology is usually associated with vascular dysfunction, the current study investigates the therapeutic potential of TPE on preserving vascular reactivity in young APPswe/PS1dE9 AD mouse model.

Method

Bi‐monthly TPE began at 6‐months of age (mo) in the treatment APP/PS1 group (n = 6), exchanging 300‐400 µL of plasma from a 2‐3 mo donor, wild‐type (WT) mouse. The control groups, APP/PS1 (n = 6) and WT group (n = 5), received no treatment. All mice were implanted with a 5mm cranial window and head‐fixed conditioned for awake optical imaging. Wide‐field optical imaging (WFOI) at 620nm light was used to assess vascular function. To this end, changes in optical imaging signal sensitive to blood oxygenation (OIS‐BOLD) produced by a 90‐sec hypercapnic stimulus (10% CO2 in air) delivered by nose cone. Peak changes from baseline OIS‐BOLD were measured (Fig. 1). Images of cortical amyloid plaques were obtained monthly using fluorescence microscopy 6‐24 hrs after Methoxy‐X04 administration (1 mg/kg, IP; Fig. 2). To account for between mouse variability in plaque accumulation, plaque data were normalized to their value immediately prior to their treatment (i.e., 6 mo data). An analysis of covariance was used to assess statics for vascular reactivity and plaque load.

Result

TPE shows a trend towards reduced cortical plaque load in 8‐12 mo treated APP/PS1 mice (Fig. 2; p = 0.1658 ± 0.023). Vascular reactivity values measured by OIS‐BOLD also show a trend towards improved vascular function although our treated group measurements did not sample older ages (Fig. 3; F(2,134) = 2.08,p = 0.124).

Conclusion

Our findings showed that there is a trend to a decrease cortical amyloid plaque load in young‐middle aged AD mice treated with TPE, as well as a trend for improved vascular function. Further studies on old‐aged mice will provide additional information about the effects of TPE on AD and vascular function.
Deconvolving Cerebrospinal Fluid Soluble TREM2 Signal and Longitudinal Associations with Cognition
Authors: Weiner Rebecca L , Dumitrescu Logan , Blennow Kaj , Zetterberg Henrik , Gifford Katherine A. , Pechman Kimberly R. ,   The Alzhemer's Disease Neuroimaging Initiative, Jefferson Angela L. , Hohman Timothy J.
Published: December 2022

Background

Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells‐2 (sTREM2) is an emerging biomarker of neuroinflammation in Alzheimer’s disease (AD). Yet, sTREM2 expression has not been systematically evaluated in relation to concomitant drivers of neuroinflammation. We previously found a novel association between high Aβ40 (but not Aβ42) and high sTREM2 levels at baseline and replicated additional associations between a fluid biomarker of blood‐brain barrier (BBB) integrity and CSF biomarkers of neurodegeneration. Therefore, we sought to determine the relative contributions of these biological correlates to CSF sTREM2 levels during the prodromal stages of AD. Additionally we investigated whether the residual variance in sTREM2 level correlated with each biomarker predicted future cognitive performance.

Method

Leveraging 155 Vanderbilt Memory and Aging Project (VMAP) participants (mean±standard deviation age=72±6, male=67%, mild cognitive impairment=47%), previously established associations between baseline CSF sTREM2 concentrations and CSF AD biomarkers (Aβx‐40, total tau, phosphorylated tau, and neurofilament light) and BBB integrity (CSF/plasma albumin ratio) were examined via hierarchical linear regression using sTREM2 as an outcome variable. Models adjusted for age, sex, education, cognitive status, and APOE‐ε4 status. Baseline CSF sTREM2 levels and corresponding residual components when adjusting for other biomarker levels in independent models were used in longitudinal mixed effects models predicting an episodic memory composite calculated as a z‐score from independent tests. Participants had up to five visits (mean±sd=2.63±1.30 visits).

Result

High baseline CSF sTREM2 levels predicted slower longitudinal memory decline in VMAP (β=1.442e‐05, p=0.035). Additionally, the component of sTREM2 signal correlated with Aβx‐40 best predicted future memory performance (β=2.217e‐05, p=0.007). Together, Aβx‐40, phosphorylated tau, and the CSF/plasma albumin ratio jointly explained 36% of variance in sTREM2 levels. Aβx‐40 levels and the CSF/plasma albumin ratio explained sTREM2 signal above and beyond established associations with tau (R2=0.21; R2=0.21; and R2=0.17, respectively).

Conclusion

We highlight potential contributions of Aβ homeostasis and BBB integrity to elevations in CSF sTREM2, underscoring novel biomarker associations relevant to disease progression. Results suggest that the tight correlation between baseline CSF sTREM2 and Aβx‐40 levels may have notable importance to cognitive trajectory in an aged cohort enriched for mild cognitive impairment.
The novel M4 PAM PET tracer [11C] MK‐6884: a novel biomarker for measuring target engagement of muscarinic M4 positive allosteric modulators (PAMs) as well as cholinergic tone in patients with Alzheimer’s disease
Authors: Li Wenping , Basile Anthony S , Tong Ling , Van Laere Koen , Masdeu Joseph C. , Hostetler Eric D , Marshall Fiona , Uslaner Jason M.
Published: December 2022

Background

The muscarinic acetylcholine receptor 4 (M4) has attracted attention as a target for treating neuropsychiatric symptoms, such as agitation and aggression, associated with Alzheimer’s disease. We have developed novel selective, potent, and in vivo suitable M4 positive allosteric modulators (PAMs) and demonstrated robust pharmacology in preclinical models predictive of antipsychotic and pro‐cognitive effects. Importantly, we have also shown that these selective M4 PAMs produce greater therapeutic margins for cholinergic adverse effects compared to less selective muscarinic receptor agonists.

Methods

To enable translation in the clinic, we set out to discover an M4 PAM PET tracer suitable for measuring central receptor occupancy (RO).

Result

[11C]MK‐6884 binds with high affinity and selectivity to the allosteric site on the M4 receptor that our other M4 PAMs bind. The affinity of [11C]MK‐6884 was found to be influenced by the concentration of orthosteric agonist in vitro and in vivo, consistent with the high cooperativity of the molecule in vitro. PET studies successfully determined the target engagement of PAMs to enable modeling the relationship between drug plasma exposure, RO, and pharmacodynamic activity. Donepezil increased the tracer binding potential of [11C]MK‐6884 in rhesus and healthy human subjects, confirming in vivo the influence of cholinergic tone on [11C]MK‐6884 binding that was observed in vitro. Consistent with a presumed cortical deficit in synaptic acetylcholine, [11C]MK‐6884 PET studies in AD patients showed lower cortical binding potential compared to healthy elderly participants, as well as notable cortical heterogeneity and bilateral asymmetry of M4 receptor binding in AD patients. Striatal binding potential was unchanged in these different populations.

Conclusion

Our findings demonstrate that the M4 PAM PET tracer [11C]MK‐6884 is a useful tool for determining target engagement of M4 PAMs, as well serving as a unique probe to study changes in cholinergic neurotransmission in neurodegenerative disease. The Enigma Biomedical Group has an exclusive license agreement with Merck & Co., Inc., for the global development and commercialization of MK‐6884. This allows Enigma and its partner, Cerveau Technologies Inc. to provide biomarkers to industry and academia to accelerate research in the field of neurodegenerative and neuropsychiatric diseases.
Chronic Treatment Study Using Class C CpG ODN in Aged Non‐Human Primate Model of Sporadic CAA (Saimiri boliviensis boliviensis).
Authors: Patel Akash G , Karimi Sohail , Nehete Pramod N , Nehete Bharti P , Murray Sean , Levine Dafna T , Soliman Muhammad T , Llanos Michael , Hopkins William D , Williams Lawrence E , Wisniewski Thomas , Scholtzova Henrieta
Published: December 2022

Background

Therapeutics that target innate immunity present promising avenues for the treatment of Alzheimer’s disease (AD) neuropathology. Our recently published study using squirrel monkeys (SQMs), a non‐human primate model of sporadic AD with extensive cerebral amyloid angiopathy (CAA), demonstrated that treatment with TLR9 agonist, Class B CpG ODN, safely reduces cognitive deficits and pathological features including parenchymal amyloid deposits, tau pathology, and CAA. Subsequently, we initiated the first chronic treatment study using Class C CpG ODN, and demonstrated its safety and efficacy in eliciting an immune response in a geriatric SQM population. Here, we assess the efficacy of Class C CpG ODN by evaluating plasma biomarkers of neurodegeneration and cognitive status using an innovative computerized testing system.

Method

Geriatric SQMs received monthly injections of Class C CpG ODN or saline. Plasma biomarkers of neurodegeneration (NfL, GFAP), neuroinflammation (YKL‐40/CHI3L1), and Aβ40/42 autoantibodies were detected longitudinally using Luminex, SIMOA, or ELISA assays. Furthermore, we have implemented an innovative, touchscreen‐based Automated Cognitive Testing System (ACTS) among socially living SQMs to monitor behavioral changes. Actical® activity monitors recorded general activity parameters (step count, activity count, energy expenditure, and intensity level).

Result

Plasma levels of NfL, GFAP, and YKL‐40 were significantly increased in saline‐administered monkeys compared to CpG ODN‐treated cohort. No changes were observed in both treatment groups in general activity parameters. Longitudinal plasma hematological/biochemical parameters and Aβ40/42 IgG and IgM titers revealed no differences between treatment groups, further validating the safety of our immunomodulatory approach. Geriatric SQMs completed the ACTS SHAPE training tasks to a 95% criterion of success within 10 days and are progressing through advanced cognitive tests [Match‐to‐Sample (MTS) and Two‐Choice Discrimination]. Preliminary MTS testing revealed that CpG ODN‐treated group performed with a greater response accuracy than saline controls over the last 1000 trials. Additional biofluid biomarkers and cognitive assessments are being finalized. Longitudinal gene expression profiles (RNA‐seq and NanoString analyses) involved in CpG ODN pathways using PBMCs are underway.

Conclusion

Our findings enhance the translational value of the SQM model for preclinical research on AD and CAA pathogenesis, as we continue to demonstrate Class C CpG ODN’s safety and therapeutic efficacy in geriatric SQMs.
Amyloid Negative, Highly Tau Positive: Clinical Characterization of a Rare Biomarker Profile
Authors: Windon Charles , Iaccarino Leonardo , Mundada Nidhi S. , Apostolova Liana G. , Carrillo Maria C. , Dickerson Brad C. , Grant Harli E. , Miller Bruce L. , Shankar Ranjani , Soleimani‐Meigooni David N. , Joie Renaud La , Rabinovici Gil D. ,   ADNI and LEADS
Published: December 2022

Background

The majority of individuals with unambiguously positive tau biomarkers (T++) have positive amyloid biomarkers. Here we describe cases with clinical features associated with an unusual biomarker profile: very high tau PET binding and negative amyloid PET (A‐T++).

Method

We searched the Longitudinal Early‐Onset Alzheimer’s Disease (AD) Study, University of California San Francisco AD Research Center and the AD Neuroimaging Initiative cohorts on 09/01/2021 for participants with completed amyloid PET (Florbetapir, Florbetaben, Pittsburgh Compound B) and Tau PET (Flortaucipir (FTP)) scans and identified 1420 participants (mean age 69, 49.7% male). Using a pathology‐based, neocortical centiloid threshold of 24.4 (amyloid positivity) and a pre‐defined region of interest (Temporal MetaROI) standardized uptake value ratio (SUVR) > 1.27 threshold (tau positivity), we identified 64 amyloid negative, tau positive cases. An additional MetaROI FTP‐SUVR threshold > 2.0 (based on visual plot of data) was then applied to identify 7 A‐T++ cases (Figure 1).

Result

Among A‐T++ individuals mean age was 66.2 (range 53.8 ‐ 77.1), 4/7 were female, mean years of education was 15 (range 12 ‐ 20), mean MMSE was 20 (range 14‐29), 3/7 were APOE e3/e4 and clinical phenotypes included amnestic and atypical AD phenotypes (Table 1).

Mean neocortical centiloid value was 11.4 (range: ‐1.39 ‐ 17.11) among A‐T++ cases and 4/7 had centiloid values between 12.2 ‐ 24.4 (may be indicative of early positivity). Mean FTP SUVR was 2.28 (range 2.03 ‐ 2.63) (Table 2). All A‐T++ cases demonstrated FTP tracer binding within the middle temporal cortex, medial temporal structures, and posterior cingulate regions (Figure 2). Neuropathological data from 1 case (UCSF3) revealed frequent CERAD Neuritic Plaques, Thal Amyloid Plaque Phase 5, and Braak Neurofibrillary Degeneration Stage 6 (autopsy performed 1 year after amyloid PET).

Conclusion

A‐T++ individuals were heterogeneous clinically but all displayed FTP tracer binding in AD‐signature regions. Four cases had amyloid centiloid values above 12.2 (threshold to detect moderate‐to‐frequent CERAD scores) but below 24.4 (threshold to detect intermediate‐to high Alzheimer’s disease neuropathologic change (ADNC) levels). Pathological data available for 1 case revealed a high level of ADNC. False negative amyloid PET in A‐T++ individuals is an important consideration; future studies are needed.
Transcranial direct current stimulation (tDCS) in cognitively symptomatic older adults
Authors: Hampstead Benjamin M. , Iordan Alexandru , Peltier Scott , Ploutz‐Snyder Robert
Published: December 2022

Background

tDCS offers an inexpensive, portable, well‐tolerated, and safe approach to neuromodulation. These benefits led to a rapid increase in its use as a potential treatment for those with Alzheimer’s disease and related dementias (ADRD), yet were accompanied by a number of methodological gaps that limit its current translational potential. This session will introduce and evaluate several such methodological factors including potential mechanisms of action, dose‐response relationships, session frequency and duration, and individual factors that may account for variable treatment response.

Method

Data from over 300 participants across the ADRD spectrum and 2,500 tDCS sessions who were enrolled at the Research Program on Cognition and Neuromodulation Based Interventions will be used to demonstrate the potential impact of the above noted methodological factors. Structural and functional neuroimaging data will be included to demonstrate both theoretical and empirical effects of tDCS.

Result

Across studies, our results demonstrate that targeted, multi‐electrode tDCS can alter underlying neurotransmitter levels and potentially “normalize” patterns of “activation” and functional connectivity in those with cognitive impairment. However, there is remarkable variability in the amount of electrical current delivered to the brain across participants (>600%) as well as the targeted brain region, which require reconsideration of the traditional dosing at the scalp approach. Moreover, there are apparent polarity‐dependent effects as well as differences between passive versus active (i.e., cognitive task performance) measurements. Ongoing work evaluates the additional impact and nature of disease pathology on these factors.

Conclusion

The combination of results highlights the complex and multifaceted nature of tDCS and may translate to other forms of neuromodulation.
Regional pattern of cortical microstructural alterations along the AD continuum and association with plasma neurofilament light
Authors: Torso Mario , Ridgway Gerard R , Valotti Michele , Chance Steven A ,   for The Alzhemer's Disease Neuroimaging Initiative
Published: December 2022

Background

Microstructural changes associated with the progression of Alzheimer's disease (AD) precede macrostructural atrophy. We investigate cortical microstructural changes along the AD continuum in patients with cerebrospinal fluid (CSF) AD biomarkers and plasma neurofilament light chain (NfL).

Method

Three hundred fifty‐one participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with CSF amyloid‐beta 42 (Aβ42) and Phosphorylated Tau 181 (pTau181) were included. The CSF pTau181‐Aβ42 ratio was used to assess the presence (+/‐) of the pathophysiological hallmarks of AD and classify the participants into four groups: 149 cognitively normal biomarker negative (CN‐), 61 cognitively normal positive (CN+), 73 patients diagnosed with Mild Cognitive Impairment positive (MCI+) and 68 AD positive (AD+).

Structural and diffusion MRI (dMRI) were used to calculate cortical mean diffusivity and three novel cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+).

Clinical, demographic and MRI data were used to characterize groups. Group differences in diffusion metrics were tested with a linear model, adjusting for age, sex and site‐ID, with false discovery rate correction (pFDR<0.05). The association between cortical diffusivity and NfL was investigated in a subset of 111 participants.

Result

At whole‐brain level, the AD+ group exhibited significantly higher AngleR, PerpPD+, ParlPD and MD values compared to the other groups. PerpPD+ was the only measure able to differentiate between all subsequent disease stages (CN‐ and CN+ vs MCI+, and MCI+ vs AD+); regional results are presented in the Figure. Along the AD continuum, the results revealed a widespread progressive pattern of higher PerpPD+, involving mainly fronto‐temporal and occipital regions. Correlation analysis showed significant association between cortical diffusivity measures (PerpPD+ and ParlPD) and NfL values.

Conclusion

Cortical diffusivity measures can detect progressive microstructural changes along the AD continuum and are significantly associated with NfL. Cortical diffusion MRI offers a microstructural marker of neurodegeneration within the ATN framework (Jack et al. 2018); as an imaging measure, regional patterns can provide disease specificity that is lacking for fluid measures like NfL.
Reduced CSF Aβ42 and Aβ42/Aβ40 ratio during early cerebral amyloid deposition in the AppNL‐F knock‐in mouse model of Alzheimer’s disease
Authors: Andersson Emelie , Saito Takashi , Saido Takaomi C. , Blennow Kaj , Zetterberg Henrik , Hansson Oskar
Published: December 2022

Background

The concentration of Aβ42 in cerebrospinal fluid (CSF) is decreased at least a decade before cognitive symptoms caused by Alzheimer’s disease (AD) manifest. This drop in concentration has been suggested to occur before abnormal levels of fibrillar Aβ in the brain are reached, but the underlying cause is not well understood. The present study aims to explore the translational potential of the App
NL‐F knock‐in mouse model, and compare it to transgenic App‐overexpressing 3xTg mice, for investigation of the early events in Aβ pathology that associates with reduced CSF Aβ42 in preclinical AD.

Method

CSF and brain tissue was collected from 3‐18 months old App
NL‐F knock‐in mice (n=56) and 3‐24 months old 3xTg mice (n=74). CSF Aβ40 and Aβ42 concentrations were measured using Single Molecule Array (Simoa) technology and immunohistochemistry was performed on brain sections for detection of cerebral Aβ deposition.

Result

In App
NL‐F knock‐in mice, CSF Aβ40 remained unchanged while CSF Aβ42 and Aβ42/Aβ40 ratio were reduced from 12 months of age after which a plateau was reached (Fig.1). The initial reduction coincided with early deposition of cortical Aβ42 in the brain that gradually increased with age (Fig.2). Accordingly, in the whole study population, CSF Aβ42 and Aβ42/Aβ40 ratio showed a moderate negative hyperbolic association with cortical Aβ42 load (Fig.3). In comparison, increased CSF Aβ40 and Aβ42 was observed in 3xTg mice prior to Aβ plaque deposition, although the Aβ42/Aβ40 ratio remained stable. These changes coincided with the accumulation of cerebral intracellular Aβ. Once Aβ plaques started to deposit in the brain from 12 months of age, a subsequent reduction of CSF Aβ42 and Aβ42/Aβ40 was observed (Fig.4).

Conclusion

In line with clinical findings, CSF Aβ42 and Aβ42/Aβ40 ratio are reduced in App
NL‐F knock‐in mice and seem to reflect pathological processes that occur slightly before deposition of amyloid in the brain is widespread. This reduction quickly starts to stabilize towards a plateau, although accumulation of cerebral amyloid steadily continues to increase. In contrast to 3xTg mice, no initial increase in CSF Aβ40 and Aβ42 was observed and further studies are needed to elucidate these differences and their translational implication.
Alzheimer Disease candidate variants are associated with cerebral amyloid angiopathy
Authors: Godrich Dana , Pasteris Jeremy , Martin Eden R. , Schellenberg Gerard D. , Pericak‐Vance Margaret A. , Cuccaro Michael L. , Scott William K. , Kukull Walter A. , Montine Thomas J. , Beecham Gary W. ,   the Alzheimer's Disease Genetics Consortium
Published: December 2022

Background

The hallmark lesions of Alzheimer Disease (AD) include tangles and plaques; however, these seldom appear alone. Lesions of AD‐related dementias such as vascular dementias and Lewy body dementias often co‐occur with AD. These co‐occurring lesions and total lesion burden are associated with a higher likelihood of dementia and severe cognitive impairment. Even amongst other lesions, cerebral amyloid angiopathy (CAA) presents a strong risk for more severe cognitive impairment. CAA also shows moderate correlations to AD (rho = 0.31), suggesting that CAA pathology could present an underlying or related process of AD pathology. We hypothesize that there is a genetic overlap between CAA and AD and therefore we investigate the influence of known AD genes on CAA.

Method

Data come from 3,495 autopsied individuals with neuropathology and array data from the National Alzheimer’s Coordinating Centers (NACC). CAA was measured according to NACC neuropathology form guidelines. We used ordinal logistic regression to model APOE genotype and 22 other known AD variants with CAA severity while adjusting for sex, age at death, and AD pathology. For the 22 other known AD variants, we tested the lead variants reported by Kunkle et al. and labeled by closest gene. We modeled APOE by carrier status and genotype.

Result

We confirmed associations for APOE with CAA severity, when modeling APOE as e4 dosage (OR=2.34, p<0.001) or by genotype (e3/e4: OR=1.96, p<0.001; e4/e4: OR=5.76, p<0.001). However, we did not see a significant association between CAA severity and APOEe2 carriers, as others have reported. Association persisted when including AD pathology terms in the model, even when extending to interaction‐based models. Genetic variations in 7 of the 22 known AD genes (BIN1, HLA‐DRB1, TREM2, CLU, PICALM, SORL1, SLC24A4) showed significant associations with CAA while accounting for AD pathology.

Conclusion

We confirmed strong associations of APOEe4 with CAA in a large clinical population. We modeled other known AD genes and 7 of them showed significant associations with CAA, demonstrating genetic overlap between AD and CAA pathologies. This study suggests that there is genetic overlap between CAA and AD pathology that could point to shared disease mechanisms for the targeting and treatment of AD.