Alzheimer's Disease Drug Development Research Articles

Innovative pathological network-based multitarget approaches for Alzheimer's disease treatment.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and isa major health threat globally. Its prevalence is forecasted to exponentially increase during the next 30 years due to the global aging population. Currently, approved drugs are merely symptomatic, being ineffective in delaying or blocking the relentless disease advance. Intensive AD research describes this disease as a highly complex multifactorial disease. Disclosure of novel pathological pathways and their interconnections has had a major impact on medicinal chemistry drug development for AD over the last two decades. The complex network of pathological events involved in the onset of the disease has prompted the development of multitarget drugs. These chemical entities combine pharmacological activities towardtwo or more drug targets of interest. These multitarget-directed ligands are proposed to modify different nodes in the pathological network aiming to delay or even stop disease progression. Here, we review the multitarget drug development strategy for AD during the last decade.

The synergistic effect of curcumin and mitoquinol mesylate on cognitive impairment and the neuropathology of Alzheimer's disease

Given the complexity and heterogeneity of Alzheimer's disease (AD) pathology, targeted monotherapy drugs may not be effective. Therefore, synergistic combination therapy of curcumin and Mito Q was proposed and evaluated in a triple-transgenic AD model mice (3 × Tg-AD mice). The cognitive ability was assessed using behavioral tests and typical pathological changes were observed through Western blotting and histological analysis. The results demonstrated a significant enhancement in cognitive ability along with the mitigation of typical AD pathological features such as Aβ aggregation, tau phosphorylation, and synaptic damage. Notably, the combination therapy demonstrated superior efficacy over individual drugs alone. These findings provide valuable insights for optimizing the development of AD drugs.

Hybrid Membrane-Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease.

The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.

Synthesis and investigation of the cholinesterase inhibitory and antioxidant capacities of some novel N'-(quinolin-4-ylmethylene)propanehydrazides against Alzheimer's disease.

One of the worst long-term health issues of the past few decades is Alzheimer's disease (AD). Unfortunately, there are currently insufficient choices for treating and caring for AD, which makes it a popular subject for drug development research. Studies on the development of drugs for AD have primarily concentrated on the use of multitarget directed ligands.Following this strategy, we designed new ChE inhibitors with additional antioxidant and metal chelator effects. In this research, eight novel N'-(quinolin-4-ylmethylene)propanehydrazide derivatives were synthesized and characterized. We then evaluated the inhibition potency of all the final compounds for cholinesterase enzymes. Among them, 4e (IC50 acetylcholinesterase[AChE] = 0.69 µM and butyrylcholinesterase[BChE]= 26.00 µM) and 4h (IC50's AChE= 7.04 µM and BChE= 16.06 µM) were found to be the most potent AChEand BChEinhibitors, respectively.

Alzheimer's disease drug development pipeline: 2024

New therapies to prevent or delay the onset of symptoms, slow progression, or improve cognitive and behavioral symptoms of Alzheimer's disease (AD) are needed. We interrogated clinicaltrials.gov including all clinical trials assessing pharmaceutical therapies for AD active in on January 1, 2024. We used the Common Alzheimer's Disease Research Ontology (CADRO) to classify the targets of therapies in the pipeline. There are 164 trials assessing 127 drugs across the 2024 AD pipeline. There were 48 trials in Phase 3 testing 32 drugs, 90 trials in Phase 2 assessing 81 drugs, and 26 trials in Phase 1 testing 25 agents. Of the 164 trials, 34% (N = 56) assess disease-modifying biological agents, 41% (N = 68) test disease-modifying small molecule drugs, 10% (N = 17) evaluate cognitive enhancing agents, and 14% (N = 23) test drugs for the treatment of neuropsychiatric symptoms. Compared to the 2023 pipeline, there are fewer trials (164vs. 187), fewer drugs (127vs. 141), fewer new chemical entities (88vs. 101), and a similar number of repurposed agents (39vs. 40). In the 2024 Alzheimer's disease drug development pipeline, there are 164 clinical trials assessing 127 drugs.The 2024 Alzheimer's disease drug development pipeline has contracted compared to the 2023 Alzheimer pipeline with fewer trials, fewer drugs, and fewer new chemical entities.Drugs in the Alzheimer's disease drug development pipeline target a wide array of targets; the most common processes targeted include neurotransmitter receptors, inflammation, amyloid, and synaptic plasticity.The total development time for a potential Alzheimer's disease therapy to progress from nonclinical studies to FDA review is approximately 13 years.

Current Progress on Central Cholinergic Receptors as Therapeutic Targets for Alzheimer's Disease.

Acetylcholine (ACh) is ubiquitously present in the nervous system and has been involved in the regulation of various brain functions. By modulating synaptic transmission and promoting synaptic plasticity, particularly in the hippocampus and cortex, ACh plays a pivotal role in the regulation of learning and memory. These procognitive actions of ACh are mediated by the neuronal muscarinic and nicotinic cholinergic receptors. The impairment of cholinergic transmission leads to cognitive decline associated with aging and dementia. Therefore, the cholinergic system has been of prime focus when concerned with Alzheimer's disease (AD), the most common cause of dementia. In AD, the extensive destruction of cholinergic neurons occurs by amyloid-β plaques and tau protein-rich neurofibrillary tangles. Amyloid-β also blocks cholinergic receptors and obstructs neuronal signaling. This makes the central cholinergic system an important target for the development of drugs for AD. In fact, centrally acting cholinesterase inhibitors like donepezil and rivastigmine are approved for the treatment of AD, although the outcome is not satisfactory. Therefore, identification of specific subtypes of cholinergic receptors involved in the pathogenesis of AD is essential to develop future drugs. Also, the identification of endogenous rescue mechanisms to the cholinergic system can pave the way for new drug development. In this article, we discussed the neuroanatomy of the central cholinergic system. Further, various subtypes of muscarinic and nicotinic receptors involved in the cognition and pathophysiology of AD are described in detail. The article also reviewed primary neurotransmitters that regulate cognitive processes by modulating basal forebrain cholinergic projection neurons.

Deep Learning-Driven Exploration of Pyrroloquinoline Quinone Neuroprotective Activity in Alzheimer's Disease.

Alzheimer's disease (AD) is a pressing concern in neurodegenerative research. To address the challenges in AD drug development, especially those targeting Aβ, this study uses deep learning and a pharmacological approach to elucidate the potential of pyrroloquinoline quinone (PQQ) as a neuroprotective agent for AD. Using deep learning for a comprehensive molecular dataset, blood-brain barrier (BBB) permeability is predicted and the anti-inflammatory and antioxidative properties of compounds are evaluated. PQQ, identified in the Mediterranean-DASH intervention for a diet that delays neurodegeneration, shows notable BBB permeability and low toxicity. In vivo tests conducted on an Aβ₁₋₄₂-induced AD mouse model verify the effectiveness of PQQ in reducing cognitive deficits. PQQ modulates genes vital for synapse and anti-neuronal death, reduces reactive oxygen species production, and influences the SIRT1 and CREB pathways, suggesting key molecular mechanisms underlying its neuroprotective effects. This study can serve as a basis for future studies on integrating deep learning with pharmacological research and drug discovery.

Molecular Deformation Is a Key Factor in Screening Aggregation Inhibitor for Intrinsically Disordered Protein Tau.

Direct inhibitor of tau aggregation has been extensively studied as potential therapeutic agents for Alzheimer's disease. However, the natively unfolded structure of tau complicates the structure-based ligand design, and the relatively large surface areas that mediate tau-tau interactions in aggregation limit the potential for identifying high-affinity ligand binding sites. Herein, a group of isatin-pyrrolidinylpyridine derivative isomers (IPP1-IPP4) were designed and synthesized. They are like different forms of molecular "transformers". These isatin isomers exhibit different inhibitory effects on tau self-aggregation or even possess a depolymerizing effect. Our results revealed for the first time that the direct inhibitor of tau protein aggregation is not only determined by the previously reported conjugated structure, substituent, hydrogen bond donor, etc. but also depends more importantly on the molecular shape. In combination with molecular docking and molecular dynamics simulations, a new inhibition mechanism was proposed: like a "molecular clip", IPP1 could noncovalently bind and fix a tau polypeptide chain at a multipoint to prevent the transition from the "natively unfolded conformation" to the "aggregation competent conformation" before nucleation. At the cellular and animal levels, the effectiveness of the inhibitor of the IPP1 has been confirmed, providing an innovative design strategy as well as a lead compound for Alzheimer's disease drug development.

Binding interactions and in silico ADME prediction of isoconessimine derivatives as potent acetylcholinesterase inhibitors

In pursuit of new acetylcholinesterase (AChE) inhibitors for treating Alzheimer's disease (AD), a series of ten previously synthesized isoconessimine compounds (7a-7j) was in silico investigated for their binding interactions with AChE and pharmacokinetics based on absorption, distribution, metabolism, and excretion (ADME) properties using molecular docking, ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) method and SwissADME tools. Docking experiments showed that all compounds bind within the active site gorge of AChE (PDB entry 1C2B), posing its aryloxy-substitutional ethyl group to catalytic site and conessine skeleton to peripheral anionic site. ONIOM interaction energy was used as an ONIOM score to improve docking score, and it ranked 7b as the most potent AChE inhibitor, in agreement with previous experiment. Residues, ASP74, TRP86, GLY122, GLU202, TRP286, GLU292, SER293, ILE294, TYR337, TYR341, and HIS447 were identified as important for the binding of the AChE-isoconessimine complex. The SwissADME investigation suggested that four compounds (7a, 7c, 7d and 7f) agree with the rules of drug-likeness. The steric and electronic effects on the aryloxy-substitutional ethyl group as important factors in the AChE inhibition were also discussed, which brings a better understanding of Alzheimer's disease drug development.

Targeting Abnormal Tau Phosphorylation for Alzheimer's Therapeutics.

Alzheimer's disease (AD) is a widespread neurodegenerative disorder characterized by progressive memory and cognitive decline, posing a formidable public health challenge. This review explores the intricate interplay between two pivotal players in AD pathogenesis: β-amyloid (Aβ) and tau protein. While the amyloid cascade theory has long dominated AD research, recent developments have ignited debates about its centrality. Aβ plaques and tau NFTs are hallmark pathologies in AD. Aducanumab and lecanemab, monoclonal antibodies targeting Aβ, have been approved, albeit amidst controversy, raising questions about the therapeutic efficacy of Aβ-focused interventions. On the other hand, tau, specifically its hyperphosphorylation, disrupts microtubule stability and contributes to neuronal dysfunction. Various post-translational modifications of tau drive its aggregation into NFTs. Emerging treatments targeting tau, such as GSK-3β and CDK5 inhibitors, have shown promise in preclinical and clinical studies. Restoring the equilibrium between protein kinases and phosphatases, notably protein phosphatase-2A (PP2A), is a promising avenue for AD therapy, as tau is primarily regulated by its phosphorylation state. Activation of tau-specific phosphatases offers potential for mitigating tau pathology. The evolving landscape of AD drug development emphasizes tau-centric therapies and reevaluation of the amyloid cascade hypothesis. Additionally, exploring the role of neuroinflammation and its interaction with tau pathology present promising research directions.

Polygalacic acid attenuates cognitive impairment by regulating inflammation through PPARγ/NF-κB signaling pathway.

We aimed to explore the role and molecular mechanism of polygalacic acid (PA) extracted from traditional Chinese medicine Polygala tenuifolia in the treatment of Alzheimer's disease (AD). The network pharmacology analysis was used to predict the potential targets and pathways of PA. Molecular docking was applied to analyze the combination between PA and core targets. Aβ42 oligomer-induced AD mice model and microglia were used to detect the effect of PA on the release of pro-inflammatory mediators and its further mechanism. In addition, a co-culture system of microglia and neuronal cells was constructed to assess the effect of PA on activating microglia-mediated neuronal apoptosis. We predict that PA might regulate inflammation by targeting PPARγ-mediated pathways by using network pharmacology. Invivo study, PA could attenuate cognitive deficits and inhibit the expression levels of inflammation-related factors. Invitro study, PA can also decrease the production of activated microglia-mediated inflammatory cytokines and reduce the apoptosis of N2a neuronal cells. PPARγ inhibitor GW9662 inversed the neuroprotective effect of PA. Both invivo and invitro studies showed PA might attenuate the inflammation through the PPARγ/NF-κB pathway. PA is expected to provide a valuable candidate for new drug development for AD in the future.

Advancements in high-resolution 3D microscopy analysis of endosomal morphology in postmortem Alzheimer's disease brains.

Abnormal endo-lysosomal morphology is an early cytopathological feature of Alzheimer's disease (AD) and genome-wide association studies (GWAS) have implicated genes involved in the endo-lysosomal network (ELN) as conferring increased risk for developing sporadic, late-onset AD (LOAD). Characterization of ELN pathology and the underlying pathophysiology is a promising area of translational AD research and drug development. However, rigorous study of ELN vesicles in AD and aged control brains poses a unique constellation of methodological challenges due in part to the small size of these structures and subsequent requirements for high-resolution imaging. Here we provide a detailed protocol for high-resolution 3D morphological quantification of neuronal endosomes in postmortem AD brain tissue, using immunofluorescent staining, confocal imaging with image deconvolution, and Imaris software analysis pipelines. To demonstrate these methods, we present neuronal endosome morphology data from 23 sporadic LOAD donors and one aged non-AD control donor. The techniques described here were developed across a range of AD neuropathology to best optimize these methods for future studies with large cohorts. Application of these methods in research cohorts will help advance understanding of ELN dysfunction and cytopathology in sporadic AD.

Female-sensitive multifunctional phytoestrogen nanotherapeutics for tailored management of postmenopausal Alzheimer's disease

Alzheimer's disease (AD) has much higher incidence and mortality in women, largely attributed to the dramatic decline in estrogen levels during menopause. Therefore, tailoring therapeutic strategies targeting estrogen deprivation is essential to achieve female-specific AD treatment. Herein, we developed a multifunctional phytoestrogen nanomodulator (LQ-LPs) and revealed its feasibility and key pharmacological mechanisms for female-sensitive AD management. Benefiting from the greatly improved bioavailability and pharmacokinetics by liposomes, LQ-LPs amplified multiple biological properties of loaded liquiritigenin against estrogen-deprived AD progression, including enhancing synaptoprotective and anti-apoptotic effects through activation of ERβ/BDNF/ERK signaling, as well as simultaneously inhibiting Ca2+ influx spike, oxidative damage, and cholinergic dysfunction caused by glutamate excitotoxicity. Taking advantage of the favorable brain-targeting properties conferred by intranasal delivery, LQ-LP administration exhibited remarkable anti-AD efficacy in reversing ovariectomy-induced neuropathology and rescuing cognitive deficits in estrogen-deprived AD mice. This work reveals for the first time the attractive promise of phytoestrogen-derived versatile nanotherapeutics for female-specific AD management, providing advanced insights into precision drug development for female AD.

Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles

Alzheimer’s disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels in individuals with AD (n = 419) compared to controls (n = 187). These AD subtypes had alterations in protein levels that were associated with distinct molecular processes: subtype 1 was characterized by proteins related to neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood–brain barrier impairment. Each subtype was related to specific AD genetic risk variants, for example, subtype 1 was enriched with TREM2 R47H. Subtypes also differed in clinical outcomes, survival times and anatomical patterns of brain atrophy. These results indicate molecular heterogeneity in AD and highlight the need for personalized medicine.

PET Imaging of Rho‐Associated Protein Kinase 2 in A Mouse Model of Alzheimer’s Disease

AbstractBackgroundRho‐associated protein kinase 2 (ROCK2) activity is implicated in Alzheimer’s disease (AD) and other central nervous system (CNS) disorders 1. In this study, we investigated the relative expression levels of ROCK2 in APP/PS1 transgenic AD mice and age‐matched wild‐type (WT) C57BL/6J mice using the ROCK2‐specific PET radioligand, [11C]ROCK201.MethodsThe ROCK2 tracer [11C]ROCK201 was synthesized according to the previously published procedure 2. PET scans were performed in a Focus‐220 scanner on 12‐month‐old APP/PS1 transgenic mice (n = 8) and WT controls (n = 5). Self‐blocking scans were performed 10 min post injection (p.i.) of the unlabeled ROCK201 (i.v., 3.3 mg/kg). Regions of interest (ROIs) were extracted from the Ma‐Benveniste‐Mirrione mouse brain atlas and regional time‐activity curves (TACs) were obtained by applying template ROIs to the averaged PET images (0 to 60 min p.i.). Distribution volume ratio (DVR) values were generated using the simplified reference tissue model 2 (SRTM2) on the 60‐min dynamic PET imaging data, with cerebellum (CB) as the reference region. ROCK2 protein expression levels were assessed immunohistochemically in brain tissues of 12‐month‐old APP/PS1 (N = 3) and WT (N = 3) mice.ResultsUptake of [11C]ROCK201 was observed throughout the mouse brain, with peak SUV of 2.6. TACs were consistently higher in the hippocampus of APP/PS1 mice than controls, within 20 min p.i. (Fig. 1a). Reduced uptake was observed in self‐blocking studies, indicating specific binding of [11C]ROCK201 in the rodent brain (Fig. 1a). TACs were well fitted with SRTM2. Compared with age‐matched WT controls, the DVR(CB) in the hippocampus of APP/PS1 mice was 9.3% higher than that of WT mice (p = 0.03) (Fig. 1b). Consistent with PET imaging results, ROCK2 protein expression is elevated by 49±2% in the CA1 of APP/PS1 mice compared to that of WT mice (Fig. 1c).ConclusionsWe demonstrated the uptake and detection sensitivity of the radioligand [11C]ROCK201 in the mouse brain, with higher tracer uptake in the hippocampi of APP/PS1 mice as compared to WT mice, supporting the use of [11C]ROCK201 in preclinical AD drug discovery and development.

PET Imaging of Rho‐Associated Protein Kinase 2 in A Mouse Model of Alzheimer’s Disease

AbstractBackgroundRho‐associated protein kinase 2 (ROCK2) activity is implicated in Alzheimer’s disease (AD) and other central nervous system (CNS) disorders 1. In this study, we investigated the relative expression levels of ROCK2 in APP/PS1 transgenic AD mice and age‐matched wild‐type (WT) C57BL/6J mice using the ROCK2‐specific PET radioligand, [11C]ROCK201.MethodThe ROCK2 tracer [11C]ROCK201 was synthesized according to the previously published procedure 2. PET scans were performed in a Focus‐220 scanner on 12‐month‐old APP/PS1 transgenic mice (n = 8) and WT controls (n = 5). Self‐blocking scans were performed 10 min post injection (p.i.) of the unlabeled ROCK201 (i.v., 3.3 mg/kg). Regions of interest (ROIs) were extracted from the Ma‐Benveniste‐Mirrione mouse brain atlas and regional time‐activity curves (TACs) were obtained by applying template ROIs to the averaged PET images (0 to 60 min p.i.). Distribution volume ratio (DVR) values were generated using the simplified reference tissue model 2 (SRTM2) on the 60‐min dynamic PET imaging data, with cerebellum (CB) as the reference region. ROCK2 protein expression levels were assessed immunohistochemically in brain tissues of 12‐month‐old APP/PS1 (N = 3) and WT (N = 3) mice.ResultUptake of [11C]ROCK201 was observed throughout the mouse brain, with peak SUV of 2.6. TACs were consistently higher in the hippocampus of APP/PS1 mice than controls, within 20 min p.i. (Fig. 1a). Reduced uptake was observed in self‐blocking studies, indicating specific binding of [11C]ROCK201 in the rodent brain (Fig. 1a). TACs were well fitted with SRTM2. Compared with age‐matched WT controls, the DVR(CB) in the hippocampus of APP/PS1 mice was 9.3% higher than that of WT mice (p = 0.03) (Fig. 1b). Consistent with PET imaging results, ROCK2 protein expression is elevated by 49±2% in the CA1 of APP/PS1 mice compared to that of WT mice (Fig. 1c).ConclusionWe demonstrated the uptake and detection sensitivity of the radioligand [11C]ROCK201 in the mouse brain, with higher tracer uptake in the hippocampi of APP/PS1 mice as compared to WT mice, supporting the use of [11C]ROCK201 in preclinical AD drug discovery and development.

Causal Associations Between Plasma Protein Levels and Alzheimer Disease

AbstractBackgroundThe aim of this study was to infer causal relationships between protein levels measured in blood and the risk of late‐onset Alzheimer disease (AD).MethodTwo‐sample Mendelian randomization (MR) was used to infer the causal effect of protein levels on AD risk. Summary statistics from genome‐wide association studies (GWAS) for 4,907 SomaScan aptamers (measuring 4,719 proteins) from Ferkingstad et al. (2021) in 35,559 Icelanders (average age = 55±17years), and for AD GWAS from Bellenguez et al. (2022). Instruments for exposures were selected at p < 5×10−8 and p < 5×10−6 thresholds respectively for the main and sensitivity analyses. Instruments were pruned for linkage disequilibrium (r2 < 0.0001) to ensure selection of independent instruments. Because APOE is highly pleiotropic and exposure effect size is hypothesized by MR not to be larger than the outcome (Steiger filtering), thus variants within ±1MB from APOE were removed in the MR‐analysis. Two tests were considered: Inverse‐Variance‐Weighted and Weighted‐Median, which allows robust MR estimates even when some invalid instruments are included.ResultAmong known AD‐GWAS genes, TREM2, PILRA, ACE, CR1, and BIN1 protein levels were associated with AD. Proteins without prior AD‐GWAS links were also found to be associated with AD including: PPBP, NRP2, AZGP2, and TNFSF13B/BAFF (Figures 1&2). Interestingly, APOE and KLOTHO levels were not associated with AD (Figures 3&4), though increased APOE level significantly associated with increase AD risk when including cis‐APOE variants at p < 5×10−6 (Figure 5).ConclusionOur study informs the directionality of association between certain plasma protein levels and AD risk, and prioritizes candidate proteins to be considered for AD drug development.

Precision medicine analysis of heterogeneity in individual-level treatment response to amyloid beta removal in early Alzheimer's disease.

Alzheimer's disease (AD) is a neurological disorder with variability in pathology and clinical progression. AD patients may differ in individual-level benefit from amyloid beta removal therapy. Random forest models were applied to the EMERGE trial to create an individual-level treatment response (ITR) score which represents individual-level benefit of high-dose aducanumab relative to the placebo. This ITR score was used to test the existence of heterogeneity in treatment effect (HTE). We found statistical evidence of HTE in the Clinical Dementia Rating-Sum of Boxes (CDR-SB;P= 0.034). The observed CDR-SB benefit was 0.79 points greater in the group with the top 25% of ITR score compared to the remaining 75% (P=0.020). Of note, the highest treatment responders had lower hippocampal volume, higher plasma phosphorylated tau 181 and a shorter duration of clinical AD at baseline. This ITR analysis provides a proof of concept for precision medicine in future AD research and drug development. Emerging trials have shown a population-level benefit from amyloid beta (Aβ) removal in slowing cognitive decline in early Alzheimer's disease (AD). This work demonstrates significant heterogeneity of individual-level treatment effect of aducanumab in early AD. The greatest clinical responders to Aβ removal therapy have a pattern of more severe neurodegenerative process.

Alzheimer's Disease: Novel Targets and Investigational Drugs for Disease Modification.

Novel agents addressing non-amyloid, non-tau targets in Alzheimer's Disease (AD) comprise 70% of the AD drug development pipeline of agents currently in clinical trials. Most of the target processes identified in the Common Alzheimer's Disease Research Ontology (CADRO) are represented by novel agents in trials. Inflammation and synaptic plasticity/neuroprotection are the CADRO categories with the largest number of novel candidate therapies. Within these categories, there are few overlapping targets among the test agents. Additional categories being evaluated include apolipoprotein E [Formula: see text] 4 (APOE4) effects, lipids and lipoprotein receptors, neurogenesis, oxidative stress, bioenergetics and metabolism, vascular factors, cell death, growth factors and hormones, circadian rhythm, and epigenetic regulators. We highlight current drugs being tested within these categories and their mechanisms. Trials will be informative regarding which targets can be modulated to produce a slowing of clinical decline. Possible therapeutic combinations of agents may be suggested by trial outcomes. Biomarkers are evolving in concert with new targets and novel agents, and biomarker outcomes offer a means of supporting disease modification by the putative treatment. Identification of novel targets and development of corresponding therapeutics offer an important means of advancing new treatments for AD.

Capturing Measures That Matter: The Potential Value of Digital Measures of Physical Behavior for Alzheimer's Disease Drug Development.

Alzheimer's disease (AD) is a devastating neurodegenerative disease and the primary cause of dementia worldwide. Despite the magnitude of AD's impact on patients, caregivers, and society, nearly all AD clinical trials fail. A potential contributor to this high rate of failure is that established clinical outcome assessments fail to capture subtle clinical changes, entail high burden for patients and their caregivers, and ineffectively address the aspects of health deemed important by patients and their caregivers. AD progression is associated with widespread changes in physical behavior that have impacts on the ability to function independently, which is a meaningful aspect of health for patients with AD and important for diagnosis. However, established assessments of functional independence remain underutilized in AD clinical trials and are limited by subjective biases and ceiling effects. Digital measures of real-world physical behavior assessed passively, continuously, and remotely using digital health technologies have the potential to address some of these limitations and to capture aspects of functional independence in patients with AD. In particular, measures of real-world gait, physical activity, and life-space mobility captured with wearable sensors may offer value. Additional research is needed to understand the validity, feasibility, and acceptability of these measures in AD clinical research.