Pharmacotherapies for the Treatment of Progressive Supranuclear Palsy: A Narrative Review.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder resulting from the deposition of misfolded and neurotoxic forms of tau protein in specific areas of the midbrain, basal ganglia, and cortex. It is one of the most representative forms of tauopathy. PSP presents in several different phenotypic variations and is often accompanied by the development of concurrent neurodegenerative disorders. PSP is universally fatal, and effective disease-modifying therapies for PSP have not yet been identified. Several tau-targeting treatment modalities, including vaccines, monoclonal antibodies, and microtubule-stabilizing agents, have been investigated and have had no efficacy. The need to treat PSP and other tauopathies is critical, and many clinical trials investigating tau-targeted treatments are underway. In this review, the PubMed database was queried to collect information about preclinical and clinical research on PSP treatment. Additionally, the US National Library of Medicine's ClinicalTrials.gov website was queried to identify past and ongoing clinical trials relevant to PSP treatment. This narrative review summarizes our findings regarding these reports, which include potential disease-modifying drug trials, modifiable risk factor management, and symptom treatments.

Nonmedication Devices in Development for the Treatment of Alzheimer's Disease.

 Huge investments continue to be made in treatment for Alzheimer's disease (AD), with more than one hundred drugs currently in development. Pharmacological approaches and drug development, particularly those targeting amyloid-ß, have dominated the therapeutic landscape. At the same time, there is also a growing interest in devices for treating AD. This review aimed to identify and describe devices under development for AD treatment. In this review, we queried the devices that are in development for the treatment of AD. PubMed was searched through the end of 2021 using the terms "device," "therapeutics," and "Alzheimer's" for articles that report on devices to treat AD. Ten devices with 31 references were identified as actively being developed for the treatment of AD. Many of these devices are far along in development. Device-based therapies are often overlooked when evaluating treatment approaches to AD. However, many devices for treating AD are in development and some show promising results.

Pharmacological Approaches Using Diabetic Drugs Repurposed for Alzheimer's Disease.

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are chronic, progressive disorders affecting the elderly, which fosters global healthcare concern with the growing aging population. Both T2DM and AD have been linked with increasing age, advanced glycosylation end products, obesity, and insulin resistance. Insulin resistance in the periphery is significant in the development of T2DM and it has been posited that insulin resistance in the brain plays a key role in AD pathogenesis, earning AD the name "type 3 diabetes". These clinical and epidemiological links between AD and T2DM have become increasingly pronounced throughout the years, and serve as a means to investigate the effects of antidiabetic therapies in AD, such as metformin, intranasal insulin, incretins, DPP4 inhibitors, PPAR-γ agonists, SGLT2 inhibitors. The majority of these drugs have shown benefit in preclinical trials, and have shown some promising results in clinical trials, with the improvement of cognitive faculties in participants with mild cognitive impairment and AD. In this review, we have summarize the benefits, risks, and conflicting data that currently exist for diabetic drugs being repurposed for the treatment of AD.

Cancer drugs with high repositioning potential for Alzheimer's disease.

INTRODUCTION: Despite the recent full FDA approval of lecanemab, there is currently no disease modifying therapy (DMT) that can efficiently slow down the progression of Alzheimer's disease (AD) in the general population. This statement emphasizes the need to identify novel DMTs in the shortest time possible to prevent a global epidemic of AD cases as the world population experiences an increase in lifespan. AREAS COVERED: Here, we review several classes of anti-cancer drugs that have been or are being investigated in Phase II/III clinical trials for AD, including immunomodulatory drugs, RXR agonists, sex hormone therapies, tyrosine kinase inhibitors, and monoclonal antibodies. EXPERT OPINION: Given the overall course of brain pathologies during the progression of AD, we express a great enthusiasm for the repositioning of anti-cancer drugs as possible AD DMTs. We anticipate an increasing number of combinatorial therapy strategies to tackle AD symptoms and their underlying pathologies. However, we strongly encourage improvements in clinical trial study designs to better assess target engagement and possible efficacy over sufficient periods of drug exposure.

Type 2 Diabetes Comorbidity and Cognitive Decline in Patients with Alzheimer's Disease.

BACKGROUND: Although insulin dysregulation and resistance likely participate in Alzheimer's disease (AD) etiologies, little is known about the correlation between type 2 diabetes mellitus (T2DM) and the progression of cognitive decline in patients with AD. OBJECTIVE: To determine whether AD patients with T2DM experience more rapid cognitive decline than those without T2DM. METHODS: All cognitive performance data and the presence or absence of T2DM comorbidity in patients with AD were derived from the US National Alzheimer's Coordinating Center's (NACC) Uniform Data Set (UDS). A search of the UDS identified 3,055 participants with AD who had more than one epoch completed. The data set culled clinically diagnosed AD dementia patients who were assessed for diabetes type identified during at least 1 visit. These patients were divided into 2 groups based on whether they had a diagnosis of T2DM. The data from these groups were then analyzed for differences in cognitive decline based on neuropsychological test battery scores and a Clinician Dementia Rating using a general linear model. RESULTS: Comparisons of the mean scores for 16 selected tests from the neuropsychological test battery showed no significant differences in baseline scores and scores at subsequent visits between the T2DM and nondiabetic groups. CONCLUSIONS: The results revealed no differences in cognitive decline metrics over the course of 5 visits in either study group. These data indicate that the presence of T2DM does not increase the rate of cognitive decline in AD. This finding contradicts expected disease burden and will need to be explored further.

Lecanemab (BAN2401): an anti-beta-amyloid monoclonal antibody for the treatment of Alzheimer disease.

INTRODUCTION: Nearly a dozen monoclonal antibodies (mAbs) directed against beta-amyloid (Aß) have been developed for the treatment of Alzheimer disease (AD), and most of these mAbs are undergoing clinical trials. Newer mAbs have targeted more specific Aß types. Lecanemab Eisai has a high affinity for large and soluble Aß protofibrils. Data from phase 2 clinical trials have suggested the possibility of a robust efficacy signal and manageable risk of amyloid-related imaging abnormalities (ARIAs). Lecanemab is currently being studied in phase 3 trials. AREAS COVERED: This article briefly reviews mAbs that target Aß in AD and discusses the biology, mechanism of action, and targets of lecanemab. EXPERT OPINION: mAbs that target Aß are an important focus of therapeutic development for AD, with several soon to be considered for US Food and Drug Administration approval. The experience of aducanumab informs the development of other mAbs, such as lecanemab. One consideration is the conformation of Aß targets. Targeting monomeric species has not resulted in robust clinical efficacy, whereas targeting Aß in the form of oligomers, protofibrils, and plaques has shown evidence of slowing clinical decline. Another consideration is that mAbs will require safety monitoring for ARIAs.

Review of Advanced Drug Trials Focusing on the Reduction of Brain Beta-Amyloid to Prevent and Treat Dementia.

Alzheimer disease (AD) is the most common neurodegenerative disease and typically affects patients older than age 65. Around this age, the number of neurons begins to gradually decrease in healthy brains, but brains of patients with AD show a marked increase in neuron death, often resulting in a significant loss of cognitive abilities. Cognitive skills affected include information retention, recognition capabilities, and language skills. At present, AD can be definitively diagnosed only through postmortem brain biopsies via the detection of extracellular amyloid beta (Aß) plaques and intracellular hyperphosphorylated tau neurofibrillary tangles. Because the levels of both Aß plaques and tau tangles are increased, these 2 proteins are thought to be related to disease progression. Although relatively little is known about the cause of AD and its exact pathobiological development, many forms of treatment have been investigated to determine an effective method for managing AD symptoms by targeting Aß. These treatments include but are not limited to using small molecules to alter the interactions of Aß monomers, reducing hyperactivation of neuronal circuits altering Aß's molecular pathway of synthesis, improving degradation of Aß, employing passive immunity approaches, and stimulating patients' active immunity to target Aß. This review summarizes the current therapeutic interventions in Phase II/III of clinical development or higher that are capable of reducing abnormal brain Aß levels to determine which treatments show the greatest likelihood of clinical efficacy. We conclude that, in the near future, the most promising therapeutic interventions for brain Aß pathology will likely be passive immunotherapies, with aducanumab and donanemab leading the way, and that these drugs may be combined with antidepressants and acetylcholine esterase inhibitors, which can modulate Aß synthesis.

COR388 (atuzaginstat): an investigational gingipain inhibitor for the treatment of Alzheimer disease.

INTRODUCTION: Evidence from in vitro and in vivo studies demonstrates that amyloid beta (Aß) oligomers have potent, broad-spectrum antimicrobial properties created by fibrils that entrap pathogens and disrupt their membranes. Data suggest that Aß may play a protective role in the innate immune response to microbial infections and that Aß in the brain plays a damaging role when the inflammatory response is not well controlled. AREAS COVERED: This paper describes the relationship between periodontal disease and Alzheimer disease (AD), the role of Porphyromonas gingivalis and its secreted gingipains in AD, and the potential of the gingipain inhibitor atuzaginstat (COR388) to modulate AD neuropathologies. EXPERT OPINION: P. gingivalis is opsonized by Aß42, is capable of entering the brain, and is an accelerant of neuropathologies in rodent models of AD. Thus, in our opinion, this bacteria is highly likely to be a pathogen capable of initiating or precipitating the progression of AD, which agrees with the pathogen hypothesis of clinical AD development.

The Cause of Alzheimer's Disease: The Theory of Multipathology Convergence to Chronic Neuronal Stress.

The field of Alzheimer's disease (AD) research critically lacks an all-inclusive etiology theory that would integrate existing hypotheses and explain the heterogeneity of disease trajectory and pathologies observed in each individual patient. Here, we propose a novel comprehensive theory that we named: the multipathology convergence to chronic neuronal stress. Our new theory reconsiders long-standing dogmas advanced by previous incomplete theories. Firstly, while it is undeniable that amyloid beta (Aß) is involved in AD, in the seminal stage of the disease Aß is unlikely pathogenic. Instead, we hypothesize that the root cause of AD is neuronal stress in the central nervous system (CNS), and Aß is expressed as part of the physiological response to protect CNS neurons from stress. If there is no return to homeostasis, then Aß becomes overexpressed, and this includes the generation of longer forms that are more toxic and prone to oligomerization. Secondly, AD etiology is plausibly not strictly compartmentalized within the CNS but may also result from the dysfunction of other physiological systems in the entire body. This view implies that AD may not have a single cause, but rather needs to be considered as a spectrum of multiple chronic pathological modalities converging to the persistent stressing of CNS neurons. These chronic pathological modalities, which include cardiovascular disease, metabolic disorders, and CNS structural changes, often start individually, and over time combine with other chronic modalities to incrementally escalate the amount of stress applied to CNS neurons. We present the case for considering Aß as a marker of neuronal stress in response to hypoxic, toxic, and starvation events, rather than solely a marker of AD. We also detail numerous human chronic conditions that can lead to neuronal stress in the CNS, making the link with co-morbidities encountered in daily clinical AD practice. Finally, we explain how our theory could be leveraged to improve clinical care for AD and related dementia in personalized medicine paradigms in the near future.

Is diabetes associated with increased pathological burden in Alzheimer's disease?

INTRODUCTION: We examined the association between Alzheimer's disease (AD) and type 2 diabetes mellitus (DM) and hypothesized that diabetes is associated with an increased pathological burden in clinically and pathologically diagnosed AD. METHODS: All data were obtained from the Uniform Data Set (UDS) v3, the Neuropathology Data Set, and the Researcher's Data Dictionary-Genetic Data from the National Alzheimer's Coordinating Center. The dataset (37 cases with diabetes and 1158 cases without) relies on autopsy-confirmed data in clinically diagnosed AD patients who were assessed for diabetes type in form A5 or D2 during at least one visit. Differences in scores were explored using a general linear model. Effect sizes were calculated using sample means and standard deviations (Cohen's d). RESULTS: The presence of diabetes was associated with a lower Thal phase of amyloid plaques (A score; 4.6 ± 0.79 vs. 4.3 ± 0.85, P < .05) and lower Braak stage for neurofibrillary degeneration (B score; 5.58 ± 0.72 vs. 5.16 ± 0.96, P < 0.05) but not for density of neocortical neuritic plaques (CERAD score-C score). The National Institute on Aging-Alzheimer's Association Alzheimer's disease neuropathologic change (ABC score) was not different between AD+DM and AD-DM. DISCUSSION: This pilot study found a significantly lower Thal phase of amyloid plaques and Braak stage for neurofibrillary degeneration in AD-confirmed individuals with diabetes compared to those without. Thus type 2 DM is not associated with increased AD pathology in clinically and pathologically confirmed cases of AD.

Critical Appraisal of Amyloid Lowering Agents in AD.

PURPOSE OF REVIEW: According to the amyloid cascade hypothesis, removing amyloid beta (Aß) should cure Alzheimer's disease (AD). In the past three decades, many agents have been tested to try to lower Aß production, prevent Aß aggregation, and dissolve Aß deposits. However, the paucity in definitive preventative or curative properties of these agents in clinical trials has resulted in more avant-garde approaches to therapeutic investigations. Immunotherapy has become an area of focus for research on disease-modifying therapies for neurodegenerative diseases. In this review, we highlight the current clinical development landscape of monoclonal antibody (mAb) therapies that target Aß plaque formation and removal in AD. RECENT FINDINGS: Multiple potential disease-modifying therapeutics for AD are in active development. Targeting Aß with mAbs has the potential to treat various stages of AD: prodromal, prodromal to mild, mild, and mild to moderate. Monoclonal antibodies discussed here include aducanumab, lecanemab, solanezumab, crenezumab, donanemab, and gantenerumab. The final decision by the FDA regarding the approval of aducanumab will offer valuable insight into the trajectory of drug development for mAbs in AD and other neurodegenerative diseases. Future directions for improving the treatment of AD will include more inquiry into the efficacy of mAbs as disease-modifying agents that specifically target Aß peptides and/or multimers. In addition, a more robust trial design for AD immunotherapy agents should improve outcomes such that objective measures of clinical efficacy will eventually lead to higher chances of drug approval.

Does Informant-Based Reporting of Cognitive Decline Correlate with Age-Adjusted Hippocampal Volume in Mild Cognitive Impairment and Alzheimer's Disease?

BACKGROUND: Informant-based measures are effective screening tools for cognitive impairment. The Alzheimer's Questionnaire (AQ) is a subjective, informant-based measure that detects amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) with high sensitivity and specificity and has been shown to predict amyloid burden. OBJECTIVE: To determine whether informant-based report of cognitive decline correlates with hippocampal volume changes in MCI and AD. METHODS: Retrospective chart review of 139 clinically referred patients with clinical diagnoses of aMCI or mild dementia due to AD was conducted. Diagnostic status (clinical diagnosis made by a neurologist), NeuroQuant measured MRI brain with percentile rank hippocampal volume, Montreal Cognitive Assessment (MoCA) total, AQ-Total score, and demographic variables were extracted from medical records. Spearman correlation was used to assess the relationship between hippocampal volume and AQ-Total. The AQ was used to assign diagnostic status. Thus, the relationship between the AQ and diagnostic status was excluded. RESULTS: The sample include 88 female and 51 male participants. The mean age was 74.37±9.45, mean MOCA was 22.65±4.18, mean education was 14.80±3.35, and mean AQ score was 10.54±5.22. Hippocampal volume and the AQ correlation was r = -0.33 [95%CI -0.47 to -0.17], p < 0.0001. CONCLUSION: In a mixed-clinical sample of patients presenting to an outpatient memory disorders center, higher endorseme-nts of functional impairments by caregivers were significantly associated with smaller hippocampal volumes. When used in conjunction with other available measures, these findings further support the role of the AQ in clinical decision-making and demonstrate an additional relationship between clinical measures and volumetric MRI.

Dementia with Lewy bodies: emerging drug targets and therapeutics.

Introduction: Dementia with Lewy bodies (DLB) is characterized by the toxic accumulation of α-synuclein protein inside neural cells; this results in neurodegeneration which is clinically accompanied by behavioral and psychological changes. DLB shares features with Parkinson's disease (PD) and Parkinson's disease dementia (PDD), but also overlaps neurochemically and pathologically with Alzheimer's disease. Symptomatic treatments for LBD differ in their effectiveness while disease-modifying and curative approaches are much needed.Areas covered: We explore emerging therapeutics for DLB through the lens of repurposing approved drugs and survey their potential for disease modifying actions in DLB. Given the complexity of DLB with multiple pathologies, potential therapeutic targets that could affect Lewy body pathology, or metabolism or neurotransmitters or immunomodulation were surveyed. We queried PubMed and ClinicalTrials.gov searches 2017-2020.Expert opinion: DLB is not simply aredux ofAD or PD; hence, treatments should not be exclusively duplicative ofAD or PD directed treatments. This opens amyriad of possibilities for therapeutic approaches that are disease specific or repurposed.

Therapeutic considerations for APOE and TOMM40 in Alzheimers disease: A tribute to Allen Roses MD.

Introduction: Four years ago this Autumn, pioneering neurologist Prof. Allen. D. Roses passed away. Hence, we have taken time to reflect on his work and legacy in Alzheimer's disease (AD) research. Prof. Roses rejected the widely accepted amyloid hypothesis, which identifies amyloid beta (Aß) protein accumulation within the brain as the cause of AD. Instead, he proposed that the epsilon type 4 allele of apolipoprotein (APOE- Ɛ4) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) were preeminent factors in the pathogenesis and progression of AD, particularly in late-onset AD (LOAD). This rejection of the amyloid hypothesis has generated new investigations into APOE and TOMM40 as risk factors for AD. Areas covered: We discuss the contributions of Prof. Roses to AD research, describe how APOE-Ɛ4 and TOMM40 have been posited to trigger neuropathological changes leading to AD, and explore paths to future clinical applications built on the foundations of his research. Expert opinion: The unconventional methodology of targeting APOE and TOMM40 offers great potential for the development of effective preventive and disease-modifying AD interventions. Future preclinical and clinical investigations will greatly benefit from the groundbreaking scientific discoveries of Prof. Roses.

MCLENA-1: A Phase II Clinical Trial for the Assessment of Safety, Tolerability, and Efficacy of Lenalidomide in Patients with Mild Cognitive Impairment Due to Alzheimer's Disease.

With the general population reaching higher ages, a surge in Alzheimer's disease (AD) incidence will happen in the coming decades, putting a heavy burden on families and healthcare systems Worldwide. This emphasizes the pressing need for AD therapeutic interventions. Accumulating evidence indicates that inflammation is prominent both in the blood and central nervous system of AD sufferers. These data suggest that systemic inflammation plays a crucial role in the cause and effects of AD neuropathology. Capitalizing on our experience from a previous clinical trial with thalidomide, we hypothesize that modulating inflammation via the pleiotropic immunomodulator lenalidomide may alter AD if administered during a proper time window in the course of the disease. Thus, in this Phase II, proof-of mechanism study, 30 amnestic mild cognitive impairment (aMCI) subjects will be treated with lenalidomide at 10 mg/day for 12 months on a 1:1 ratio, followed by a 6 months washout period. The primary objective of this study is to investigate the effect of lenalidomide on cognition, which is assessed at regular intervals. The secondary objective is to assess the safety and tolerability of lenalidomide in aMCI patients evaluated through adverse events, vital signs, clinical biochemistry, and physical and neurological examinations. Tertiary objectives are to analyze the effects of lenalidomide on brain amyloid loads (Florbetapir PET imaging) and neurodegeneration (volumetric MRI) by comparing pre- and post-dosing data. Finally, exploratory objectives will investigate whether blood inflammatory markers can serve as surrogate markers of therapeutic efficacy. Our study should determine whether lenalidomide is safe in AD subjects and whether it can alter the clinical progression of AD when administered before dementia onset. If effective, lenalidomide would become the first drug capable of delaying the trajectory of AD, which could lead the way to find additional, less toxic treatments in the near future.

Clinical drug development for dementia with Lewy bodies: past and present.

Introduction: Dementia with Lewy bodies (DLB) is an under-researched area despite being the second most common type of degenerative dementia after Alzheimer's disease. It is an area of unmet need with no approved symptomatic or disease-modifying therapies. The pharmacological management of DLB is complex and challenging because early trials of drugs for DLB have resulted in no demonstrable efficacy. Randomized controlled trials (RCTs) in the DLB population have only recently been initiated. Understanding results from previous and current clinical trials in DLB can provide insights for future research and development.Areas covered: We provide an overview of the DLB drug development landscape and the current treatment strategies. We reviewed ClinicalTrials.gov to identify all clinical trials for the treatment of DLB.Expert opinion: DLB drug development has significantly improved in recent years with eight agents now in clinical trials. However, more rigorous RCTs are urgently needed. Diagnostic criteria must be optimized to accurately diagnose patients for clinical trials and care. New biomarker strategies are necessary to improve diagnostic capabilities and trial designs, and novel drug targets should be identified to develop DLB specific disease-modifying therapies. Evaluating the current drug development landscape can provide insight into how best to optimize development practices.

Tau immunotherapies for Alzheimer's disease.

INTRODUCTION: Alzheimer's dementia (AD) is the most common form of dementia in the World. Pathologically, it is characterized by extracellular ß-amyloid plaques and intraneuronal neurofibrillary tangles (NFTs). The latter is composed of irregular, pathological forms of the tau protein. Currently, FDA-approved symptomatic treatments are limited to the targeting of cholinergic deficits and glutamatergic dysfunctions. However, as understanding of ß-amyloid plaques and NFTs expands, these dysfunctional proteins represent potential therapeutic interventions. The present review article evaluates active and passive immunotherapies in clinical development for AD to date and their potential to significantly improve the treatment of AD going forward. AREAS COVERED: All clinical trials that have targeted ß-amyloid to date have produced somewhat disappointing results, leading to a shift in intervention focus to targeting tau protein. A key component in understanding the value of targeting tau in therapeutic paradigms has come from the conceptualization of prion-like pathological spread of tau isoforms from neuron to neuron, and referred to as 'tauons'. Immunotherapies currently under investigation include approaches aiming at preventing pathological tau aggregation, stabilizing microtubules, and blocking of tauons. EXPERT OPINION: A multi-targeted approach that would use biologics targeting tau offers great promise to the development of effective AD therapeutic interventions.