Search

Human apolipoprotein E (apoE) is a 299-amino acid secreted glycoprotein binding cholesterol and phospholipids, and with three common isoforms (APOE ε2, APOE ε3, and APOE ε4). The exact mechanism by which APOE gene variants increase/decrease Alzheimer's disease (AD) risk is not fully understood, but APOE isoforms differently affect brain homeostasis and neuroinflammation, blood–brain barrier (BBB) permeability, glial function, synaptogenesis, oral/gut microbiota, neural networks, amyloid beta (Aβ) deposition, and tau-mediated neurodegeneration. In this perspective, we propose a comprehensive interpretation of APOE-mediated effects within AD pathophysiology, describing some specific cellular, biochemical, and epigenetic mechanisms and updating the different APOE-targeting approaches being developed as potential AD therapies. Intracisternal adeno-associated viral-mediated delivery of APOE ε2 is being tested in AD APOE ε4/ε4 carriers, while APOE mimetics are being used in subjects with perioperative neurocognitive disorders. Other approaches including APOE ε4 antisense oligonucleotides, anti-APOE ε4 monoclonal antibodies, APOE ε4 structure correctors, and APOE–Aβ interaction inhibitors produced positive results in transgenic AD mouse models.

Alzheimer's disease (AD) is the main cause of dementia and represents a huge burden for patients, carers, and healthcare systems. Extensive efforts for over 20 years have failed to find effective disease-modifying drugs. Although amyloid-β (Aβ) accumulation in the brain predicts cognitive decline, effective reduction of plaque load by numerous drug candidates has not yielded significant clinical benefits. A similar pattern is now emerging for drugs which target hyperphosphorylated tau, and trials with anti-inflammatory drugs have been negative despite neuroinflammation appearing to have a crucial role in AD pathogenesis.This article reviews key drugs that have been discontinued while in development for AD and delineates the future landscape for present and alternative approaches.Anti-Aβ drugs have failed to validate the Aβ cascade hypothesis of AD. Early findings suggest that the same is happening with therapeutics targeting tau and focussing future research solely on anti-tau drugs is inappropriate. Alternative targets should be pursued, including apolipoprotein E, immunomodulation, plasma exchange, protein autophagy and clearance, mitochondrial dysfunction, abnormal glucose metabolism, neurovascular unit support, epigenetic dysregulation, synaptic loss and dysfunction, microbiota dysbiosis, and combination therapies. Meanwhile, repurposing of drugs approved for other indications is justified where scientific rationale and robust preclinical evidence exist.

Alzheimer's Disease (AD) represents a large and growing challenge to patients, carers and healthcare systems, yet extensive efforts to develop therapeutics to modify its course have been met with repeated failure in recent decades. Although the evident presence of accumulated β-amyloid (Aβ) in AD brains has singled it out as an obvious therapeutic target, the effective reduction of plaque load or soluble Aβ by numerous drug candidates has not produced commensurate clinical benefits - calling into question the Aβ cascade hypothesis of AD. A similar path is now unfolding in the pursuit of therapeutics targeting hyperphosphorylated tau-comprised neurofibrillary tangles.This perspective reviews the basis of the Aβ cascade hypothesis of AD and how clinical trials of anti-Aβ drugs have failed to support it, and reflects upon the early findings suggesting that a similar path is being followed with therapeutics targeting tau. Other potential approaches to identifying therapeutics for AD are explored herein.The relevance of the Aβ cascade hypothesis to the development of therapeutics for AD appears disproven. Drugs targeting tau appear to be suffering the same fate but may yet produce better results. Alternative approaches are being pursued, some of them with initial small-scale, but promising, results.

According to the β-amyloid (Aβ) hypothesis of Alzheimer's disease (AD), brain Aβ accumulation is the primary cascade event leading to cognitive deficit and dementia. Numerous anti-Aβ drugs either inhibiting production or aggregation of Aβ or stimulating its clearance have failed to show clinical benefit in large scale AD trials, with β- and γ-secretase inhibitors consistently worsening cognitive and clinical decline. In June 2021, the FDA approved aducanumab, an anti-Aβ monoclonal antibody for early AD based on its ability to reduce brain amyloid plaques, while two other amyloid-clearing antibodies (lecanemab and donanemab) have recently produced encouraging cognitive and clinical results. We reviewed AD trials using PubMed, meeting abstracts and ClinicalTrials.gov and evaluated the effects of such drugs on cerebrospinal fluid (CSF) Aβ levels, correlating them with cognitive effects. We found that β-secretase and γ-secretase inhibitors produce detrimental cognitive effects by significantly reducing CSF Aβ levels. We speculate that monoclonal antibodies targeting Aβ protofibrils, fibrils or plaques may improve cognitive performance in early AD by increasing soluble Aβ levels through Aβ aggregate disassembly and/or stabilization of existing Aβ monomers.These findings suggest that the real culprit in AD may be decreased levels of soluble monomeric Aβ due to sequestration into brain Aβ aggregates and plaques.

In the last 15 years, huge efforts against Alzheimer's disease (AD) with drugs targeting β-amyloid (Aβ) and tau have produced poor clinical results. Aducanumab, a recently FDA-approved anti-Aβ monoclonal antibody has been greeted with distrust by most experts, hospitals and insurance companies for its level of efficacy and poor tolerability.We reviewed literature on Alzheimer trials using PubMed, meeting abstracts and ClnicalTrials.gov and discuss what we can learn from past failures of investigational drugs for Alzheimer's disease, especially anti-Aβ and anti-tau drugs.It is our opinion that previous failures of anti-AD drugs suggest that soluble Aβ and tau are not appropriate drug targets. In addition, pivotal clinical trials of future clinical candidates should avoid major protocol amendments and futility analyses. Study protocols should adopt better measures to protect study blinding and minimize the potential introduction of major biases in the evaluation of clinical results. Finally, alternative biological targets should be pursued as well as more multimodal approaches to addressing neurodegeneration in AD.

Introduction Primary tauopathies are neurological disorders in which tau protein deposition is the predominant pathological feature. Alzheimer's disease is a secondary tauopathy with tau forming hyperphosphorylated insoluble aggregates. Tau pathology can propagate from region to region in the brain, while alterations in tau processing may impair tau physiological functions. Methods We reviewed literature on tau biology and anti-tau drugs using PubMed, meeting abstracts, and ClnicalTrials.gov. Results The past 15 years have seen >30 drugs interfering with tau aggregation, processing, and accumulation reaching the clinic. Initial results with tau aggregation inhibitors and anti-tau monoclonal antibodies have not shown clinical efficacy. Discussion The reasons for these clinical failures are unclear but could be linked to the clearing of physiological forms of tau by non-specific drugs. Research is now concentrating efforts on developing reliable translational animal models and selective compounds targeting specific tau epitopes, neurotoxic tau aggregates, and post-translational tau modifications.

The amyloid-β (Aβ) cascade hypothesis of the Alzheimer’s disease (AD) assumes that the brain accumulation of this 40–42 amino acid peptide represents the initial event of the pathological process a...

Introduction: As the global burden of Alzheimer's disease (AD) grows, an effective disease-modifying therapy remains a distant prospect following the repeated failure of multiple therapeutics targeting β-amyloid and (it seems) tau over many years of costly effort. The repeated failure of single-target therapies to meaningfully modify disease progression raises major questions about the validity of many aspects of drug development in this area, especially target selection.Area covered: The authors explore the critical questions raised by a review of the collective experience to date, relating to why findings with non-clinical models and clinical biomarkers so frequently fail to translate to positive outcomes in clinical trials, which alternatives should be considered, and how we can design and conduct clinical trials that can successfully identify and quantify meaningful benefits in the future.Expert opinion: It is our opinion that we must recognize and accept the need to consider less specific, more multimodal approaches to addressing neurodegeneration in AD if we are to make progress - and we must avoid repeating the well intentioned, but ultimately erroneous, assumptions of the past.

Neuroinflammation, a key early pathomechanistic alteration of Alzheimer’s disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a longitudinal study in a monocentric cohort of cognitively healthy individuals at risk for Alzheimer’s disease exploring whether age, sex, and the apolipoprotein E e4 allele affect plasma YKL-40 concentrations. We investigated whether YKL-40 is associated with brain amyloid-β (Aβ) deposition, neuronal activity, and neurodegeneration as assessed via neuroimaging biomarkers. Finally, we investigated whether YKL-40 may predict cognitive performance. We found an age-associated increase of YKL-40 and observed that men display higher concentrations than women, indicating a potential sexual dimorphism. Moreover, YKL-40 was positively associated with memory performance and negatively associated with brain Aβ deposition (but not with metabolic signal). Consistent with translational studies, our results suggest a potentially protective effect of glia on incipient brain Aβ accumulation and neuronal homeostasis.

Dementia with Lewy bodies (DLB) has no approved symptomatic or disease-modifying treatments in the US and Europe, despite being the second most common cause of neurodegenerative dementia.Herein, the authors briefly review the DLB drug development pipeline, providing a summary of the current pharmacological intervention studies. They then focus on the anticonvulsant zonisamide, a benzisoxazole derivative with a sulfonamide group and look at its value for treating parkinsonism in DLB.Several new compounds are being tested in DLB, the most innovative being those aimed at decreasing brain accumulation of α-synuclein. Unfortunately, new drug testing is challenging in terms of consistent diagnostic criteria and lack of reliable biomarkers. Few randomized controlled trials (RCTs) are well-designed, with enough power to detect significant drug effects. Levodopa monotherapy can treat the parkinsonism in DLB, but it can cause agitation or visual hallucination worsening. Two Phase II/III RCTs of DLB patients recently reported a statistically significant improvement in motor function in those receiving zonisamide as an adjunctive treatment to levodopa. New biomarker strategies and validated outcome measures for DLB or prodromal DLB may enhance clinical trial design for the development of specific disease-modifying treatments.

The dominant theory of Alzheimer disease (AD) has been that amyloid-β (Aβ) accumulation in the brain is the initial cause of the degeneration leading to cognitive and functional deficits. Autosomal dominant Alzheimer disease (ADAD), in which pathologic mutations of the amyloid precursor protein (APP) or presenilins (PSENs) genes are known to cause abnormalities of Aβ metabolism, should thus offer perhaps the best opportunity to test anti-Aβ drugs. Two long-term preventive studies (Dominantly Inherited Alzheimer Network Trials Unit Adaptive Prevention Trial [DIAN-TU-APT] and Alzheimer Preventive Initiative–ADAD) were set up to evaluate the efficacy of monoclonal anti-Aβ antibodies (solanezumab, gantenerumab, and crenezumab) in carriers of ADAD, but the results of the DIAN-TU-APT study have shown that neither solanezumab nor gantenerumab slowed cognitive decline in 144 subjects with ADAD followed for 4 years, despite one of the drugs (gantenerumab) significantly affected biomarkers relevant to their intended mechanism of action. Surprisingly, solanezumab significantly accelerated cognitive decline of both asymptomatic and symptomatic subjects. These failures further undermine the Aβ hypothesis and could support the suggestion that ADAD is triggered by accumulation of other APP metabolites, rather than Aβ.

Frontotemporal dementia (FTD) encompasses a spectrum of clinical syndromes characterized by progressive executive, behavioural and language dysfunction. The various FTD spectrum disorders are associated with brain accumulation of different proteins: tau, the transactive response DNA binding protein of 43 kDa (TDP43), or fused in sarcoma (FUS) protein, Ewing sarcoma protein and TATA-binding protein-associated factor 15 (TAF15) (collectively known as FET proteins). Approximately 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN or MAPT genes. Currently available treatments are symptomatic and provide limited benefit. However, the increased understanding of FTD pathogenesis is driving the development of potential disease-modifying therapies. Most of these drugs target pathological tau — this category includes tau phosphorylation inhibitors, tau aggregation inhibitors, active and passive anti-tau immunotherapies, and MAPT-targeted antisense oligonucleotides. Some of these therapeutic approaches are being tested in phase II clinical trials. Pharmacological approaches that target the effects of GRN and C9orf72 mutations are also in development. Key results of large clinical trials will be available in a few years. However, clinical trials in FTD pose several challenges, and the development of specific brain imaging and molecular biomarkers could facilitate the recruitment of clinically homogenous groups to improve the chances of positive clinical trial results. In this Review, Panza and colleagues provide an overview of the current understanding of pathogenic mechanisms of frontotemporal dementia spectrum disorders and discuss how this knowledge is driving the development of potential disease-modifying drugs.

Purpose PI3Ks are potential therapeutic targets in immune-inflammatory diseases. These studies aimed to investigate the safety, tolerability and PK profile of seletalisib, a selective inhibitor of PI3Kδ in humans. Methods These phase I, randomised, double-blind, placebo-controlled, single-centre studies (NCT02303509, NCT02207595) evaluated single and multiple oral doses of seletalisib (5–90 mg QD and 30 mg BID) in healthy adults and subjects with mild-to-moderate psoriasis (Study-1). Pharmacodynamic effects on markers of inflammation were assessed via changes in ex vivo basophil degranulation and histological assessment of psoriatic skin biopsies. Results Seletalisib was well tolerated at doses ≤15 mg (Study-1) and ≤45 mg QD (Study-2) for 14 days. No safety concerns or dose-limiting toxicities were identified (Study-1). Incidence of gastrointestinal-related AEs was not dose related but higher incidences of rash AEs were associated with higher-dose seletalisib (Study-2 rash AEs: 18 in 12 seletalisib-treated subjects versus 1 in 1 placebo-treated subject). Mean seletalisib plasma concentration-time profiles increased with increasing doses after single and multiple dosing, with no major deviations from dose-proportionality. There was no unexpected accumulation or loss of exposure after multiple dosing (time-independent pharmacokinetic profile). Apparent t 1/2 values were supportive of once-daily dosing (geometric mean t1/2: Study-1, 17.7–21.1 h; Study-2, 18.1–22.4 h). No clinically significant food effect was observed (Study-1). Pharmacodynamic findings demonstrated ex vivo inhibition of basophil degranulation, improvements in histological assessment of skin biopsies and other markers of psoriatic biology and preliminary evidence of target engagement in psoriatic skin tissue. Conclusions Seletalisib safety, tolerability and pharmacokinetic/pharmacodynamic profiles support its continued clinical development in immune-inflammatory diseases. Electronic supplementary material The online version of this article (doi:10.1007/s00228-017-2205-7) contains supplementary material, which is available to authorized users.

Introduction: The amyloid hypothesis of Alzheimer's disease (AD) states that brain accumulation of amyloid-β (Aβ) oligomers and soluble aggregates represents the major causal event of the disease. Several small organic molecules have been synthesized and developed to inhibit the enzyme (β-site amyloid precursor protein cleaving enzyme-1 or BACE1) whose action represents the rate-limiting step in Aβ production.Areas covered: We reviewed the pharmacology and clinical trials of major BACE1 inhibitors.Expert opinion: In transgenic mouse models of AD, BACE1 inhibitors dose-dependently lower Aβ levels in brain and cerebrospinal fluid (CSF) but the evidence for attenuation or reversal cognitive or behavioral deficits is very scanty. In AD patients, BACE1 inhibitors robustly lower plasma and CSF Aβ levels and reduce brain plaques but without cognitive, clinical, or functional benefit. To date, seventeen BACE1 inhibitors have failed in double-blind, placebo-controlled clinical trials in patients with mild-to-moderate or prodromal AD, or in cognitively normal subjects at risk of developing AD. Several of these studies were prematurely interrupted due to toxicity or cognitive and behavioral worsening compared to placebo-treated patients. Elenbecestat, the last BACE1 inhibitor remaining in late clinical testing for AD, was recently discontinued due to safety concerns.

© Copyright © 2020 Hiebert, Lawrence, Ganjavi, Watling, Owen, Seergobin and MacDonald. Obsessive compulsive disorder (OCD) is a prevalent psychiatric disorder characterized by obsessions and compulsions. Studies investigating symptomatology and cognitive deficits in OCD frequently implicate the striatum. The aim of this study was to explore striatum-mediated cognitive deficits in patients with OCD as they complete a stimulus-response learning task previously shown to differentially rely on the dorsal (DS) and ventral striatum (VS). We hypothesized that patients with OCD will show both impaired decision-making and learning, coupled with reduced task-relevant activity in DS and VS, respectively, compared to healthy controls. We found that patients with OCD (n = 14) exhibited decision-making deficits and learned associations slower compared to healthy age-matched controls (n = 16). Along with these behavioral deficits, OCD patients had reduced task-relevant activity in DS and VS, compared to controls. This study reveals that responses in DS and VS are altered in OCD, and sheds light on the cognitive deficits and symptoms experienced by patients with OCD.

Alzheimer’s disease is associated with cerebral accumulation of amyloid-β peptide and hyperphosphorylated tau. In the past 28 years, huge efforts have been made in attempting to treat the disease by reducing brain accumulation of amyloid-β in patients with Alzheimer’s disease, with no success. While anti-amyloid-β therapies continue to be tested in prodromal patients with Alzheimer’s disease and in subjects at risk of developing Alzheimer’s disease, there is an urgent need to provide therapeutic support to patients with established Alzheimer’s disease for whom current symptomatic treatment (acetylcholinesterase inhibitors and N-methyl d-aspartate antagonist) provide limited help. The possibility of an infectious aetiology for Alzheimer’s disease has been repeatedly postulated over the past three decades. Infiltration of the brain by pathogens may act as a trigger or co-factor for Alzheimer’s disease, with Herpes simplex virus type 1, Chlamydia pneumoniae, and Porphyromonas gingivalis being most frequently implicated. These pathogens may directly cross a weakened blood–brain barrier, reach the CNS and cause neurological damage by eliciting neuroinflammation. Alternatively, pathogens may cross a weakened intestinal barrier, reach vascular circulation and then cross blood–brain barrier or cause low grade chronic inflammation and subsequent neuroinflammation from the periphery. The gut microbiota comprises a complex community of microorganisms. Increased permeability of the gut and blood–brain barrier induced by microbiota dysbiosis may impact Alzheimer’s disease pathogenesis. Inflammatory microorganisms in gut microbiota are associated with peripheral inflammation and brain amyloid-β deposition in subjects with cognitive impairment. Oral microbiota may also influence Alzheimer’s disease risk through circulatory or neural access to the brain. At least two possibilities can be envisaged to explain the association of suspected pathogens and Alzheimer’s disease. One is that patients with Alzheimer’s disease are particularly prone to microbial infections. The other is that microbial infection is a contributing cause of Alzheimer’s disease. Therapeutic trials with antivirals and/or antibacterials could resolve this dilemma. Indeed, antiviral agents are being tested in patients with Alzheimer’s disease in double-blind placebo-controlled studies. Although combined antibiotic therapy was found to be effective in animal models of Alzheimer’s disease, antibacterial drugs are not being widely investigated in patients with Alzheimer’s disease. This is because it is not clear which bacterial populations in the gut of patients with Alzheimer’s disease are overexpressed and if safe, selective antibacterials are available for them. On the other hand, a bacterial protease inhibitor targeting P. gingivalis toxins is now being tested in patients with Alzheimer’s disease. Clinical studies are needed to test if countering bacterial infection may be beneficial in patients with established Alzheimer’s disease.