Role of monomeric amyloid-ß in cognitive performance in Alzheimer's disease: Insights from clinical trials with secretase inhibitors and monoclonal antibodies.

According to the ß-amyloid (Aß) hypothesis of Alzheimer's disease (AD), brain Aß accumulation is the primary cascade event leading to cognitive deficit and dementia. Numerous anti-Aß drugs either inhibiting production or aggregation of Aß or stimulating its clearance have failed to show clinical benefit in large scale AD trials, with ß- and γ-secretase inhibitors consistently worsening cognitive and clinical decline. In June 2021, the FDA approved aducanumab, an anti-Aß 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) Aß levels, correlating them with cognitive effects. We found that ß-secretase and γ-secretase inhibitors produce detrimental cognitive effects by significantly reducing CSF Aß levels. We speculate that monoclonal antibodies targeting Aß protofibrils, fibrils or plaques may improve cognitive performance in early AD by increasing soluble Aß levels through Aß aggregate disassembly and/or stabilization of existing Aß monomers.These findings suggest that the real culprit in AD may be decreased levels of soluble monomeric Aß due to sequestration into brain Aß aggregates and plaques.

Plasma ATN(I) classification and precision pharmacology in Alzheimer's disease.

Evaluating potential therapies for Alzheimer's disease (AD) depends on use of biomarkers for appropriate subject selection and monitoring disease progression. Biomarkers that predict onset of clinical symptoms are particularly important for AD because they enable intervention before irreversible neurodegeneration occurs. The amyloid-ß-tau-neurodegeneration (ATN) classification system is currently used as a biological staging model for AD and is based on three classes of biomarkers evaluating amyloid-ß (Aß), tau pathology and neurodegeneration or neuronal injury. Promising blood-based biomarkers for each of these categories have been identified (Aß42/Aß40 ratio, phosphorylated tau, neurofilament light chain), and this matrix is now being expanded toward an ATN(I) system, where "I" represents a neuroinflammatory biomarker. The plasma ATN(I) system, together with APOE genotyping, offers a basis for individualized evaluation and a move away from the classic "one size fits all" approach toward a biomarker-driven individualisation of therapy for patients with AD.

Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer's disease?

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 (Aß) 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-Aß interaction inhibitors produced positive results in transgenic AD mouse models.

A critical appraisal of tau-targeting therapies for primary and secondary tauopathies.

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.

Time to test antibacterial therapy in Alzheimer's disease.

Alzheimer's disease is associated with cerebral accumulation of amyloid-ß 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-ß in patients with Alzheimer's disease, with no success. While anti-amyloid-ß 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-ß 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.

Efficacy and safety of bimekizumab as add-on therapy for rheumatoid arthritis in patients with inadequate response to certolizumab pegol: a proof-of-concept study.

OBJECTIVE: Evaluate the efficacy and safety of dual neutralisation of interleukin (IL)-17A and IL-17F with bimekizumab, a monoclonal IgG1 antibody, in addition to certolizumab pegol (CZP) in patients with rheumatoid arthritis (RA) and inadequate response (IR) to certolizumab pegol. METHODS: During this phase 2a, double-blind, proof-of-concept (PoC) study (NCT02430909), patients with moderate-to-severe RA received open-label CZP 400 mg at Weeks 0, 2 and 4, and 200 mg at Week 6. Patients with IR at Week 8 (Disease Activity Score 28-joint count C-reactive protein (DAS28(CRP))>3.2) were randomised 2:1 to CZP (200 mg every 2 weeks (Q2W)) plus bimekizumab (240 mg loading dose then 120 mg Q2W) or CZP plus placebo. The primary efficacy and safety variables were change in DAS28(CRP) between Weeks 8 and 20 and incidence of treatment-emergent adverse events (TEAEs). RESULTS: Of 159 patients enrolled, 79 had IR at Week 8 and were randomised to CZP plus bimekizumab (n=52) or CZP plus placebo (n=27). At Week 20, there was a greater reduction in DAS28(CRP) in the CZP-IR plus bimekizumab group compared with the CZP-IR plus placebo group (99.4% posterior probability). The most frequent TEAEs were infections and infestations (CZP plus bimekizumab, 50.0% (26/52); CZP plus placebo, 22.2% (6/27)). CONCLUSIONS: PoC was confirmed based on the rapid decrease in disease activity achieved with 12 weeks of CZP plus bimekizumab. No unexpected or new safety signals were identified when neutralising IL-17A and IL-17F in patients with RA concomitantly treated with CZP, but the rate of TEAEs was higher with dual inhibition.

Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation.

OBJECTIVE: Interleukin (IL)-17A has emerged as pivotal in driving tissue pathology in immune-mediated inflammatory diseases. The role of IL-17F, sharing 50% sequence homology and overlapping biological function, remains less clear. We hypothesised that IL-17F, together with IL-17A, contributes to chronic tissue inflammation, and that dual neutralisation may lead to more profound suppression of inflammation than inhibition of IL-17A alone. METHODS: Preclinical experiments assessed the role of IL-17A and IL-17F in tissue inflammation using disease-relevant human cells. A placebo-controlled proof-of-concept (PoC) clinical trial randomised patients with psoriatic arthritis (PsA) to bimekizumab (n=39) or placebo (n=14). Safety, pharmacokinetics and clinical efficacy of multiple doses (weeks 0, 3, 6 (240 mg/160 mg/160 mg; 80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and 560 mg/320 mg/320 mg)) of bimekizumab, a humanised monoclonal IgG1 antibody neutralising both IL-17A and IL-17F, were investigated. RESULTS: IL-17F induced qualitatively similar inflammatory responses to IL-17A in skin and joint cells. Neutralisation of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro cytokine responses and neutrophil chemotaxis than inhibition of IL-17A or IL-17F alone. The PoC trial met both prespecified efficacy success criteria and showed rapid, profound responses in both joint and skin (pooled top three doses vs placebo at week 8: American College of Rheumatology 20% response criteria 80.0% vs 16.7% (posterior probability >99%); Psoriasis Area and Severity Index 100% response criteria 86.7% vs 0%), sustained to week 20, without unexpected safety signals. CONCLUSIONS: These data support IL-17F as a key driver of human chronic tissue inflammation and the rationale for dual neutralisation of IL-17A and IL-17F in PsA and related conditions. TRIAL REGISTRATION NUMBER: NCT02141763; Results.

First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3Kδ inhibitor for the treatment of immune and inflammatory diseases.

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.

Overview of preclinical and clinical studies investigating pharmacokinetics and drug-drug interactions of padsevonil.

BACKGROUND: Padsevonil is an antiseizure medication candidate intended to benefit patients with drug-resistant epilepsy. Our investigations aimed at characterizing pharmacokinetics and drug-drug-interaction (DDI) profile of padsevonil. RESEARCH DESIGN AND METHODS: An overview of preclinical and clinical pharmacology studies conducted during padsevonil development is provided. RESULTS: In preclinical studies, cytochrome (CYP) 3A4 was identified as the main P450 isoform involved in padsevonil metabolism, with potential minor contribution from CYP2C19. Padsevonil was shown to be a time-dependent CYP2C19-inhibitor, weak CYP3A4-inducer, weak inhibitor of P-gp/OCT1/MATE2-K, and potent OCT2-inhibitor. Initial clinical pharmacology studies in healthy participants showed that padsevonil had (i) good absorption, (ii) clearance mediated mainly by metabolism, and (iii) time-dependent kinetics. A study in genotyped participants confirmed the role of CYP2C19 in clearance and time-dependent kinetics; the major contribution of CYP3A4 was confirmed in DDI studies with CYP3A4-inducers (carbamazepine, oxcarbazepine) and -inhibitor (erythromycin). Padsevonil did not affect pharmacokinetics of valproate/lamotrigine/levetiracetam/oxcarbazepine or oral contraceptives. In a cocktail clinical study, padsevonil showed moderate CYP2C19 inhibition (omeprazole) and weak CYP3A4 induction (oral midazolam). No specific effects on CYP1A2 (caffeine), CYP2C9 (S-warfarin), and CYP2D6 (dextromethorphan) were observed. CONCLUSIONS: The studies presented helped in understanding padsevonil disposition and risks of DDIs, which would inform dosing and prescribing. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/identifiers are NCT04131517, NCT03480243, NCT03695094, NCT04075409.

Clinical Bridging Studies and Modeling Approach for Implementation of a Patient Centric Sampling Technique in Padsevonil Clinical Development.

Volumetric absorptive microsampling (VAMS) techniques have gained popularity these last years as innovative tool for collection of blood pharmacokinetic (PK) samples in clinical trials as they offer many advantages over dried blood spot and conventional venous blood sampling. The use of Mitra®, a blood collection device based on volumetric absorptive microsampling (VAMS) technology, was implemented during clinical development of padsevonil (PSL), an anti-seizure medication (ASM) candidate. The present study describes the approach used to bridge plasma (obtained from conventional venous blood sampling) and blood exposures (obtained with Mitra®) to support the use of Mitra as sole blood PK sampling method in clinical trials. Paired blood (using Mitra®) and plasma samples (using conventional venous blood sampling) were collected in healthy volunteers as well as in patients with epilepsy. PSL concentration in plasma and blood were analyzed using different approaches which included evaluation of blood-to-plasma ratios (B/P) over time, linear regression, Bland-Altman analysis as well as development of a linear-mixed effect model based on clinical pharmacology studies. Results showed that the observed in vivo B/P and the measured bias between the 2 collection methods were consistent with the measured in vitro B/P. Graphical analysis demonstrated a clear time effect on the B/P which was confirmed in the linear mixed effect model with sampling time identified as significant covariate. Finally, the built-in model was validated using independent datasets and was shown to adequately predict plasma concentration based on blood concentration with a mean bias of less than 9% (predicted versus observed plasma concentration).

Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer's disease?

Human apolipoprotein E (ApoE) is a 299-amino acid secreted glycoprotein that binds cholesterol and phospholipids. ApoE exists as three common isoforms (ApoE2, ApoE3, and ApoE4) and heterozygous carriers of the ε4 allele of the gene encoding ApoE (APOE) have a fourfold greater risk of developing Alzheimer's disease (AD). The enzymes thrombin, cathepsin D, α-chymotrypsin-like serine protease, and high-temperature requirement serine protease A1 are responsible for ApoE proteolytic processing resulting in bioactive C-terminal-truncated fragments that vary depending on ApoE isoforms, brain region, aging, and neural injury. The objectives of the present narrative review were to describe ApoE processing, discussing current hypotheses about the potential role of various ApoE fragments in AD pathophysiology, and reviewing the current development status of different anti-ApoE drugs. The exact mechanism by which APOE gene variants increase/decrease AD risk and the role of ApoE fragments in the deposition are not fully understood, but APOE is known to directly affect tau-mediated neurodegeneration. ApoE fragments co-localize with neurofibrillary tangles and amyloid ß (Aß) plaques, and may cause neurodegeneration. Among anti-ApoE approaches, a fascinating strategy may be to therapeutically overexpress ApoE2 in APOE ε4/ε4 carriers through vector administration or liposomal delivery systems. Another approach involves reducing ApoE4 expression by intracerebroventricular antisense oligonucleotides that significantly decreased Aß pathology in transgenic mice. Differences in the proteolytic processing of distinct ApoE isoforms and the use of ApoE fragments as mimetic peptides in AD treatment are also under investigation. Treatment with peptides that mimic the structural and biological properties of native ApoE may reduce Aß deposition, tau hyperphosphorylation, and glial activation in mouse models of Aß pathology. Alternative strategies involve the use of ApoE4 structure correctors, passive immunization to target a certain form of ApoE, conversion of the ApoE4 aminoacid sequence into that of ApoE3 or ApoE2, and inhibition of the ApoE-Aß interaction.

What have we learned from past failures of investigational drugs for Alzheimer's disease?

INTRODUCTION: In the last 15 years, huge efforts against Alzheimer's disease (AD) with drugs targeting ß-amyloid (Aß) and tau have produced poor clinical results. Aducanumab, a recently FDA-approved anti-Aß monoclonal antibody has been greeted with distrust by most experts, hospitals and insurance companies for its level of efficacy and poor tolerability. AREA COVERED: 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-Aß and anti-tau drugs. EXPERT OPINION: It is our opinion that previous failures of anti-AD drugs suggest that soluble Aß 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.

Can Anti-ß-amyloid Monoclonal Antibodies Work in Autosomal Dominant Alzheimer Disease?

The dominant theory of Alzheimer disease (AD) has been that amyloid-ß (Aß) 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 Aß metabolism, should thus offer perhaps the best opportunity to test anti-Aß 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-Aß 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 Aß hypothesis and could support the suggestion that ADAD is triggered by accumulation of other APP metabolites, rather than Aß.

Accelerating Alzheimer's disease drug discovery and development: what's the way forward?

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 ß-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.

Pharmacological management of dementia with Lewy bodies with a focus on zonisamide for treating parkinsonism.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Should drug discovery scientists still embrace the amyloid hypothesis for Alzheimer's disease or should they be looking elsewhere?

INTRODUCTION: 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 ß-amyloid (Aß) in AD brains has singled it out as an obvious therapeutic target, the effective reduction of plaque load or soluble Aß by numerous drug candidates has not produced commensurate clinical benefits - calling into question the Aß cascade hypothesis of AD. A similar path is now unfolding in the pursuit of therapeutics targeting hyperphosphorylated tau-comprised neurofibrillary tangles. AREAS COVERED: This perspective reviews the basis of the Aß cascade hypothesis of AD and how clinical trials of anti-Aß 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. EXPERT OPINION: The relevance of the Aß 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.

Discontinued disease-modifying therapies for Alzheimer's disease: status and future perspectives.

INTRODUCTION: 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-ß (Aß) 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. AREAS COVERED: This article reviews key drugs that have been discontinued while in development for AD and delineates the future landscape for present and alternative approaches. EXPERT OPINION: Anti-Aß drugs have failed to validate the Aß 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.

Perspective: Is therapeutic plasma exchange a viable option for treating Alzheimer's disease?

Therapeutic plasma exchange, consisting of removing blood plasma and exchanging it with donated blood products, has been proposed for treating Alzheimer's disease (AD) to remove senescent or toxic factors. In preclinical studies, administration of plasma from young healthy mice to AD transgenic mice improved cognitive deficits without affecting brain amyloid plaques. Initial encouraging results have been collected in a double-blind, placebo-controlled study in nine AD patients receiving young plasma. In a 14-month double-blind, placebo-controlled study in 322 AD patients, multiple infusions with plasma enriched with albumin with or without immunoglobulins slowed cognitive, functional, and clinical decline, especially in moderately affected patients. Clinical trials of plasma fractions containing hypothetically beneficial proteins are also under way. These initial positive clinical results need to be confirmed in larger and more rigorous controlled studies in which the possible benefits of plasma exchange approaches can be weighed against the intrinsic side effects of repetitive infusion procedures.

Development of disease-modifying drugs for frontotemporal dementia spectrum disorders.

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.