Anti-tau Drugs Research Articles

Current and future therapeutic strategies for Alzheimer's disease: an overview of drug development bottlenecks.

Alzheimer's disease (AD) is the most common chronic neurodegenerative disease worldwide. It causes cognitive dysfunction, such as aphasia and agnosia, and mental symptoms, such as behavioral abnormalities; all of which place a significant psychological and economic burden on the patients' families. No specific drugs are currently available for the treatment of AD, and the current drugs for AD only delay disease onset and progression. The pathophysiological basis of AD involves abnormal deposition of beta-amyloid protein (Aβ), abnormal tau protein phosphorylation, decreased activity of acetylcholine content, glutamate toxicity, autophagy, inflammatory reactions, mitochondria-targeting, and multi-targets. The US Food and Drug Administration (FDA) has approved five drugs for clinical use: tacrine, donepezil, carbalatine, galantamine, memantine, and lecanemab. We have focused on the newer drugs that have undergone clinical trials, most of which have not been successful as a result of excessive clinical side effects or poor efficacy. Although aducanumab received rapid approval from the FDA on 7 June 2021, its long-term safety and tolerability require further monitoring and confirmation. In this literature review, we aimed to explore the possible pathophysiological mechanisms underlying the occurrence and development of AD. We focused on anti-Aβ and anti-tau drugs, mitochondria-targeting and multi-targets, commercially available drugs, bottlenecks encountered in drug development, and the possible targets and therapeutic strategies for future drug development. We hope to present new concepts and methods for future drug therapies for AD.

Effectiveness and safety of anti-tau drugs for Alzheimer's disease: Systematic review and meta-analysis.

To assess the cognitive effectiveness and safety of tau-targeting drugs for Alzheimer's disease (AD) METHODS: The MEDLINE, Embase, Cochrane Library, PsycINFO, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform databases were searched from inception to 22 November 2021. A systematic review and meta-analysis of randomized controlled trials were performed RESULTS: Thirty-four randomized controlled trials comprising 5549 participants, of which fifteen (51.7%) had a low risk of bias, were included. The meta-analysis showed no differences in the cognitive subscale of the AD: Assessment Scale (ADAS-Cog) between anti-tau drugs and placebo (mean difference [MD]: -0.77, 95% CI: -1.64 to 0.10; minimal important difference 3.1-3.8 points, moderate certainty evidence). For ADAS-Cog, the results subgroup analysis suggested a statistical effect of tau posttranslational modifications on drug inhibition (MD: -0.80, 95% CI: -1.43 to -0.17), which was not seen with tau aggregation inhibitors or immunotherapy (interaction p=0.24). A total of 11.0%, 5.2%, and 4.8% of drugs inhibiting tau aggregation, immunotherapy, and drugs targeting posttranslational modifications, respectively, had a reduced risk of dropouts due to adverse events (AEs). Current evidence suggests that anti-tau drugs are unlikely to have an important impact on slowing cognitive impairment. Although the subgroup analysis suggested that inhibition of tau posttranslational modifications is statistically effective and generally safer because of reduced dropouts due to AEs, the analysis has limited credibility. Additional large-scale and well-designed randomized and placebo-controlled trials will be necessary to explore the benefit of a certain type of anti-tau drug for AD.

β-Amyloid-Dependent and -Independent Genetic Pathways Regulating CSF Tau Biomarkers in Alzheimer Disease.

Background and ObjectivesAbnormal metabolism of β-amyloid (Aβ) and soluble phosphorylated tau (P-tau), as well as neurodegeneration, are key components of Alzheimer disease (AD), but it is unclear how these different processes are related to genetic risk factors for AD.MethodsIn the Swedish BioFINDER study, we tested associations between a priori defined polygenic risk scores (PRSs) for AD (excluding single-nucleotide polymorphism [SNP] within the APOE region in the main analysis) and biomarkers in CSF (total tau [T-tau] and P-tau181; Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-42/1-40; and neurofilament light [NfL]) in cognitively unimpaired (CU) individuals (n = 751), and in patients with mild cognitive impairment (MCI) (n = 212) and AD dementia (n = 150). Results were validated in the Alzheimer's Disease Neuroimaging Initiative data set with 777 individuals (AD = 119, MCI = 442, and CU = 216).ResultsPRSs with SNPs significant at p < 5e-03 (∼1,742 variants) were associated with higher CSF P-tau181 (β = 0.13, p = 5.6e-05) and T-tau (β = 0.12, p = 4.3e-04). The associations between PRS and tau measures were partly attenuated but remained significant after adjusting for Aβ status. Aβ pathology mediated 37% of the effect of this PRS on tau levels. Aβ-dependent and Aβ-independent subsets of the PRS were identified and characterized. There were also associations between PRSs and CSF Aβ biomarkers with nominal significance, but not when corrected for multiple comparisons. There were no associations between PRSs and CSF NfL.DiscussionGenetic pathways implicated in causing AD are related to altered levels of soluble tau through both Aβ-dependent and Aβ-independent mechanisms, which may have relevance for anti-tau drug development.

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

ABSTRACT Introduction 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. Area covered We reviewed literature on tau biology and anti-tau drugs 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. Expert opinion 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 minimise the potential introduction of major biases in the evaluation of the clinical results. Finally, alternative biological targets should be pursued as well as more multimodal approaches to addressing neurodegeneration in AD.

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

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. We reviewed literature on tau biology and anti-tau drugs using PubMed, meeting abstracts, and ClnicalTrials.gov. 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. 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.

A Proposal to Make Biomedical Research into Alzheimer's Disease More Democratic Following an International Survey with Researchers.

Background:Therapeutic research into Alzheimer’s disease (AD) has been dominated by the amyloid cascade hypothesis (ACH) since the 1990s. However, targeting amyloid in AD patients has not yet resulted in highly significant disease-modifying effects. Furthermore, other promising theories of AD etiology exist.Objective:We sought to directly investigate whether the ACH still dominates the opinions of researchers working on AD and explore the implications of this question for future directions of research.Methods:During 2019, we undertook an international survey promoted with the help of the Alzheimer’s Association with questions on theories and treatments of AD. Further efforts to promote a similar study in 2021 did not recruit a significant number of participants.Results:173 researchers took part in the 2019 survey, 22% of which held “pro-ACH” opinions, tended to have more publications, were more likely to be male, and over 60. Thus, pro-ACH may now be a minority opinion in the field but is nevertheless the hypothesis on which the most clinical trials are based, suggestive of a representation bias. Popular vote of all 173 participants suggested that lifestyle treatments and anti-tau drugs were a source of more therapeutic optimism than anti-amyloid treatments.Conclusion:We propose a more democratic research structure which increases the likelihood that promising theories are published and funded fairly, promotes a broader scientific view of AD, and reduces the larger community’s dependence on a fragile economic model.

Predicting future rates of tau accumulation on PET.

Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer's clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in thecognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer's disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion.

New Horizons in Alzheimer Research from Amyloid and Beyond

The Amyloid and Tau Hypothesis of Alzheimer’s disease once thought to be the key have shown marginal results but are bolstered by the recent revival of the Aducanumab study and some positive data on some anti-Tau drugs. It still behoves us to look at other mechanisms which include whole blood transfusions, an Epigenetic approach, a-derivative of a Parkinson's drug a low dose of an anti-epileptic drug, an antibiotic against P Gingivitis and many new approaches not directly involving Amyloid and Tau. Other newer approaches were also presented at CTAD 2019.

Alzheimer’s Anti-Tau Drug Fails Phase III, Shows Benefit in Monotherapy

TORONTO — A phase III trial of an anti-tau drug has posted negative topline results, conferring no cognitive or functional benefi ts when given in conjunction with standard-of-care Alzheimer’s disease medications. The drug, LTMX (TauRx), also did not slow the progression of brain atrophy on imaging in either of two doses tested, according to a company press release. Although the study didn’t meet its clinical endpoints in the overall cohort of 891 patients with mild to moderate disease, TauRx promoted it as “promising,” based on a subgroup analysis of the 15% of patients who took the drug as monotherapy. Among these patients, LMTX was associated with dose-dependent, statistically signifi cant improvements in the Alzheimer’s Disease Assessment Scale measures of cognition (ADAS-cog) and Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL). The drug was also associated with a slowing of brain ventricular expansion, compared with controls, suggesting that it could be preserving brain mass. Nevertheless, the trial must be read as another negative one, said David S. Knopman, MD, of the Mayo Clinic, Rochester, MN, who moderated a press briefing where the data were presented. “I think the secondary results are interesting, especially imaging fi ndings. But ... because this is a small subset of just 15%, it’s very diffi cult to interpret.”

Trial watch: Phase III trial of anti-tau drug generates mixed messages.

Trial watch: Phase III trial of anti-tau drug generates mixed messages.

Search for Alzheimer’s Drugs Turns to New Strategies

Search for Alzheimer’s Drugs Turns to New Strategies