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Frontiers in Neurology, 2022
Second-generation anti-amyloid monoclonal antibodies are emerging as a viable therapeutic option for individuals with prodromal and mild dementia due to Alzheimer's disease (AD). Passive immunotherapy with aducanumab (Aduhelm), lecanemab, donanemab, and gantenerumab all lower CNS amyloid (Aβ) burden but come with a significant risk of amyloid-related imaging abnormality (ARIA)-the most common side effect of this class of drugs. While usually asymptomatic and detected only on brain MRI, ARIA may lead to new signs and symptoms including headache, worsening confusion, dizziness, visual disturbances, nausea, and seizures. In addition, one fatality related to ARIA-E (edema) with aducanumab and one fatality due to ARIA-H (hemorrhage) with donanemab are reported to date. ARIA-E may be associated with excessive neuroinflammation and saturation of perivascular clearance pathways, while ARIA-H may be related to vascular amyloid clearance with weakening and rupture of small blood vessels. The risk of ARIA-E is higher at treatment initiation, in ApoE4 carriers, with higher dosage, and with >4 of microhemorrhages on a baseline MRI. The risk of ARIA-H increases with age and cerebrovascular disease. Dose titration mitigates the risk of ARIA, and contraindications include individuals with >4 microhemorrhages and those prescribed anti-platelet or anti-coagulant drugs. A brain MRI is required before aducanumab is initiated, before each scheduled dose escalation, and with any new neurologic sign or symptom. Management of ARIA ranges from continued antibody treatment with monthly MRI monitoring for asymptomatic individuals to temporary or permanent suspension for symptomatic individuals or those with moderate to severe ARIA on MRI. Controlled studies regarding prevention and treatment of ARIA are lacking, but anecdotal evidence suggests that a pulse of intravenous corticosteroids may be of benefit, as well as a course of anticonvulsant for seizures.
Animal models of Alzheimer disease: Historical pitfalls and a path forward
Alzheimer disease (AD) is a medically and financially overwhelming condition, and incidence rates are expected to triple by 2050. Despite decades of research in animal models of AD, the disease remains incompletely understood, with few treatment options. This review summarizes historical and current AD research efforts, with emphasis on the disparity between preclinical animal studies and the reality of human disease and how this has impacted clinical trials. We provide a mechanism for shifting the focus of AD research away from animal models to focus primarily on human biology as a means to improve the applicability of research findings to human disease. Implementation of these alternatives may hasten development of improved strategies to prevent, detect, ameliorate, and possibly cure this devastating disease.
Alzheimer's Research & Therapy
The body of evidence suggesting a causative, initiating role of beta amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD) is substantial. Yet, only a few anti-amyloid agents have shown meaningful efficacy in clinical trials. We evaluated the unifying characteristics of anti-amyloid agents with positive clinical or biomarker effects in long-duration trials and analyzed how pharmacological characteristics determine their clinical product profiles. Four agents with the potential for near term approval fulfill these criteria: the injectable antibodies, aducanumab, gantenerumab, and BAN2401, and a small molecule oral agent, ALZ-801. Aducanumab and BAN2401 showed significant efficacy on both clinical and biomarker outcomes; gantenerumab showed significant biomarker effects, with no clinical efficacy reported to date; and ALZ-801 showed significant clinical effects in the high-risk population of patients homozygous for the ε4 allele of apolipoprotein E gene (APOE4) and a dose-depen...
Frontiers in aging neuroscience, 2018
Neuritic plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer's disease (AD), while the role of brain amyloid deposition in the clinical manifestation or brain atrophy remains unresolved. We aimed to explore the relation between brain amyloid deposition, cortical thickness, and plasma biomarkers. We used C-Pittsburgh compound B-positron emission tomography to assay brain amyloid deposition, magnetic resonance imaging to estimate cortical thickness, and an immunomagnetic reduction assay to measure plasma biomarkers. We recruited 39 controls, 25 subjects with amnesic mild cognitive impairment (aMCI), and 16 subjects with AD. PiB positivity (PiB+) was defined by the upper limit of the 95% confidence interval of the mean cortical SUVR from six predefined regions (1.0511 in this study). All plasma biomarkers showed significant between-group differences. The plasma Aβ level was positively correlated with the mean cortical thickness of both the PiB+ and PiB- ...
Alzheimer's disease (AD) is the most commonly diagnosed etiology of dementia and may be caused by the progressive accumulation and deposition of neurotoxic Ab/ amyloid plaques and aggregates in brain with aging—the amyloid hypothesis of AD. However, Ab/amyloid deposition is likely necessary but not sufficient to cause AD, and other putative downstream pathologies, including the aggregation of phospho-tau in neurofibrillary tangles, synaptic and neuronal loss, and glial and inflammatory responses, are likely equally important to AD pathogenesis. The majority of AD is sporadic (> 95%) but the discovery of rare early onset familial forms of AD has been pivotal to our understanding of its pathogenesis and in developing novel therapeutic strategies. Currently available drugs for patients with AD provide modest, temporary, and palliative benefits, but they consistently demonstrate safety and efficacy on cognitive, functional, behavioral, and global outcome measures. Novel potential disease-modifying therapies now in preclinical research or clinical trials may be more effective in preventing or arresting the progressive dementia of AD and will provide a test of the amyloid hypothesis.
Psychedelics as Novel Therapeutics in Alzheimer's Disease: Rationale and Potential Mechanisms
Current Topics in Behavioral Neurosciences, 2021
Serotonin 2A receptor (5-HT2AR) agonist “classic psychedelics” are drawing increasing interest as potential mental health treatments. Recent work suggests psychedelics can exert persisting anxiolytic and antidepressant effects lasting up to several months after a single administration. Data indicate acute subjective drug effects as important psychological factors involved in observed therapeutic benefits. Additionally, animal models have shown an important role for 5-HT2AR agonists in modulating learning and memory function with relevance for Alzheimer’s Disease (AD) and related dementias. A number of biological mechanisms of action are under investigation to elucidate 5-HT2AR agonists’ therapeutic potential, including enhanced neuroplasticity, anti-inflammatory effects, and alterations in brain functional connectivity. These diverse lines of research are reviewed here along with a discussion of AD pathophysiology and neuropsychiatric symptoms to highlight classic psychedelics as potential novel pharmacotherapies for patients with AD. Human clinical research suggests a possible role for high-dose psychedelic administration in symptomatic treatment of depressed mood and anxiety in early-stage AD. Preclinical data indicate a potential for low- or high-dose psychedelic treatment regimens to slow or reverse brain atrophy, enhance cognitive function, and slow progression of AD. In conclusion, rationale and potential approaches for preliminary research with psychedelics in patients with AD are presented, and ramifications of this line of investigation for development of novel AD treatments are discussed.
2021
The primary pathological hallmarks of Alzheimer's disease are extracellular amyloid plaques and intraneuronal tangles of hyperphosphorylated tau (Masters et al., 1985). It is well known, however, that amyloid plaques do not correlate well with cognitive decline in AD (Terry et al., 1991; Hsia et al., 1999) and are not present in the earliest stages of the disease (Nyborg et al., 2013). Research from the previous two decades strongly indicates that soluble AβOs, not plaques, are the more appropriate amyloid beta species to target in AD (Ashe, 2020; Hampel et al., 2021). Amyloid β oligomers are potent neurotoxins that show ADdependent accumulation in the brain of AD patients (
Precision pharmacology for Alzheimer's disease
Pharmacological research, 2018
The complex multifactorial nature of polygenic Alzheimer's disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels - from molecules to organ systems - and through adaptation, to compensation, and decompensation to systems failure. Adaptation and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment. An individual vulnerability to stressors exists on the basis of individual triggers, drivers, and thresholds accounting for the initiation and failure of adaptive and compensatory responses. Consequently, the distinct pattern of AD pathophysiology in space and time must be investigated on the basis of the individual biological makeup. This requires the implementation of systems biology and neurophysiology to facilitate Precision Medicine (PM) and Precision Pharmacology (PP). The regu...