Evolution of Disease-modifying Therapy for Transthyretin Cardiac Amyloidosis.

Transthyretin cardiac amyloidosis (ATTR-CA) represents an inexorably progressive and fatal cardiomyopathy. Increased understanding of the underlying pathogenesis responsible for the misfolding of transthyretin and the subsequent accumulation of amyloid fibrils within the myocardium has led to the development of several disease-modifying therapies that act on different stages of the disease pathway. Tafamidis is the first, and to date remains the only, therapy approved for the treatment of ATTR-CA, which, alongside acoramidis, stabilizes the transthyretin tetramer, preventing disaggregation, misfolding and formation of amyloid fibrils. Gene-silencing agents, such as patisiran, vutrisian and eplontersen, and novel gene-editing therapies, such as NTLA-2001, act to reduce the hepatic synthesis of transthyretin. Anti-amyloid therapies represent another strategy in the treatment of ATTR-CA and are designed to bind amyloid fibril epitopes and stimulate macrophage-mediated removal of amyloid fibrils from the myocardium. Many of these treatments are at an early investigational stage but represent an important area of unmet clinical need and could potentially reverse disease and restore cardiac functions even in patients with advanced disease.

Management of MCI in the Outpatient Setting.

PURPOSE OF REVIEW: We review current literature related to the clinical assessment of Mild Cognitive Impairment (MCI). We compile recommendations related to the evaluation of MCI and examine literature regarding the use of clinical biomarkers in this assessment, the role of non-pharmacologic therapy in the prevention of cognitive decline, and recent approval of anti-amyloid therapy in the treatment of MCI. RECENT FINDINGS: The role of imaging and plasma biomarkers in the clinical assessment of MCI has expanded. There is data that non-pharmacologic therapy may have a role in the prevention of neurocognitive decline. Anti-amyloid therapies have recently been approved for clinical use. Clinical assessment of MCI remains multifactorial and includes screening and treating for underlying psychiatric and medical co-morbidities. The use of biomarkers in clinical settings is expanding with the rise of anti-amyloid therapies. These new diagnostics and therapeutics require nuanced discussion of risks and benefits. Psychiatrist's skillset is uniquely suited for these complex evaluations.

What Threshold of Amyloid Reduction Is Necessary to Meaningfully Improve Cognitive Function in Transgenic Alzheimer's Disease Mice?

Background: Amyloid-ß plaques (Aß) are associated with Alzheimer's disease (AD). Pooled assessment of amyloid reduction in transgenic AD mice is critical for expediting anti-amyloid AD therapeutic research. Objective: The mean threshold of Aß reduction necessary to achieve cognitive improvement was measured via pooled assessment (n = 594 mice) of Morris water maze (MWM) escape latency of transgenic AD mice treated with substances intended to reduce Aß via reduction of beta-secretase cleaving enzyme (BACE). Methods: Machine learning and statistical methods identified necessary amyloid reduction levels using mouse data (e.g., APP/PS1, LPS, Tg2576, 3xTg-AD, control, wild type, treated, untreated) curated from 22 published studies. Results: K-means clustering identified 4 clusters that primarily corresponded with level of Aß: untreated transgenic AD control mice, wild type mice, and two clusters of transgenic AD mice treated with BACE inhibitors that had either an average 25% "medium reduction" of Aß or 50% "high reduction" of Aß compared to untreated control. A 25% Aß reduction achieved a 28% cognitive improvement, and a 50% Aß reduction resulted in a significant 32% improvement compared to untreated transgenic mice (p < 0.05). Comparatively, wild type mice had a mean 41% MWM latency improvement over untreated transgenic mice (p < 0.05). BACE reduction had a lesser impact on the ratio of Aß42 to Aß40. Supervised learning with an 80% -20% train-test split confirmed Aß reduction was a key feature for predicting MWM escape latency (R2 = 0.8 to 0.95). Conclusions: Results suggest a 25% reduction in Aß as a meaningful treatment threshold for improving transgenic AD mouse cognition.

Navigating the dementia landscape: Biomarkers and emerging therapies.

The field of dementia research has witnessed significant developments in our understanding of neurodegenerative disorders, with a particular focus on Alzheimer's disease (AD) and Frontotemporal Dementia (FTD). Dementia, a collection of symptoms arising from the degeneration of brain cells, presents a significant healthcare challenge, especially as its prevalence escalates with age. This abstract delves into the complexities of these disorders, the role of biomarkers in their diagnosis and monitoring, as well as emerging neurophysiological insights. In the context of AD, anti-amyloid therapy has gained prominence, aiming to reduce the accumulation of amyloid-beta (Aß) plaques in the brain, a hallmark of the disease. Notably, Leqembi recently received full FDA approval, marking a significant breakthrough in AD treatment. Additionally, ongoing phase 3 clinical trials are investigating novel therapies, including Masitinib and NE3107, focusing on cognitive and functional improvements in AD patients. In the realm of FTD, research has unveiled distinct neuropathological features, including the involvement of proteins like TDP-43 and progranulin, providing valuable insights into the diagnosis and management of this heterogeneous condition. Biomarkers, including neurofilaments and various tau fragments, have shown promise in enhancing diagnostic accuracy. Neurophysiological techniques, such as transcranial magnetic stimulation (TMS), have contributed to our understanding of AD and FTD. TMS has uncovered unique neurophysiological signatures, highlighting impaired plasticity, hyperexcitability, and altered connectivity in AD, while FTD displays differences in neurotransmitter systems, particularly GABAergic and glutamatergic circuits. Lastly, ongoing clinical trials in anti-amyloid therapy for AD, such as Simufilam, Solanezumab, Gantenerumab, and Remternetug, offer hope for individuals affected by this devastating disease, with the potential to alter the course of cognitive decline. These advancements collectively illuminate the evolving landscape of dementia research and the pursuit of effective treatments for these challenging conditions.

Alzheimer's Disease Stage Transitions Among United States Veterans.

BACKGROUND: Alzheimer's disease (AD) and related dementias are progressive neurological disorders with stage-specific clinical features and challenges. An important knowledge gap is the "window of time" within which patients transition from mild cognitive impairment or mild AD to moderate or severe AD. Better characterization/establishment of transition times would help clinicians initiating treatments, including anti-amyloid therapy. OBJECTIVE: To describe cognitive test score-based AD stage transitions in Veterans with AD in the US Veterans Affairs Healthcare System (VAHS). METHODS: This retrospective analysis (2010-2019) identified Veterans with AD from the VAHS Electronic Health Record (EHR) notes. AD stage was based on Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), or Saint Louis University Mental Status (SLUMS) Examination scores in the EHR. RESULTS: We identified 296,519 Veterans with cognitive test-based AD staging. Over the 10-year study, the proportion of veterans with MMSE scores declined from 24.9% to 9.5% while those with SLUMS rose from 9.0% to 17.8%; and MoCA rose from 5.0% to 25.4%. The average forward transition times between each stage were approximately 2-4 years, whether assessed by MMSE, MoCA, or SLUMS. CONCLUSION: The average transition time for cognitive test-based assessments of initial cognitive decline, early-stage AD, and moderate/severe AD in the VAHS is 2-4 years. In view of the short window for introducing disease-modifying therapy and the significant benefits of early treatment of AD, our data suggest a critical need for treatment guidelines in the management of AD.

Anti-Amyloid Therapy, AD, and ARIA: Untangling the Role of CAA.

Anti-amyloid therapies (AATs), such as anti-amyloid monoclonal antibodies, are emerging treatments for people with early Alzheimer's disease (AD). AATs target amyloid ß plaques in the brain. Amyloid-related imaging abnormalities (ARIA), abnormal signals seen on magnetic resonance imaging (MRI) of the brain in patients with AD, may occur spontaneously but occur more frequently as side effects of AATs. Cerebral amyloid angiopathy (CAA) is a major risk factor for ARIA. Amyloid ß plays a key role in the pathogenesis of AD and of CAA. Amyloid ß accumulation in the brain parenchyma as plaques is a pathological hallmark of AD, whereas amyloid ß accumulation in cerebral vessels leads to CAA. A better understanding of the pathophysiology of ARIA is necessary for early detection of those at highest risk. This could lead to improved risk stratification and the ultimate reduction of symptomatic ARIA. Histopathological confirmation of CAA by brain biopsy or autopsy is the gold standard but is not clinically feasible. MRI is an available in vivo tool for detecting CAA. Cerebrospinal fluid amyloid ß level testing and amyloid PET imaging are available but do not offer specificity for CAA vs amyloid plaques in AD. Thus, developing and testing biomarkers as reliable and sensitive screening tools for the presence and severity of CAA is a priority to minimize ARIA complications.

Comparative Study of Safety and Efficacy of Angiotensin-Receptor Blockers and Anti Amyloid-ß Monoclonal Antibodies for the Treatment of Alzheimer's Disease: A Systematic Review.

Amyloid-ß (Aß) plaques and Neurofibrillary tangles are hallmarks of Alzheimer's disease (AD) pathology. Recent advances to find a cure for AD have led to the exploration of Anti-Aß monoclonal antibodies and angiotensin-receptor blockers (ARBs). The antibodies can decrease plaque formation or remove already formed plaques. ARBs increase angiotensin II (AT2) levels and decrease the effect of AT2 on the AT1 receptor (AT1R). This systematic analysis reviews evidence of monoclonal antibodies (Aducanumab, Lecanemab, Donanemab, and Solanezumab) and ARBs in managing AD. An in-depth methodical search was conducted across PubMed, Science Direct, and Mendeley. PRISMA 2020 guidelines were followed for this study. Randomized control trials for antibodies and ARBs and one retrospective cohort study were included. The comparison was made among studies that shared similar measured outcomes. Antibodies were found to be more effective than ARBs, with Aducanumab and Lecanemab being the most effective. ARBs, on the other hand, were found to be the safer choice. Further trials of longer duration and larger sample sizes are needed to explore both groups' long-term safety and efficacy.

Aduhelm, a novel anti-amyloid monoclonal antibody, for the treatment of Alzheimer's Disease: A comprehensive review.

Alzheimer's disease (AD) is the most common form of dementia affecting millions of individuals, including family members who often take on the role of caregivers. This debilitating disease reportedly consumes 8% of the total United States healthcare expenditure, with medical and nursing outlays accounting for an estimated $290 billion. Cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists have historically been the most widely used pharmacologic therapies for patients with AD; however, these drugs are not curative. The present investigation describes the epidemiology, pathophysiology, risk factors, presentation, and current treatment of AD followed by the role of the novel monoclonal antibody, Adulhelm, in the treatment of AD. Currently, Adulhelm is the only Food and Drug Administration (FDA) approved drug that acts to slow the progression of this disease. Adulhelm is an anti-amyloid drug that functions by selectively binding amyloid aggregates in both the oligomeric and fibrillar states. Studies show Adulhelm may help to restore neurological function in patients with AD by reducing beta-amyloid plaques and reestablishing neuronal calcium permeability. At present, there is concern the magnitude of this drug's benefit may only be statistically significant, although not clinically significant. Despite skepticism, Adulhelm has proven to significantly decrease amyloid in all cortical brain regions examined. With such high stakes and potential, further research into Adulhelm's clinical efficacy is warranted in the treatment of AD.

Aducanumab, a Novel Anti-Amyloid Monoclonal Antibody, for the Treatment of Alzheimer's Disease: A Comprehensive Review.

Alzheimer's disease (AD) is the most common form of dementia affecting millions of individuals, including family members who often take on the role as caregiver. This debilitating disease reportedly consumes 8% of the total United States healthcare expenditure, with medical and nursing outlays accounting for an estimated $290 billion. Cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists have historically been the most widely used pharmacologic therapies for patients with AD, however, these drugs are not curative. This review discusses the epidemiology, pathophysiology, risk factors, presentation, and current treatment of AD followed by the role of the novel monoclonal antibody, aducanumab, in treatment of AD. Currently aducanumab is the only Food and Drug Administration (FDA) approved drug that acts to slow progression of this disease. Aducanumab is an anti-amyloid drug which functions by selectively binding amyloid aggregates in both the oligomeric and fibrillar states. Studies show aducanumab may help to restore neurological function in patients with AD by reducing beta-amyloid plaques and reestablishing neuronal calcium permeability. However, there is concern the magnitude of this drug's benefit may only be statistically significant and not clinically significant. Despite this skepticism, aducanumab has proven to significantly decrease amyloid in all cortical brain regions examined. In summary, aducanumab has provided hope for those working toward the goal of providing patients a safe and viable treatment option in the management of AD.

Potential eligibility for Aducanumab therapy in an Irish specialist cognitive service-Utilising cerebrospinal fluid biomarkers and appropriate use criteria.

OBJECTIVES: Aducanumab is a monoclonal antibody which has recently been licenced for use by the food and drug administration for treatment of patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild AD dementia. Appropriate use criteria (AUC) for Aducanumab in clinical practice are available. We look to review patients in our specialist interdisciplinary cognitive service with positive cerebrospinal fluid (CSF) biomarkers for AD for their hypothetical eligibility for Aducanumab, or a similar anti-amyloid agent. METHODS: Retrospective analysis was undertaken of patients with positive AD-biomarker CSF analysis. Data available at time of CSF analysis was reviewed to determine hypothetical eligibility for Aducanumab. RESULTS: Seventy patients had positive AD-CSF biomarkers. Forty nine of these were seen in the Gerontology-led service, with 21 in the neurology cohort. Average patient age was 70 years old. Forty patients (57%) met eligibility criteria for Aducanumab therapy by AUC guidelines. CONCLUSION: We highlight the patients within our service who would be appropriate for Aducanumab or similar anti-amyloid agents should licencing be granted in the European Union, and the need to develop the resources and capacity to deliver this or other emerging disease modifying AD therapies. CLINICAL TRIAL REGISTRATION: All patients in the combined cognitive clinic provide consent re willingness to be contacted re research.

Clinical Staging of Alzheimer's Disease: Concordance of Subjective and Objective Assessments in the Veteran's Affairs Healthcare System.

INTRODUCTION: Uncertainty surrounding the accurate assessment of the early-stage Alzheimer's disease (AD) may cause delayed care and inappropriate patient access to new AD therapies. METHODS: To analyze clinical assessments of patients with AD in the Veteran's Affairs (VA) Healthcare System and evaluate concordance between subjective and objective assessments, we processed clinical notes extracted by text integration utilities between April 1, 2008 and October 14, 2021. Veterans who had mild, moderate, or severe AD with clinical notes documenting both clinician's judgement of AD severity and objective test scores from the Mini-Mental State Examination or the Montreal Cognitive Assessment were included. Using clinician-defined severity cohorts, we determined concordance between the clinician's (subjective) assessments and the test-derived (objective) assessments of AD severity. Concordance was assessed over time and by selected symptoms and comorbidities, as well as healthcare system factors. RESULTS: A total of 8888 notes were initially extracted; the final analysis sample included 7514 notes corresponding to 4469 unique patients (mean [standard deviation] age of 78 [9] years; 96.5% male; 77.8% White). Subjective and objective assessments were concordant in approximately half (53%) of overall notes. In the mild Alzheimer's cohort, patients were assessed to have more severe disease by objective test scores in 40% of notes. Concordance varied about 21-73%, 47-58%, and 40-64% across symptoms/comorbidities, clinician types, and Veteran's Integrated Service Networks, respectively. The proportion of concordant notes was higher in visits to dementia (61%) instead of non-dementia clinics (53%). CONCLUSIONS: We found higher concordance between clinician's assessment and test-based assessment of Alzheimer's disease severity in dementia specialty clinics. Discordance is especially high for the subjectively assessed mild AD cohort where objective assessments showed a higher severity level in 40% of notes. These data indicate a critical need for improved understanding of clinical assessments and decision-making to identify appropriate patients for anti-amyloid therapy.

The Future of AD Clinical Trials with the Advent of Anti-Amyloid Therapies: An CTAD Task Force Report.

BACKGROUND: Aducanumab (ADUHELMTM) was approved for the treatment of Alzheimer's disease (AD) in the US. This approval was supported by an effect on the cerebral amyloid plaque load and evidence of cognitive efficacy to be confirmed in post-marketing trials. Other anti-amyloid antibodies are under investigation in phase III (donanemab, lecanemab, gantenerumab) and have shown preliminary evidence of a cognitive benefit in phase II trials. Although these agents target a small segment of patients with mild cognitive impairment due to AD or mild AD dementia, their advent will change the design of future clinical trials both for anti-amyloid and non-amyloid drugs. These changes will promote the selection of patients in clinical trials by amyloid and tau biomarkers that identify patients with appropriate biology and may follow the treatment response to approved amyloid antibodies. The use of these agents creates the opportunity to test combined drug therapies and to conduct comparative assessments with innovative therapies and newly approved drugs available in clinical practice. Blood-based AD biomarkers should be implemented in research and could facilitate the recruitment into clinical trials. Anti-amyloid antibodies will have positive (e.g., more early diagnosis) and negative impacts (some subjects will be reluctant to participate in trials and risk assignment to placebo) on AD trials in the immediate future. We present the results of the CTAD Task Force on this topic, in Boston, November 6, 2021.

The Amyloid Cascade Hypothesis in Alzheimer's Disease: It's Time to Change Our Mind.

Since its discovery in 1984, the beta amyloid peptide has treaded the boards of neurosciences as the star molecule in Alzheimer's disease pathogenesis. In the last decade, however, this vision has been challenged by evidence-based medicine showing the almost complete failure of clinical trials that experimented anti-amyloid therapies with great hopes. Moreover, data have accumulated which clearly indicate that this small peptide plays a key role in the physiological processes of memory formation. In the present review, we will discuss the different aspects of the amyloid cascade hypothesis, highlighting its pros and cons, and we will analyse the results of the therapeutic approaches attempted to date that should change the direction of Alzheimer's disease research in the future.

Prevention of Alzheimer's disease: a global challenge for next generation neuroscientists.

The incidence of dementia is rapidly increasing in developed countries due to social and demographic changes. This trend is expected to worsen in the coming decades, with the number of cases possibly even tripling in the next 25 years. Therefore Alzheimer's disease (AD) prevention is becoming a global health priority. Our knowledge of the pathophysiological process leading to the development of pathological brain lesions that characterize AD has increased exponentially in recent years. However, the phenotypic expression of AD not only depends on the development of senile plaques and neurofibrillary tangles but other factors also play a role. Thus, over the last few decades, epidemiological studies have revealed several risk factors for developing AD, such as vascular or lifestyle related factors. Having the current knowledge on AD, two different strategies have been developed for the prevention of AD: one is based on primary prevention by acting on modifiable risk factors, the other is a pathophysiology-driven approach aimed to identify individuals in a preclinical stage of the disease and treating them with drugs purporting to act on molecular targets of the amyloid cascade. Several promising trials with these approaches are currently ongoing and results are expected in the next few years. The intrinsic limitations in the design of preventive trials should be overcome through a global effort involving healthy population, healthcare professionals, governments, industry, and scientific institutions. This exertion will be more than compensated if we can make AD a preventable disease.

Can BACE1 inhibition mitigate early axonal pathology in neurological diseases?

ß-Secretase-1 (BACE1) is the rate-limiting enzyme for the genesis of amyloid-ß (Aß) peptides, the main constituents of the amyloid plaques in the brains of Alzheimer's disease (AD) patients. BACE1 is being evaluated as an anti-Aß target for AD therapy. Recent studies indicate that BACE1 elevation is associated with axonal and presynaptic pathology during plaque development. Evidence also points to a biological role for BACE1 in axonal outgrowth and synapse formation during development. Axonal, including presynaptic, pathology exists in AD as well as many other neurological disorders such as Parkinson's disease, epilepsy, stroke, and trauma. In this review, we discuss pharmaceutical BACE1 inhibition as a therapeutic option for axonal pathogenesis, in addition to amyloid pathology. We first introduce the amyloidogenic processing of amyloid-ß protein precursor and describe the normal expression pattern of the amyloidogenic proteins in the brain, with an emphasis on BACE1. We then address BACE1 elevation relative to amyloid plaque development, followed by updating recent understanding of a neurotrophic role of BACE1 in axon and synapse development. We further elaborate the occurrence of axonal pathology in some other neurological conditions. Finally, we propose pharmacological inhibition of excessive BACE1 activity as an option to mitigate early axonal pathology occurring in AD and other neurological disorders.