Anti-amyloid Monoclonal Antibody Research Articles

Clinical Arterial Spin-Labeling MR Imaging to Screen for Typical and Atypical Neurodegenerative Disease in the New Era of Alzheimer Treatment.

The clinical standard of care in the diagnosis of neurodegenerative diseases relies on [18F] FDG-PET/CT or PET MR imaging. Limitations of FDG-PET include cost, the need for IV access, radiation exposure, and availability. Arterial spin-labeling MR imaging has been shown in research settings to be useful as a proxy for FDG-PET in differentiating Alzheimer disease from frontotemporal dementia. However, it is not yet widely used in clinical practice, except in cerebrovascular disease. Here, we present 7 patients, imaged with our routine clinical protocol with diverse presentations of Alzheimer disease and other neurodegenerative diseases, in whom arterial spin-labeling-derived reduced CBF correlated with hypometabolism or amyloid/tau deposition on PET. Our case series illustrates the clinical diagnostic utility of arterial spin-labeling MR imaging as a fast, accessible, and noncontrast screening tool for neurodegenerative disease. Arterial spin-labeling MR imaging can guide patient selection for subsequent PET or fluid biomarker work-up, as well as for possible therapy with antiamyloid monoclonal antibodies.

Adapting prescribing criteria for amyloid-targeted antibodies for adults with Down syndrome.

Prior authorization criteria for Federal Drug Administration (FDA) approved immunotherapeutics, among the class of anti-amyloid monoclonal antibodies (mAbs), established by state drug formulary committees, are tailored for adults with late-onset Alzheimer's disease. This overlooks adults with Down syndrome (DS), who often experience dementia at a younger age and with different diagnostic assessment outcomes. This exclusion may deny DS adults access to potential disease-modifying treatments. To address this issue, an international expert panel convened to establish adaptations of prescribing criteria suitable for DS patients and parameters for access to Centers for Medicare & Medicaid Services (CMS) registries. The panel proposed mitigating disparities by modifying CMS and payer criteria to account for younger onset age, using alternative language and assessment instruments validated for cognitive decline in the DS population. The panel also recommended enhancing prescribing clinicians' diagnostic capabilities for DS and initiated awareness-raising activities within healthcare organizations. These efforts facilitated discussions with federal officials, aimed at achieving equity in access to anti-amyloid immunotherapeutics, with implications for national authorities worldwide evaluating these and other new disease-modifying therapeutics for Alzheimer's disease.

Messenger RNA-encoded antibody approach for targeting extracellular and intracellular tau.

Monoclonal antibodies have emerged as a leading therapeutic agent for the treatment of disease, including Alzheimer's disease. In the last year, two anti-amyloid monoclonal antibodies, lecanemab and aducanumab, have been approved in the USA for the treatment of Alzheimer's disease, whilst several tau-targeting monoclonal antibodies are currently in clinical trials. Such antibodies, however, are expensive and timely to produce and require frequent dosing regimens to ensure disease-modifying effects. Synthetic in vitro-transcribed messenger RNA encoding antibodies for endogenous protein expression holds the potential to overcome many of the limitations associated with protein antibody production. Here, we have generated synthetic in vitro-transcribed messenger RNA encoding a tau-specific antibody as a full-sized immunoglobulin and as a single-chain variable fragment. In vitro transfection of human neuroblastoma SH-SY5Y cells demonstrated the ability of the synthetic messenger RNA to be translated into a functional tau-specific antibody. Furthermore, we show that the translation of the tau-specific single-chain variable fragment as an intrabody results in the specific engagement of intracellular tau. This work highlights the utility of messenger RNA for the delivery of antibody therapeutics, including intrabodies, for the targeting of tau in Alzheimer's disease and other tauopathies.

Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies.

Amyloid-related imaging abnormalities (ARIA) were the most common adverse events reported in the phase 3 ENGAGE and EMERGE trials of aducanumab, an anti-amyloid monoclonal antibody. APOE ε4 carrier status has been shown to increase risk of ARIA in prior trials of aducanumab and other anti-amyloid therapies; however, the remainder of the human genome has not been evaluated for ARIA risk factors. Therefore, we sought to determine in a hypothesis-free manner whether genetic variants beyond APOE influence risk of ARIA in aducanumab-treated patients. We performed genome-wide association studies (GWAS) of ARIA in participants in the ENGAGE and EMERGE trials. Participants had mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia and were amyloid-positive on PET scans. All participants underwent regular MRI monitoring to detect and diagnose ARIA. Of the 3,285 participants in the intent-to-treat population, this analysis included 1,691 with genotyping array data who received at least one dose of aducanumab with at least one post-baseline MRI. All participants in the study cohort were of European ancestry; 51% were female. The mean age was 70.3 years. 31% had ARIA-E, 19% had ARIA-H microhemorrhage, and 14% had ARIA-H superficial siderosis. We identified one genome-wide significant (p < 5.0 × 10-8) association at the chromosome 19 locus encompassing APOE. The APOE association with ARIA was stronger in ε4/ε4 homozygotes (OR = 4.28, 4.58, 7.84; p < 2.9 × 10-14 for ARIA-E, ARIA-H microhemorrhage, and ARIA-H superficial siderosis, respectively) than in ε3/ε4 heterozygotes (OR = 1.74, 1.46, 3.14; p ≤ 0.03). We found greater odds of radiographically severe ARIA (OR = 7.04-24.64, p ≤ 2.72 × 10-5) than radiographically mild ARIA (OR = 3.19-5.00, p ≤ 1.37 × 10-5) among ε4/ε4 homozygotes. APOE ε4 was also significantly associated with both symptomatic (ε4/ε4 OR = 3.64-9.52; p < 0.004) and asymptomatic (ε4/ε4 OR = 4.20-7.94, p < 1.7 × 10-11) cases, although among ARIA cases, APOE did not appear to modulate symptomatic status. No other genome-wide significant associations were found. We identified a strong, genome-wide significant association between APOE and risk of ARIA. Future, larger studies may be better powered to detect associations beyond APOE. These findings indicate that APOE is the strongest genetic risk factor of ARIA incidence, with implications for patient management and risk-benefit treatment decisions. Both trials (ENGAGE [221AD301]: NCT02477800 and EMERGE [221AD302]: NCT02484547) were registered in June 2015 at clinicaltrials.gov and enrolled patients from August 2015 to July 2018.

Risk factors in developing amyloid related imaging abnormalities (ARIA) and clinical implications.

Alzheimer's disease (AD) affects over 6 million people over the age of 65. The advent of new anti-amyloid monoclonal antibodies as treatment for early Alzheimer's disease these immunotherapeutics may slow disease progression but also pose significant risks. Amyloid related imaging abnormalities (ARIA) identified on MRI following administration of these new monoclonal antibodies can cause both brain edema (ARIA-E) and hemorrhage (ARIA-H). While most ARIA is asymptomatic, some patients can develop headache, confusion, nausea, dizziness, seizures and in rare cases death. By analyzing lecanemab, aducanumab, gantenerumab, donanemab, and bapineuzumab clinical trials; risk factors for developing ARIA can be identified to mitigate some of the ARIA risk. Risk factors for developing ARIA-E are a positive Apoε4 carrier status and prior multiple cerebral microhemorrhages. Risk factors for ARIA-H are age, antithrombotic use, and history of prior strokes. With lecanemab, ARIA-E and ARIA-H were seen at lower rates 12 and 17%, respectively, compared to aducanumab (ARIA-E 35% and ARIA-H 19%) in treated patients. ARIA risk factors have impacted inclusion and exclusion criteria, determining who can receive lecanemab. In some clinics, almost 90% of Alzheimer's patients are excluded from receiving these new anti-amyloid therapeutics. This review aims to discuss risk factors of ARIA and highlight important areas for further research. With more anti-amyloid monoclonal antibodies approved by the Food and Drug Administration, considering patient risk factors for developing ARIA is important to identify to minimize patient's risk while receiving these new therapies.

Polypharmacological Potential of Phosphodiesterase 5 Inhibitors for the Treatment of Neurocognitive Disorders.

The prevalence of neurocognitive disorders (NCD) increases every year as the population continues to age, leading to significant global health concerns. Overcoming this challenge requires identifying biomarkers, risk factors, and effective therapeutic interventions that might provide meaningful clinical benefits. For Alzheimer's disease (AD), one of the most studied NCD, approved drugs include acetylcholinesterase inhibitors (rivastigmine, donepezil, and galantamine), an NMDA receptor antagonist (memantine), and anti-amyloid monoclonal antibodies (aducanumab and lecanemab). These drugs offer limited relief, targeting singular pathological processes of the AD. Given the multifactorial nature of the NCDs, a poly-pharmacological strategy may lead to improved outcomes compared to the current standard of care. In this regard, phosphodiesterase 5 (PDE5) inhibitors emerged as promising drug candidates for the treatment of neurocognitive disorders. These inhibitors increase cGMP levels and CREB signaling, thus enhancing learning, memory and neuroprotection, while reducing Aβ deposition, tau phosphorylation, oxidative stress, and neuroinflammation. In the present article, we evaluate the therapeutic potential of different PDE5 inhibitors to outline their multifaceted impact in the NCDs.

Therapeutic effects of long-term HBOT on Alzheimer's disease neuropathologies and cognitive impairment in APPswe/PS1dE9 mice

Alzheimer's disease (AD) is the most common neurodegenerative disorder with the pathological hallmarks of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. Although there is a hope that anti-amyloid monoclonal antibodies may emerge as a new therapy for AD, the high cost and side effect is a big concern. Non-drug therapy is attracting more attention and may provide a better resolution for the treatment of AD. Given the fact that hypoxia contributes to the pathogenesis of AD, hyperbaric oxygen therapy (HBOT) may be an effective intervention that can alleviate hypoxia and improve AD. However, it remains unclear whether long-term HBOT intervention in the early stage of AD can slow AD progression and ultimately prevent cognitive impairment in this disease. In this study we applied consecutive 3-month HBOT interventions on 3-month-old APPswe/PS1dE9 AD mice which represent the early stage of AD. When the APPswe/PS1dE9 mice at 9-month-old which represent the disease stage we measured cognitive function, 24-h blood oxygen saturation, Aβ and tau pathologies, vascular structure and function, and neuroinflammation in APPswe/PS1dE9 mice. Our results showed that long-term HBOT can attenuate the impairments in cognitive function observed in 9-month-old APPswe/PS1dE9 mice. Most importantly, HBOT effectively reduced the progression of Aβ plaques deposition, hyperphosphorylated tau protein aggregation, and neuronal and synaptic degeneration in the AD mice. Further, long-term HBOT was able to enhance blood oxygen saturation level. Besides, long-term HBOT can improve vascular structure and function, and reduce neuroinflammation in AD mice. This study is the first to demonstrate that long-term HBOT intervention in the early stage of AD can attenuate cognitive impairment and AD-like pathologies. Overall, these findings highlight the potential of long-term HBOT as a disease-modifying approach for AD treatment.

Safety and Tolerability of Cael-101, an Anti-Amyloid Monoclonal Antibody, Combined with Anti-Plasma Cell Dyscrasia Therapy in Patients with Light-Chain Amyloidosis: 24-Month Results of a Phase 2 Study

Background: Light-chain (AL) amyloidosis is a rare, systemic disease caused by plasma cell dyscrasia (PCD). Immunoglobulin light chains misfold and deposit in organs as insoluble amyloid fibrils. The extent of cardiomyopathy due to amyloid deposition determines patient survival. Current therapies target PCD to halt amyloid formation but do not treat existing amyloid deposits in organs. CAEL-101 is a novel, investigational, potentially first-in-class therapy to remove amyloid fibrils from organs. Aims: To present safety, tolerability, and biomarker data after 110 weeks of treatment with CAEL-101, administered initially with cyclophosphamide-bortezomib-dexamethasone (CyBorD) ± daratumumab. Methods: Adult patients with AL amyloidosis (European Modification of Mayo Stage I-IIIa) and measurable hematologic disease were eligible for this ongoing, open-label, phase 2 study (NCT04304144). Other forms of amyloidosis and multiple myeloma were excluded. CAEL-101 ≤1000 mg/m 2 was administered with CyBorD therapy ± daratumumab as directed by the investigator. In addition to safety assessments, cardiac response was assessed by change over time in N-terminal pro-brain natriuretic peptide (NT-proBNP). Results: Patients (N = 25; mean age 65 years; 72% male) with Mayo Stage I (n = 2; 8%), II (n = 19; 76%), and IIIa (n = 4; 16%) AL amyloidosis were enrolled to be treated with CAEL-101. All 25 patients experienced treatment-emergent adverse events (TEAEs); 6 (24%) experienced TEAEs possibly related to CAEL-101, 17 (68%) experienced ≥1 adverse event of ≥Grade 3 severity, and 15 (60%) experienced ≥1 serious adverse event. There were a total of 447 TEAEs reported of which only 67 (15%) were Grade ≥3. As of the cutoff date of 22 May 2023, 12 (48%) patients had discontinued the study due death (n = 3), patient withdrawal (n = 3), physician decision (n = 2), heart transplant (n = 2), heart and kidney transplant (n = 1), and adverse event (n = 1). The most common adverse events reported by ≥5 (20%) patients were fatigue (n = 12), anemia (n = 10), nausea (n = 10), constipation(n = 9), diarrhea (n = 9), cough (n = 8), dizziness (n = 8), insomnia (n = 7), peripheral neuropathy (n = 7), dyspnea (n = 6), hypokalemia (n = 6), rash (n = 6), and headache (n = 5), peripheral edema (n = 5), vomiting (n = 5). There were 22 cardiac-evaluable patients (baseline NT-proBNP &amp;gt;332 ng/L) enrolled in this trial. After 110 weeks of CAEL-101 treatment, 6 (27%) patients were cardiac responders (&amp;gt;30% NT-proBNP decrease and more than 300 ng/L decrease, if baseline NT-proBNP ≥650 ng/L), 7 (32%) patients were stable (neither response nor progression), and 2 (9%) patients showed cardiac disease progression (&amp;gt;30% increase and ≥300 ng/L increase from baseline in the absence of eGFR decline of ≥25%); data for 7 (32%) patients were missing. Cardiac response over time to 110 weeks of CAEL-101 treatment is shown in Figure). Conclusions: Patients in this analysis have been treated for ≥24 months and CAEL-101 was generally well tolerated without evidence of organ toxicity. Long-term safety evaluation of CAEL-101 continues in this study. Most TEAEs (85%) were mild to moderate. Two phase 3 trials (NCT04504825 and NCT04512235) are in progress to study the efficacy and safety of CAEL-101 in cardiac AL amyloidosis European Modification Mayo Stages IIIa and IIIb.

Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer's Disease.

Two monoclonal antibodies (mAbs), aducanumab and lecanemab, have received accelerated approval from the US FDA for initiation of treatment in early Alzheimer's disease patients who have proven β-amyloid pathology (Aβ). One of these, lecanemab, has subsequently received full approval and other monoclonal antibodies are poised for positive review and approval. Anti-amyloid mAbs share the feature of producing a marked reduction in total brain Aβ revealed by amyloid positron emission tomography. Trials associated with slowing of cognitive decline have achieved a reduction in measurable plaque Aβ in the range of 15-25 centiloids; trials of agents that did not reach this threshold were not associated with cognitive benefit. mAbs have differences in terms of titration schedules, MRI monitoring schedules for amyloid-related imaging abnormalities (ARIA), and continuing versus interrupted therapy. The approximate 30% slowing of decline observed with mAbs is clinically meaningful in terms of extended cognitive integrity and delay of onset of the more severe dementia phases of Alzheimer's disease. Approval of these agents initiates a new era in Alzheimer's disease therapeutics with disease-modifying properties. Further advances are needed, i.e. greater efficacy, improved safety, enhanced convenience, and better understanding of ill-understood observations such as brain volume loss.

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 β 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 β plays a key role in the pathogenesis of AD and of CAA. Amyloid β accumulation in the brain parenchyma as plaques is a pathological hallmark of AD, whereas amyloid β 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 β 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.

Anti-amyloid Monoclonal Antibodies in Alzheimer’s Disease: A New Hope

Objectives: The current review aimed to collect the updated clinical investigations of monoclonal antibodies (mAbs) in Alzheimer’s disease (AD) patients and assess the feasibility and efficacy of the immunotherapies with mAbs in AD. Design: A narrative review. Participants: People with AD. Outcome measures: The occurrence of AD. Results: The failure of all attempts to cure AD during the previous decades by focusing on the pathogenic factors revealed that the pathophysiology of AD is multifaceted. In recent years, anti-amyloid mAbs that exhibit beneficial effects in AD treatment have been marketed, and different studies have attempted to assess their effects. We investigated the current research to determine the potential benefits and outcomes of clinical trials of mAbs in AD cases in the review. Conclusions: This study concentrated on determining how these drugs affect AD pathology. It offers potential support for using anti-amyloid mAb immunotherapy for AD and evaluates the lessons learned from these clinical studies to conduct further research on the beneficial and harmful impacts of these therapeutic agents.

Targeting immunometabolic pathways for combination therapy in Alzheimer's disease.

The recent success of disease-modifying anti-amyloid monoclonal antibodies in slowing Alzheimer's disease (AD) symptoms has been an exciting step forward for the field. Despite successfully clearing amyloid from the brain, however, only modest symptomatic improvement has been demonstrated, and treatment-related side effects such as amyloid-related imaging abnormalities (ARIA) limit use for some. These limitations suggest that fully efficacious AD treatment may require combination therapy regimens, as are used in other complex disorders such as cancer and HIV. One reasonable strategy may be to use agents that address the biological changes that predict future amyloid accumulation, or accompany amyloid accumulation in preclinical disease states. Immunometabolic pathways, including the insulin signaling pathway, are dysregulated at the earliest stages of AD, concomitant with amyloid accumulation. It is plausible that agents that target these pathways may work synergistically with anti-amyloid therapies to halt AD progression. Insulin signaling is integrally involved in innate and adaptive immune systems, with pleiotropic effects that moderate pro- and anti-inflammatory responses. Metabolic modulators that enhance insulin sensitivity and function, such as GLP-1 receptor agonists, SGLT2 inhibitors, and insulin itself have been shown to improve immune function and reduce chronic inflammation. Additional effects of insulin and metabolic modulators demonstrated in preclinical and clinical studies of AD include increased clearance of amyloid-β, slowed tau progression, improved vascular function and lipid metabolism, reduced synaptotoxicity, and improved cognitive and functional outcomes. A large number of compounds that treat metabolic disorders have been extensively characterized with respect to mechanism of action and safety, and thus are readily available to be repurposed for combination therapy protocols. Determining the most successful combination regimens of these agents together with disease-modifying therapies, and the appropriate timing of treatment, are promising next steps in the quest to treat and prevent AD.

The Anti-Amyloid Monoclonal Antibody Lecanemab: 16 Cautionary Notes.

After the CLARITY-AD clinical trial results of lecanemab were interpreted as positive, and supporting the amyloid hypothesis, the drug received accelerated Food and Drug Administration approval. However, we argue that benefits of lecanemab treatment are uncertain and may yield net harm for some patients, and that the data do not support the amyloid hypothesis. We note potential biases from inclusion, unblinding, dropouts, and other issues. Given substantial adverse effects and subgroup heterogeneity, we conclude that lecanemab's efficacy is not clinically meaningful, consistent with numerous analyses suggesting that amyloid-β and its derivatives are not the main causative agents of Alzheimer's disease dementia.

Meaningful benefit and minimal clinically important difference (MCID) in Alzheimer's disease: Open peer commentary.

Approval of the anti-amyloid monoclonal antibodies has stimulated an important discussion of the value to be placed on the magnitude of slowing achieved by treatment compared to placebo. The minimal clinically important difference (MCID) was reviewed in the context of other measures and analyses that provide perspective on the meaningfulness of treatment responses. TheMCID is a clinician-anchored approach to making this determination. The MCID applies best to symptomatic therapies for which the drug-placebo difference remains constant. Disease-modifying therapies produce a progressive divergence of drug and placebo trajectories; early in the course the MCID would not be achieved, later the MCID will be achieved, and with continuing therapy the MCID will be exceeded. Clinicians are not the only stakeholders involved in determining the value proposition of slowing disease progression. Patient-reported outcomes and caregiver-related measures offer important complementary insights. Analytic approaches also widen the perspective on the observed drug-placebo differences. Risk ratios, numbers needed to treat versus number needed to harm, time-to-event analyses, and predictive benefits based on biomarkers all add depth to the discussion. Multiple stakeholder perspectives are needed to determine the importance to be attributed to the therapeutic changes observed with monoclonal antibody therapies and other emerging treatments.

Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer's Disease Therapeutics.

Two anti-amyloid monoclonal antibodies (MABs)-lecanemab (Leqembi®) and aducanumab (Aduhelm®)-have been approved in the USA for the treatment of Alzheimer's disease (AD). Anti-amyloid monoclonal antibodies are the first disease-modifying therapies for AD that achieve slowing of clinical decline by intervening in the basic biological processes of the disease. These are breakthrough agents that can slow the inevitable progression of AD into more severe cognitive impairment. The results of trials of anti-amyloid MABs support the amyloid hypothesis and amyloid as a target for AD drug development. The success of MABs reflects a relentless application of neuroscience knowledge to solving major challenges facing humankind. The success of these transformative agents will foster the development of more anti-amyloid MABs, other types of anti-amyloid therapies, treatments of other targets of AD biology, and new approaches to therapies for an array of neurodegenerative disorders. Monoclonal antibodies have side effects and, during the period of treatment initiation, patients must be closely monitored for the occurrence of amyloid-related imaging abnormalities (ARIA) and infusion reactions. A successful first step in the development of disease-modifying therapy for AD defines desirable features for the next phase of therapeutic development including less frequent ARIA, more convenient administration, and greater efficacy. Unprecedented agents make new demands on patients and care partners, clinicians, payers, and health care systems. Collaboration among stakeholders is essential to take advantage of the therapeutic benefits offered by these agents and to make them widely available. Monoclonal antibodies usher in a new era in AD therapy and define a new landscape of what is possible for therapeutic development for neurodegenerative disorders.

Alignment of human aquaporin 4 and ß-amyloid proteins may indicate involvement of ß-amyloid in brain water homeostasis and prevention of brain edema.

Alignment of human aquaporin 4 and ß-amyloid proteins may indicate involvement of ß-amyloid in brain water homeostasis and prevention of brain edema.

Assessing preparedness for Alzheimer disease-modifying therapies in Australasian health care systems.

Assessing preparedness for Alzheimer disease-modifying therapies in Australasian health care systems.

Clinical and Scientific Challenges to Effectiveness Studies Under Coverage with Evidence Development in Alzheimer's Disease.

The Centers for Medicare and Medicaid Services (CMS) has recently issued a national coverage determination for US Food and Drug Administration (FDA)-approved anti-amyloid monoclonal antibodies (mAbs) for the treatment of Alzheimer's disease (AD) under coverage with evidence development (CED). CED schemes are complex, costly, and challenging, and often fail to achieve intended objectives because of administrative and implementation issues. AD is a heterogeneous, progressive neurodegenerative disorder with complex care pathway that additionally presents scientific challenges related to the choice of study design and methods used in evaluating CED schemes. These challenges are herein discussed. Clinical findings from the US Veterans Affairs healthcare system help inform our discussion of specific challenges to CED-required effectiveness studies in AD.

Advances in Alzheimer's Dementia: An update from Banner Alzheimer's Institute

Alzheimer's Disease is the most prevalent cause of neurodegenerative disease accounting for 60-80% of dementia cases. With an aging population, the prevalence of AD is projected to reach 12.7 million. Clinical features for AD include difficulties with memory, language, learning, orientation, mood, communication, judgement, behavior, and eventually physical deterioration in the form of difficulty walking, speaking, and swallowing. AD is a progressive disease and pathological changes sometimes start decades before clinical symptoms manifest. AD involves the accumulation of extra-cellular beta amyloid plaques and intracellular tau protein tangles leading to neuronal dysfunction and degeneration. As age is one of the key risk factors for AD, it tends to predominantly affects older adults. Women are disproportionately affected by the disease, as they represent higher number of patients and caregivers.A confirmatory diagnosis of Alzheimer's disease can be formulated only on autopsy currently. A biomarker is a measurable indicator of the presence or severity of a disease state, and it could be used to improve the diagnosis and management of patients. Fluid- based biomarkers and radiological studies are quickly changing that paradigm in AD management. CSF and blood-based biomarkers are key in early and accurate diagnosis accelerating drug development and clinical care in dementia. Levels of Aβ42, phosphorylated tau (p-tau) proteins, and total tau (t-tau) proteins start to change years, sometimes decades before the appearance of AD symptoms. AD biomarkers include amyloid and tau deposition, neurodegeneration, inflammation, and synaptic dysfunctions. The analysis of core CSF biomarkers (total tau (T-tau), phosphorylated tau (P-tau) and β-amyloid 42 (Aβ42)) have shown excellent diagnostic accuracy in diagnosing AD (especially in atypical presentations), mild cognitive impairment (MCI) due to AD and differentiating AD from other psychiatric disorders (1). pTau217, pTau181, Glial fibrillary acidic protein (GFAP) and Neurofilament light (NFL) show promise of accuracy in both CSF and plasma.Until recently, available treatments for AD (donepezil, galantamine, rivastigmine and memantine) were symptomatic and had modest benefits. Several drugs with the potential to modify the disease process are in various stages of development. Among the promising agents, monoclonal antibodies against amyloid are some of the forerunners. Most recently, one of these drugs, aducanumab (Aduhelm) received FDA approval under accelerated pathway in June 2021. However, due to the Centers for Medicare & Medicaid Services (CMS)’s decision to restrict its coverage, aducanumab has not been accessible to the majority of patients. Nevertheless, other anti-amyloid monoclonal antibodies including donanemab, gantenerumab, and lecanemab are expected to read out topline results in late 2022/2023. In addition, there are multiple trials on other mechanisms like reducing tau, attenuating inflammation, and improving synaptic transmission.

Eisai to seek FDA approval for lecanemab, one of dozens of drugs in the Alzheimer pipeline

This fall, biotech Biogen and pharmaceutical company Eisai released topline data on their new antiamyloid monoclonal antibody le-canemab. In the confirmatory phase 3 Clarity AD study, a double-blind, placebo-controlled clinical trial that included 1,795 participants with mild cognitive impairment and early Alzheimer disease (AD), the drug slowed cognitive decline by 27% over 18 months compared to placebo.