Alzheimer Disease and the Evolving Treatment Landscape

To claim CE credit for this activity, please visit https://www.pharmacytimes.org/courses/a-supplement-to-the-american-journal-of-managed-care-advancing-alzheimer-disease-treatment-updates-and-insights-for-managed-care

ABSTRACT

Alzheimer disease (AD) is an irreversible, progressive neurodegenerative disorder that destroys memory and the ability to think, slowly over time. AD is the leading type of dementia, accounting for 60% to 80% of cases, and the sixth leading cause of death in the United States. AD, which can range from mild to severe, is thought to occur secondary to the aggregation and accumulation of β-amyloid peptides, abnormal phosphorylation of tau protein, and neuroinflammation. Current treatment options vary depending on the severity of AD, and emerging treatment options continue to arise. Managed care organizations are in an excellent position to implement viable patient care ecosystems to support patients and caregivers in decreasing AD progression and its consequences. Vigilance in identifying AD and providing early treatment is crucial to improving patient outcomes and burden of disease on patients, caregivers, and health systems.

Am J Manag Care. 2022;28(suppl 10):S179-S187. https://doi.org/10.37765/ajmc.2022.89235

Overview of Alzheimer Disease and Pathophysiology

Alzheimer disease (AD) is an irreversible, progressive neurodegenerative disease that leads to issues with language, memory, the ability to care for oneself, geographical disorientation, and executive function or thinking skills that are required for daily activities. It is the leading cause of dementia among the aging population, accounting for 60% to 80% of dementia cases, and is the sixth leading cause of death in the United States.^1-3 Not only does AD disrupt the regular lifestyle of an individual, it can also progress to a complete loss of independence, requiring all of the individual’s needs to be met by caregivers, and oftentimes leads to institutionalization.³

AD affects 6.5 million people in the United States and 30 million to 35 million people worldwide. The prevalence of AD is projected to increase to 13.8 million and 150 million people in the United States and worldwide, respectively, by 2060. The most significant risk factor for developing the disease is age; the older one is, the more likely they are to experience the disease, with an 11% chance of developing AD for individuals older than 65 years and a 33% chance for individuals older than 85 years.^3,4 In age-specific global prevalence of AD, women are 1.17 times more likely than men to have a diagnosis of AD.⁵ Also, Hispanic and African American individuals are 1.5- to 2-fold more likely than White individuals to experience AD.¹ Other risk factors include the accumulation of β-amyloid (Aβ) and tau, as well as genetics, female gender, lower level of education, lifestyle behaviors (ie, smoking, diet, exercise, and high alcohol intake), concomitant diseases (ie, sleep disorder, diabetes, cardiovascular [CV] disease, obesity), and environmental factors.^2-4,6,7

The pathophysiology of AD is multifactorial, which makes treating and curing the disease difficult (Figure 1⁸). The pathological hallmarks of AD are cerebral plaques containing aggregates of Aβ derived from amyloid precursor protein as well as neurofibrillary tangles (NFTs) that contain hyperphosphorylated and aggregated tau (Figure 2⁴).^4,8 The accumulation of Aβ is thought to be the initial insult, which is the basis for the amyloid cascade hypothesis and abnormal phosphorylation of tau protein, creating the formation of NFTs within neurons.⁹ It has also been hypothesized that microglial activation results from Aβ formation. This microglial activation assists in clearing Aβ in the normal brain, but in the AD brain, this process may become less efficient with time, and the sustained microglial activation may enhance the core pathology of AD.¹⁰ Acetylcholinesterase, an enzyme that usually causes the hydrolysis of acetylcholine, may promote Aβ assembly by forming stable complexes with Aβ fibrils. These complexes are more dangerous to neurons than the fibrils alone, which may explain why the cholinergic neurons are destroyed.^11,12 Hyperphosphorylated tau ensues disassembly of microtubules damaging the cytoskeleton and signal transduction in neuronal cells.⁸ Degeneration of neurons, particularly cholinergic neurons, which are the seat of memory processes, has been noted and evidenced as atrophy that is appreciated via brain imaging. It is hypothesized that this degeneration contributes to the explanation for memory decline and forms a theoretical justification for pharmacologic therapies that support cognitive function. It is also postulated that this degeneration can contribute to radical formation that may cause inflammatory processes in the brain that further impair brain function.^8,10 Neuroinflammation occurs when injury, infection, or disease stimulates brain cells to produce proinflammatory mediators, such as cytokines and chemokines, that ultimately contribute to neuronal damage and death.¹³ Genetic data and imaging suggest that Aβ plaque deposition occurs before cortical tau pathology.⁹

Clinical Presentation of Alzheimer Disease

Changes in the brain may occur long before clinical symptoms are detected, making early diagnosis of AD particularly challenging. These changes in the brain anatomy lead to neuronal death and a progressive worsening of the symptoms of dementia: memory loss, cognitive decline, and eventually the inability to perform activities of daily living.³ AD progresses on a spectrum of 3 phases: preclinical, mild cognitive impairment, and then dementia, which is further stratified into mild, moderate, or severe stages. How quickly patients progress through the continuum varies and is influenced by factors including age, genetics, and sex.³

• Preclinical phase: potential biological changes in the brain but no symptoms
• Mild cognitive impairment: mild symptoms that most likely do not interfere with daily activities
• Dementia (mild/moderate/severe): progression from mild to severe is determined by the interference with everyday activities on a continuum from some to many to most being unable to be completed

AD often presents as short-term memory loss, and as the disease progresses, symptoms can escalate to disorientation, mood swings, agitation, psychosis, language issues, and sleep changes. AD can also lead to death in severe disease when there is a loss of bodily function.4 The stages of progression start with mild AD, which may include memory loss and other cognitive difficulties such as wandering and getting lost, taking longer to complete routine daily tasks, and personality changes. Moderate AD presents when damage occurs in the areas of the brain that control language, reasoning, and sensory processing with signs and symptoms of increased memory loss, difficulty recognizing family and friends, and inability to learn new things. Some patients may experience depression, hallucinations, delusions, and paranoia as the disease progresses. Severe AD is identified when plaques and NFTs spread throughout the brain with signs and symptoms of the inability to communicate, and eventually, the bodily functions may cease.¹

Currently, the diagnosis of AD is made consequent to subjective symptom reporting, cognitive testing, and a series of lab testing that assists in ruling out reversible or treatable conditions that can cause cognitive changes. This lab testing may include imaging studies such as CT scans, magnetic resonance imaging (MRI), and/or positron emission tomography (PET) scans. PET scans are tracer molecules that provide an analysis of proteins from cerebrospinal fluid (CSF). Although there are no validated blood biomarkers for AD, there are 3 CSF biomarkers of Aβ42, total tau protein, and phosphorylated tau that can be used as a biomarker for the diagnosis of AD.¹⁴ The accuracy with PET is 100% specificity and 96% sensitivity in AD.¹⁵

The International Working Group recommends that a confirmed diagnosis of AD must include both the presence of biomarkers (Aβ and tau positivity) and specific clinical phenotypes common to AD (amnestic AD, logopenic variant primary progressive aphasia, and posterior cortical atrophy). However, in clinical practice, biomarker data are not commonly used, partly due to costs and limited access.¹⁶ MRI is used to show the contrast between gray and white matter. Figure 3⁴ shows a side-by-side comparison of a healthy volunteer and someone with AD. The AD brain shows atrophy, dilation of the lateral ventricle, and a smaller hippocampus.⁴ An MRI is used to rule out other conditions such as strokes, tumors, brain trauma, and evidence of cerebral atrophy. Additional diagnoses to rule out that can mimic or exacerbate symptoms of AD include depression, dehydration, electrolyte and metabolic abnormalities, anemia, ischemia, hypoxia, thyroid and vitamin deficiencies, and infections (eg, pneumonia, urinary tract infection, HIV, tertiary syphilis).¹ Blood-based biomarkers revealing Aβ, phosphorylated tau 217, and neurofilament light in the CSF have been investigated and validated in clinical research. This less invasive test may assist in earlier and more accurate diagnosis of AD and may become a part of the diagnostic workup once FDA approval is received, and the cost is more practical.^17-20

Burden of Alzheimer Disease

AD is associated with significant mortality. The number of deaths from AD, as recorded on death certificates, increased 145% between 2000 and 2019, while deaths from the number one cause of death (heart disease) decreased by 7.3%. During this same time period, the death rate from AD increased 33%, 51%, and 78% for people aged 65 to 74 years, aged 75 to 84 years, and 85 years and older, respectively. The mortality rate of women is higher than men.³

The life expectancy of an individual with AD after initial diagnosis averages 4 to 8 years but some may live for 20 years, with up to 40% of that time spent in the severe stage.³ An analysis estimating the life expectancy among patients 70 years and older showed that 61% of patients with AD compared with 30% of the general population were expected to die before age 80.²¹ As AD progresses, non-memory symptoms such as immobility, difficulty swallowing, and malnutrition become more prevalent. These symptoms affect activities of daily living and correlate with significant morbidity and decreased autonomy and quality of life (QOL) in patients.^3,22 Caregivers, of which a majority are women, are heavily relied on for assisting with these activities of daily living. It is estimated that more than 11 million Americans provide unpaid care for patients with AD and other dementias.³ Although caregivers report positivity with family togetherness and helping others, the role can pose challenges such as emotional stress, depression, anxiety, hypertension, CV disease, and dementia. It may even lead to mortality in caregivers.^3,23,24

Evolving Alzheimer Disease Management and Treatment Landscape

The initial approach to treating AD addressed the degeneration of cholinergic neurons in the brain and attempted to make more acetylcholine available to assist with memory processes.^12,25 The next approach was to target the Aβ growth and accumulation. The initial target of Aβ was secondary to the accumulation of Aβ, being considered the initial insult that creates accumulation of tau and tau-mediated neurodegeneration in AD. Treatments that target removal of Aβ have been the mechanism of focus for development as a disease modification treatment for AD, although no significant benefit clinically has been demonstrated thus far. One hypothesis of this failure is that treatment is not occurring soon enough in the progression of AD. Preclinical evidence demonstrates that tau pathology can progress independent of Aβ accumulation and downstream of genetic risk factors for AD. A new treatment approach for AD is being studied around neuroinflammation.^4,9

Current Treatment Options

Management of AD requires shared goals among the clinician, patient, and caregivers. Treatment and goal setting of AD is dynamic, multifactorial, and multidisciplinary.¹ Three cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and one N-methyl-D-aspartate-antagonist (memantine) are currently FDA approved for treatment of AD.^26-30 All of these products are available for oral administration.^26-28,30 Rivastigmine is additionally available in a transdermal patch designed to improve tolerability and aid in adherence.²⁹ These drugs have similar effects with improvements above baseline on measure of cognition on the AD Assessment Scale cognitive subscale in the range of about 4% and global function as well as temporary stabilization of activities of daily living.³¹ Donepezil and transdermal rivastigmine are indicated for mild, moderate, or severe AD, whereas galantamine and oral rivastigmine are solely indicated for mild to moderate AD.^26-29 If a patient progresses to moderate or severe AD while on these drugs, memantine can be added, or memantine-donepezil can be used as monotherapy.³⁰ Adverse effects (AEs) of cholinesterase inhibitors include nausea, vomiting, loss of appetite, muscle cramps, diarrhea, sleep disturbances, and in rare instances, syncope, and CV effects such as bradycardia and dizziness. Additionally, atrioventricular block has been noted with donepezil. The addition of memantine adds AEs of headache, constipation, confusion, and dizziness.²

There are several non-FDA−approved therapies that have been used by consumers to address AD symptoms, but there is varying evidence in the scientific literature to substantiate their use, and none have been documented to modify the disease in any way. Some examples of herbal products that have been used include, but are not limited to, ginkgo, huperzine A, turmeric, gotu kola, sesame oil, and coconut oil.^32,33 There are also several other proprietary products such as Focus Factor, Prevagen, and Procera AVH, which contain a variety of substances that also make claims of helping improve memory.³⁴ Medical foods, which are designed to replace the nutritional deficits associated with certain disease states, have also been used for patients with AD, but like the herbal and proprietary products mentioned earlier, their efficacy for slowing down the progression of the disease has not been proven to be scientifically superior to the cholinesterase inhibitors or memantine.^34,35 The role in therapy for these products has yet to be determined, and consumers are advised to seek medical guidance before using them.

The limitations of the current traditional therapies are that they only focus on improving symptoms related to AD and in time, their effectiveness may wane due to the progression of the disease. Therefore, there is an unmet need for treatment options that can cure or change the course of AD. As understanding of the pathophysiology of AD has progressed, research interest has shifted from symptom reduction treatments to disease-modifying therapies that aim to decrease the formation of Aβ plaques and NFTs.²

The first disease-modifying therapy (aducanumab) was FDA approved for the treatment of AD in June 2021.^36,37 Aducanumab, a once-monthly intravenous infusion, is a immunoglobulin gamma 1 monoclonal antibody with high affinity to Aβ. Aducanumab lowers Aβ levels by reducing soluble and insoluble Aβ oligomers and fibrils, which are associated with the pathogenesis of AD.³⁷

The approval and use of aducanumab have been controversial for many reasons. One major concern is that although the drug reduces plaques in the brain, it is uncertain if this is linked to improved patient symptoms and QOL.³⁸ Two phase 3, randomized, double-blind, placebo-controlled, global studies, EMERGE and ENGAGE, evaluated the efficacy of monthly doses of aducanumab in slowing cognitive and functional impairment in patients aged 50 to 85 years with early AD (mild cognitive impairment or mild dementia).39 Patients were randomized to low- (3 or 6 mg/kg) or high-dose (10 mg/kg) aducanumab or placebo based on the presence of a genetic marker for AD, APOE ε4. The primary outcome was clinical dementia rating scale sum of boxes (CDR-SB).³⁹

When analyzed together, there was no change in the primary outcome, so the 2 trials were terminated prematurely for not meeting the prespecified futility analysis.^39-41 However, a post hoc analysis of the EMERGE trial found a significant reduction of clinical decline for the primary end point at 78 weeks (22% compared with placebo; P = .01) in patients treated with high-dose aducanumab. This provided sufficient efficacy to justify submission of a New Drug Application to the FDA and subsequent approval under an accelerated approval process.⁴¹ However, the FDA has required another trial, ICARE AD-US, which will evaluate the safety and effectiveness of the drug in 6000 patients, to be completed by 2030 to determine if there is a clinical benefit for patients.^38,42 A second concern regarding aducanumab is that it is not totally clear of its role in early versus late AD, because the labeling broadly alludes to AD but the studies were done in patients with mild cognitive impairment or early dementia as a result of AD.³⁷ A third concern is that the route of administration and the cost of therapy (initially $56,000 per year) may create some access to care issues.^43,44

Additionally, pooled safety data from the EMERGE and ENGAGE studies demonstrated that aducanumab caused amyloid-related imaging abnormalities, such as brain edema, sulcal effusion, or hemosiderin deposits resulting from brain microhemorrhages, in 41% of patients compared with 10% receiving placebo.⁴⁵ Therefore, before initiating therapy and before the seventh and twelfth infusions, an MRI should be obtained.³⁷ This requirement adds concerns for patients who may not be able to obtain MRIs due to use of implanted pacemakers, intracranial aneurysm clips, cochlear implants, and other conditions. Other possible AEs include headache, falls, dizziness, and nasopharyngitis.^37,39

Emerging Treatment Options

A hallmark of AD is the formation of Aβ plaques and NFTs, which are the focus of many investigational treatments under development.⁹ Novel treatments that target the dysregulated process before Aβ and tau pathology could be imperative to the treatment landscape. Investigational treatments are summarized in the Table.^46-69 In the United States, donanemab, gantenerumab, and lecanemab have received recognition as breakthrough therapy and are expected to go through an accelerated approval process by the FDA over the next 1 to 2 years.

Donanemab

Donanemab is a humanized immunoglobulin gamma 1 monoclonal antibody that recognizes Aβ (p3-42), a pyroglutamate form of Aβ aggregated within amyloid plaques, and removes the plaque.70 The TRAILBLAZER-ALZ, TRAILBLAZER-ALZ 2, and TRAILBLAZER-ALZ 3 studies evaluate the safety, tolerability, and efficacy of donanemab versus placebo, whereas TRAILBLAZER-ALZ 4 evaluates donanemab versus aducanumab.50-53 TRAILBLAZER-ALZ, TRAILBLAZER-ALZ 2, and TRAILBLAZER-ALZ 4 enrolled subjects with early symptomatic AD.50,51,53 TRAILBLAZER-ALZ 3 is evaluating cognitively normal patients at high risk for AD based on elevated plasma tau and is designed to answer the question that if started early enough, might donanemab prevent the onset of symptoms in patients at high risk for AD.52 Results from TRAILBLAZER-ALZ showed a significant reduction (32%) in the primary outcome of change in the Integrated Alzheimer’s Disease Rating Scale from baseline at−6.86 with donanemab versus −10.06 with placebo (P = .04) at 76 weeks.⁵⁰

Gantenerumab

Gantenerumab is a fully human antibody that targets Aβ peptides and induces phagocytosis by activating microglia.⁵⁴ The Scarlet RoAD and Marguerite RoAD studies evaluated monthly subcutaneous injections of gantenerumab in patients with prodromal and mild AD, respectively.^54,71 Both studies were stopped early for futility, but analyses indicated a dose-dependent reduction in Aβ plaques (secondary end point) that spurred further investigation of gantenerumab at higher doses (1200 mg).^54,71 A subset of subjects from each trial entered into an open-label extension study and preliminary results showed continued reduction in Aβ plaques in patients receiving gantenerumab compared with placebo at 1, 2, and 3 years.^54,55 Furthermore, the safety and efficacy study of higher doses of gantenerumab in participants with early AD is being evaluated in 2 randomized, placebo-controlled, phase 3 clinical studies in the GRADUATE 1 and GRADUATE 2 trials.^56,57 The primary end point of these trials is CDR-SB.^56,57 The Dominantly Inherited Alzheimer Network Trials Unit trial compared gantenerumab and solanezumab with placebo but failed to meet its primary end point on the Dominantly Inherited Alzheimer Network Multivariate Cognitive End Point.^58,59

Lecanemab

Lecanemab is a monoclonal antibody that binds to large Aβ protofibrils, a soluble toxic version of Aβ, leading to their removal.⁷² A phase 2 clinical trial, Study 201, evaluated the efficacy and safety of lecanemab.^60,72 Although the analysis at 12 months did not meet the primary end point of significantly improving Alzheimer’s Disease Composite Score, it did not meet futility conditions. The 18-month data did show a significant decrease of 30% in cognitive decline and a lower accumulation of Aβ. An open-label extension study is ongoing.⁷² CLARITY AD is a phase 3 study that evaluates the efficacy of lecanemab in patients with early AD, and the primary end point is the change from baseline CDR-SB.⁶¹ The phase 3 study AHEAD3-45 has 2 sub-studies of patients that are cognitively normal but have elevated brain amyloid.⁶²

Conclusions

Currently, there are no cures for AD, but the future is promising, given quicker diagnosis, potential for disease-modifying therapy, and knowledge of emerging treatments. With a focus on the AD hallmarks of Aβ and tau, and exploration into new treatment approaches, there is a possibility of a cure. Managed care professional knowledge of the emerging treatment options and strategies is key to clinical decisions that will improve the QOL among patients living with AD and their caregivers.

Author affiliation: Angela M. Hill, PharmD, RPh, CPh, is a Professor and Associate Dean of Clinical Affairs, University of South Florida Tanjea College of Pharmacy, Tampa, FL.

Funding source: This activity is supported by an educational grant from Lilly.

Author disclosure: Dr Hill has no relevant financial relationships with commercial interests to disclose.

Authorship information: Analysis and interpretation of data; concept and design; critical revision of the manuscript for important intellectual content; drafting of the manuscript; supervision.

Address correspondence to: ahill2@usf.edu

Medical writing and editorial support provided by: Lori Huang, PharmD, and Brittany Hoffmann-Eubanks, PharmD, MBA.

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