Therapeutic Landscape of Early Symptomatic Alzheimer’s Disease Translated into Everyday Practice for Geriatric Providers

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease associated with memory loss, cognitive decline, and functional impairment.¹ AD accounts for 60–80% of all cases of dementia.^1,2 Globally, by 2050, an estimated 130.8–175.9 million people will be living with AD and other dementias.^3,4 In the US, AD is expected to more than double among adults aged ≥65 years by 2060, from 6.07 million in 2020 to 13.85 million in 2060.⁵

AD is characterized by the progressive accumulation of amyloid beta peptide soluble aggregates that lead to the deposition of extracellular amyloid plaques in the brain, followed by the formation of hyperphosphorylated tau protein aggregates (ie, neurofibrillary tangles) inside neurons.^1,6,7 Amyloid plaques may be deposited in the brain ~20 years before the onset of cognitive impairment.⁸ Moreover, AD has a cognitively unimpaired phase characterized predominantly by neuropathological changes but may include subjective cognitive decline or subtle neurobehavioral changes.^9,10 This phase is followed by an initial symptomatic phase characterized by cognitive decline with minimal functional impact, which is termed mild cognitive impairment (MCI) due to AD.^1,11,12 MCI due to AD symptoms (eg, memory loss) can be confused with normal aging (“benign senescent forgetfulness”).^11,13,14 MCI and mild dementia due to AD (which includes cognitive and functional impairments) comprise early symptomatic AD and up to 90.2% of individuals with early symptomatic AD in the US remain undiagnosed.^11,13–15

The advent of US Food and Drug Administration (FDA)-approved amyloid-targeting therapies (ATTs) for the treatment of early symptomatic AD (ie, MCI and mild dementia due to AD) has the potential to improve outcomes for patients with AD.^1,16,17 Therefore, an accurate diagnosis in the early stages of AD is critical for optimal treatment intervention and advanced-care planning.¹ Prescribing health professionals trained in geriatrics—such as primary care physicians, geriatricians, psychiatrists, and neurologists as well as nurse practitioners, physician assistants, and dementia care specialists—play a frontline role in providing care to patients with AD.¹ Their responsibilities include the diagnosis, treatment, and monitoring of patients with AD, as well as serving as points of contact for patients and their care partners throughout the patients’ treatment journey.¹ Therefore, it is important that they have timely access to new medical developments that can facilitate the early diagnosis and treatment of AD.

This review focuses on the recent advances in the therapeutic landscape of AD, including the paradigm shift in defining AD as a biological disease.⁹ Specifically, the review will discuss (a) the recent advances in the diagnosis of early symptomatic AD (MCI and mild dementia due to AD), (b) ATTs targeting amyloid plaques that can improve outcomes for patients with early symptomatic AD, and (c) the role of geriatric-trained providers in managing the care of older adults living with AD. Relevant articles published in recent years were identified through general searches of PubMed/MEDLINE using key terms such as “diagnosis of AD”, “early symptomatic AD”, “Alzheimer’s disease modifying therapy”, “amyloid-targeting therapy”, “donanemab”, and “lecanemab” as well as by reviewing reference lists of pertinent articles, and the findings were synthesized narratively.

Diagnosis of Early Symptomatic AD

Patients typically seek medical advice when they experience impaired memory, difficulties in making decisions, reduced vocabulary in speech or writing, visuospatial issues (eg, getting lost, misplacing things), and changes in mood (eg, depression), or willingness to engage socially.^1,12,18 Care partners or primary care providers (PCPs) familiar with a patient’s medical history may also recommend follow-up consultations based on changes they notice in a patient’s cognitive abilities.^1,18 Additionally, patient care navigators (eg, social workers, case managers, nurses who help coordinate the patients’ treatment journey, or office staff in medical homes) may recommend follow-up consultations when a patient requires repeat emergency care visits or hospital admissions due to issues related to cognitive or functional decline.^1,18

How to Navigate Diagnosis of Memory or Cognitive Loss in Patients with MCI or Mild Dementia Due to AD

Clinical Assessments

PCPs may perform clinical evaluation of AD based on a patient’s medical, social, and family history; a patient’s performance on cognitive, functional, and behavioral assessments during a medical visit (eg, Medicare Annual Wellness Visit, memory loss consultation, routine follow-up); and input from the patient’s care partner.^11,12,18 Criteria considered in the clinical diagnosis of AD include cognitive and functional decline over time noticed by the patient, their care partner, or PCP; family history of AD; and differential diagnosis that rules out other causes of cognitive and functional decline (eg, older adults may have co-morbidities that mask or temporarily affect cognition).^1,12,18 Risk factors considered in the diagnosis of AD include age, family history, physical inactivity, smoking, low socialization frequency, excessive alcohol intake, chronic diseases (eg, diabetes, sleep apnea), air pollution, and apolipoprotein E ε4 (APOE ε4) genotype.^1,12 PCPs may assess whether a change in a patient’s cognitive abilities is due to co-morbidities and refer them to additional screening or specialist care (eg, dementia specialists, neurologists, geriatricians) if required.¹² As polypharmacy (use of ≥5 medications or any medication lacking a valid indication) can affect cognitive or functional abilities in older adults,¹⁹ PCPs may deprescribe certain medications based on the Beers Criteria.²⁰

Several validated patient-reported assessments are available to aid in the diagnosis of AD in clinical practice (Table 1).^4,12,21–28 Informant-reported validated assessments may be undertaken by the patient’s care partners or providers if the patient is unable or unwilling to meaningfully participate in the assessments.^12,28,29 Patients with an abnormal evaluation on cognitive assessments may be referred for follow-up cognitive and laboratory testing to rule out other causes of cognitive impairment.¹ Providers may also recommend laboratory evaluations to rule out reversible causes of memory loss, including a complete blood count, a complete metabolic panel, urinalysis, urine culture, thyroid function, tests for syphilis and human immunodeficiency virus infection (if the patient has a history of risk factors for sexually transmitted infections), and heavy metal screening.¹

Table 1 Clinical Assessments for AD in Clinical Practice Settingsa

PCPs may order additional clinical assessments to confirm the diagnosis of AD, depending on the resources available in their health systems. These assessments may include tests for biomarkers of AD,^30–32 which are discussed in the next section.

Biological Diagnosis of AD

The 2018 National Institute on Aging and Alzheimer’s Association Research Framework defined AD as a biological disease.⁹ This framework was recently updated to incorporate the use of biomarkers in the staging and diagnosis of AD.⁹

The presence of amyloid plaque deposition in the brain can be confirmed by positron emission tomography (PET) using FDA-approved tracers such as 18-F florbetapir, 18-F flutemetamol, and 18F-florbetaben.^33–37 AD pathophysiology can also be validated through PET imaging of tau using 18-F flortaucipir; cerebrospinal fluid testing with FDA-approved assays measuring Aβ42/Aβ40, P-tau181/Aβ42, or total tau/Aβ42 ratios, as well as evidence of atrophy on structural brain magnetic resonance imaging.^9,38–43

Blood-based biomarkers (BBMs) have the potential to support the diagnosis of early symptomatic AD.^30–32 Plasma biomarkers may reflect current rates of amyloid production, unlike imaging biomarkers (eg, PET) which indicate accumulation of amyloid plaques over time in the brain.⁴⁴ Further, several of the currently available commercial BBM tests have a strong correlation with amyloid detected on PET and can provide accurate information on AD pathology.^45,46 For example, the plasma P-tau217 biomarker was shown to provide diagnostic accuracy (90%) that was comparable to FDA-approved cerebrospinal fluid biomarkers (87–90%) in patients with MCI due to AD.^45,46 The clinical utility of BBMs was demonstrated in a recent study by Palmqvist et al, which showed that PCPs had a diagnostic accuracy of 58% in identifying clinical AD after an evaluation without the use of BBMs.³² The diagnostic accuracy increased to 89–90% when PCPs used BBMs in their evaluation (plasma % of P-tau217/non-phosphorylated tau217).³² BBM tests for AD currently available in the US include assays to measure the Aβ42/Aβ40 ratio, P-tau217, and P-tau181 individually or in combination.^45–47 The US FDA recently cleared the use of a plasma P-tau217/Aβ42 ratio in specialized care settings to facilitate early detection of amyloid plaques in individuals with signs and symptoms of AD.⁴⁸ The BBM test is currently cleared for individuals with cognitive impairment but not for individuals with without symptoms of AD (eg, cognitively unimpaired AD). The use of a highly accurate BBM test for individuals with cognitive impairment where AD is suspected may speed up the diagnostic process.

Barriers to Diagnosis of Early Symptomatic AD

Early symptomatic AD is frequently underdiagnosed in clinical practice settings.^1,32,49,50 The underdiagnosis of AD is even higher in older adults from Black/African American and Hispanic/Latino groups.^1,49–51 Barriers to the diagnosis of early symptomatic AD in clinical practice settings include a lack of understanding of symptoms of AD vs normal aging, presence of dementia due to other diseases (eg, dementia with Lewy body disease, frontotemporal and vascular dementia, Parkinson’s disease, mixed dementia/mixed etiology dementia), lack of information regarding the clinical use of biomarkers in AD diagnosis, and lack of standardized protocols or processes (eg, standardized order sets for imaging) to aid in the diagnosis of AD.^{1,11,13,50,52,53} Other barriers to the diagnosis of AD include constraints on the providers’ time, limited healthcare resources (eg, limited insurance coverage, out-of-pocket costs to the patient, access to health centers, long waiting lists), linguistic barriers, cultural differences in the perception of cognitive decline (eg, stigma), geographical location (eg, urban vs rural), and potential biases in the healthcare system.^1,50–52

Therapeutic Landscape for Early Symptomatic AD

Non-Pharmacological Interventions

Non-pharmacological interventions for AD include maintaining a healthy diet, nutritional supplementation, regular physical activity or exercise, appropriate sleep hygiene, cognitive-oriented interventions, avoiding social isolation, and regular assessments for hearing, sense of smell (anosmia), and chronic conditions.^54–59 Emerging evidence indicates that these interventions may improve the quality of life of patients with AD or delay symptom onset in older adults at risk of AD.^60,61 For example, the randomized-controlled FINGER⁶² and US POINTER⁶⁰ clinical trials showed cognitive benefits of multidomain lifestyle interventions in older adults at elevated risk of cognitive decline and dementia. However, existing evidence does not demonstrate disease-modifying effect of these non-pharmacological interventions on AD pathophysiology and disease progression.

Symptomatic Treatments

Currently approved symptomatic treatment for AD includes drugs that target cognitive or non-cognitive symptoms.^4,6,63–65 These symptomatic treatments provide symptom relief but do not alter the course of AD or slow its progression.^6,66

Treatments to manage cognitive symptoms of AD include acetylcholinesterase inhibitors and glutamate modulators. Acetylcholinesterase inhibitors enhance neurotransmitter availability.^4,6,67,68 Donepezil is an acetylcholinesterase inhibitor indicated for mild, moderate, and severe clinical stages of AD historically diagnosed by clinical symptomatology.⁶⁹ The acetylcholinesterase inhibitors galantamine and rivastigmine are both approved for mild-to-moderate dementia clinically attributed to AD.^67,68 Glutamate receptor modulators such as memantine (approved for moderate-to-severe dementia due to AD) reduce neuronal damage.^4,70 An oral combination of donepezil and memantine is approved for moderate-to-severe AD.⁷¹

Treatments to manage non-cognitive symptoms of AD such as altered sleep-wake cycle and behavioral manifestations include suvorexant and brexpiprazole.^63–65 Suvorexant is an orexin receptor antagonist used to treat insomnia in patients with mild-to-moderate AD.^63,64 Brexpiprazole is an atypical antipsychotic approved for the treatment of agitation associated with dementia in patients with moderate-to-severe AD (agitation usually does not present in early symptomatic AD).⁶⁵

Amyloid-Targeting Therapies for Early Symptomatic AD

In recent years, there has been a paradigm shift in defining AD as a biological disease and a focus on developing treatments that target the processes underlying the pathology of AD.⁹ ATTs have demonstrated disease-modifying properties and can slow disease progression as well as cognitive and functional decline in patients with MCI or mild dementia due to AD.^6,72 Two ATTs (lecanemab and donanemab) are currently approved in the US for the treatment of patients with MCI or mild dementia due to AD with confirmed amyloid beta pathology.^16,17 The approved ATTs have demonstrated reduction of amyloid plaques and disease modifying properties.^6,7 However, treatment with ATTs does not lead to a reversal of existing cognitive or functional deficits due to AD.⁷³

Treatment Eligibility and Fit

Currently approved ATTs (lecanemab and donanemab) are recommended for patients with MCI or mild dementia due to AD (ie, early symptomatic AD) and cannot be used to treat patients with moderate or severe dementia due to AD.^16,17,73 The presence of amyloid plaques should be confirmed prior to initiating treatment with donanemab or lecanemab.^16,17

Individuals who are carriers of APOE ε4 are more susceptible to developing amyloid-related imaging abnormalities (ARIA) associated with ATTs.^{1,15–17,72,74} Therefore, prescribers should discuss with patients how APOE can affect ARIA risk and recommend testing for APOE ε4 status before initiating treatment with ATTs.^16,17

Box 1 describes the key considerations before starting treatment with ATTs.

Box 1 Key Considerations Before Starting Treatment with ATTs

Mechanism of Action and Administration

Donanemab is a humanized immunoglobulin gamma 1 monoclonal antibody that targets the insoluble N-truncated pyroglutamate amyloid-beta and reduces cerebral amyloid plaque deposits in the brain.^15,17,75 Donanemab is administered every 4 weeks as an intravenous infusion over ~30 minutes.¹⁷ The recommended dosing for donanemab is 350 mg for the 1^st dose, 750 mg for the 2^nd dose, 1050 mg for the 3^rd dose, and 1400 mg for the 4^th and subsequent doses.⁷⁶ In the TRAILBLAZER-ALZ 2 clinical trial (NCT04437511), more than half of the participants met the prespecified amyloid reduction criteria (<24.10 Centiloids) by week 52 and were eligible to complete their course of therapy.¹⁵ Lecanemab is a humanized immunoglobulin gamma 1 monoclonal antibody that targets aggregated soluble and insoluble forms of amyloid-beta and reduces amyloid-beta plaques in the brain.¹⁶ Lecanemab is administered once every 2 weeks as an intravenous infusion over ~1 hour (10 mg/kg) for 18 months.¹⁶ After 18 months, patients may continue treatment with lecanemab once every two weeks or may be transitioned to maintenance dosing (ie, intravenous infusion over ~1 hour [10 mg/kg] every 4 weeks or subcutaneous administration [360 mg] every week) at the discretion of their provider.¹⁶

Safety

The most frequently reported adverse events in patients receiving ATTs include infusion-related reactions, ARIA (ARIA with edema [ARIA-E] and ARIA with hemosiderin deposition [ARIA-H], which includes microhemorrhage and superficial siderosis), and headache.^16,17 Symptoms associated with ARIA may include headache, dizziness, nausea, confusion, changes in vision, focal neurologic deficits, or gait difficulty.^16,17 Patients who have two copies of the APOE ε4 allele have a higher incidence of ARIA events associated with treatment with ATTs.^{1,15–17,74,77,78} Other risk factors for ARIA in patients receiving ATTs include cerebrovascular disease and cerebral amyloid angiopathy.^16,17,79,80 Caution should be exercised when administering ATTs to patients who are concurrently receiving non-aspirin antithrombotic medications. The ability to draw definitive conclusions remains limited due to the small number of patients exposed to non-aspirin antithrombotic agents during ATT treatment in clinical trials.^16,76,79

Efficacy

In the Phase 3 TRAILBLAZER-ALZ 2 trial of donanemab vs placebo (NCT04437511), donanemab reduced cognitive and functional decline on the integrated AD Rating Scale (iADRS) by 22.3% at week 76.¹⁵ Donanemab was associated with a significant reduction in amyloid plaque deposition and slowing of P-tau217 accumulation in patients with early symptomatic AD.¹⁵ At 76 weeks, brain amyloid-beta plaques decreased by 87 Centiloids in patients who received donanemab and decreased by 0.67 Centiloids in patients who received placebo.¹⁵ Further, at 76 weeks, amyloid clearance was achieved by 76.4% of patients who received donanemab vs 0.3% with placebo.¹⁵ Patients who received donanemab experienced a 37.4% lower risk of progressing to the next stage of AD compared with placebo.¹⁵ Treatment with donanemab delayed disease progression by 5.3 months as measured by the IADRS and 5.2 months as measured by the Clinical Dementia Rating Sum of Boxes (CDR-SB), another composite scale of cognition and function.⁸¹ The subsequent phase 3b TRAILBLAZER-ALZ 6 trial examining the safety of different dosing regimens of donanemab (NCT05738486), included one arm receiving the dosing regimen used in TRAILBLAZER-ALZ 2 trial (dosing regimen 1: 700 mg [2×350 mg vials] for the first three doses and 1400 mg subsequently) and three additional arms that had different dosing regimens for doses 1–3, with the 4^th and subsequent doses being the same 1400 mg of donanemab.⁸² Dosing regimen 2, the dosing schedule currently recommended by the US FDA, involved the administration of 350 mg donanemab (1 x 350 mg vial) for the 1^st dose, 700 mg (2 x 350 mg vials) for the 2^nd dose, 1050 mg (3 x 350 mg vials) for the 3^rd dose, and 1400 mg (4 x 350 mg vials) for the 4^th and subsequent doses.⁸² The incidence of ARIA-E at 12 months was 15.6% for patients who received dosing regimen 2 of donanemab compared with 24.2% for patients who received dosing regimen 1 (ie, 34.7% lower relative risk).⁸² Among patients with two copies of the APOE ε4 allele, 24.0% of the patients who received the recommended dosing had ARIA-E compared to 57.0% of patients who received dosing regimen 1 (ie, 29.4% lower relative risk).⁸² Importantly, patients who received the currently recommended dosing schedule in which a single vial from dose 1 was shifted to dose 3, experienced a reduced rate of ARIA.⁸² Moreover, these patients had similar amyloid plaque and P-tau217 reductions to patients who received the standard dosing from TRAILBLAZER-ALZ 2.⁸²

In the phase 3 CLARITY-AD trial of lecanemab vs placebo (NCT03887455), lecanemab reduced global cognitive and functional decline by 27.0%, as assessed by the CDR-SB at 18 months.^74,83 The amyloid plaque burden was also significantly lower in patients receiving lecanemab.⁷⁴ The adjusted mean change from baseline was ~55.5 Centiloids in patients who received lecanemab and 3.6 Centiloids in patients who received placebo.⁷⁴ At 18 months, worsening in the CDR-SB scores was significantly reduced in patients receiving lecanemab compared with patients receiving placebo.⁷⁴ Lecanemab was estimated to slow AD progression by ~3.2 months at 12 months and by ~5 months at 18 months as measured by the CDR-SB.⁸⁴

However, it must be noted that no head-to-head studies have been conducted to compare the efficacy of donanemab and lecanemab in the treatment of AD.

When Treatment is Completed with ATTs

Treatment-related decision-making should be based on the provider’s medical discretion regarding the ATT used and the patient’s desired outcomes. Providers may consider treatment is completed with donanemab based on a reduction in amyloid plaques to minimal levels confirmed via amyloid PET imaging.¹⁷ The Centers for Medicare and Medicaid Services ended the limitation of one amyloid PET scan per patient per life,⁸⁵ so providers can now decide when to conduct a repeat amyloid PET scan based on their clinical judgement. However, it must be noted that access to PET imaging may vary in clinical practice due to differences in health systems, local insurance coverage, and access to imaging centers. Currently, there is no specific guidance on when providers should consider treatment completion with lecanemab.¹⁶ Nevertheless, at the discretion of the provider, patients receiving lecanemab may be transitioned to maintenance dosing after 18 months, comprising a regimen of 10 mg/kg intravenous infusion over ~1 hour every 4 weeks or 360 mg via subcutaneous administration every week.¹⁶

Coordination Between the Patient’s Collaborative Care Team

Optimal care for patients with AD requires multi-level coordination between the patient and their care partners, patient care navigators, and providers (eg, PCPs, dementia specialists, neurologists, geriatricians, nurses, social workers, care managers, supporting staff).^1,86 Some of the key tasks for ensuring the safety and continuity of a patient’s treatment journey include scheduling referrals, helping patients communicate any concerns like potential side effects while they are receiving ATTs, patient counseling, communicating with the patients’ care partner(s), and managing transitions of patient care between providers.^1,16,17,87 Where there are transitions of patient care between providers, the patient’s PCP may continue to be a trusted source of information for the patients (eg, the patient may prefer to consult with their PCP before they reach out to a specialist).¹ PCPs may also help the patient understand the different steps in the AD treatment journey.

Patients who do not have a care partner may require additional support in their AD treatment journey. Patient care navigators can play a crucial role by providing support, coordinating medical appointments with healthcare providers, and ensuring seamless communication within the care team to ensure integrated and continuous care.^1,88 Patient care navigators may also monitor the patient’s condition and manage their care plan based on changes in the patient’s health status. They may also advocate for the patient’s needs within the healthcare system and ensure that the patient receives appropriate services and resources. However, access to patient care navigators varies depending on the health system. Health systems that do not have dedicated patient care navigators may have staff (eg, certified nursing assistants, social workers, nurses) who may share responsibilities that are usually covered by a patient care navigator.

Communication with Patients Living with AD and Their Care Partners

Effective communication between a provider and the patient and their care partner is key to ensuring patient-centered care and safety.⁸⁹ This includes the use of clear and straightforward language in explaining the available treatment options for early symptomatic AD (ie, symptomatic treatments and ATTs) as well as the benefits and expected outcomes of treatment with ATTs.⁸⁹ Providers should ensure that patients and their care partners understand that treatment with ATTs may delay cognitive and functional decline but cannot reverse existing cognitive or functional deficits due to AD. Providers should also discuss with the patient and their care partner the risk of adverse events associated with ATT treatment (eg, infusion-related reactions and ARIA) and encourage them to report any adverse events and seek medical assistance whenever required.⁸⁹ Providers should explain the importance of APOE testing and that APOE ε4 carriers have a higher risk for ARIA.^1,89 Patients should be advised to carry information about their ATT treatment (eg, patient cards), which will help emergency care providers assess if the patient is experiencing ATT-related symptoms.¹⁷ Providers should also ensure that patients and their care partners fully understand the complex AD treatment journey and discuss the commitments that will be necessary throughout the treatment.⁸⁹ This includes APOE genotype testing before starting treatment with ATTs, the need for regular medical visits, organizing infusion or magnetic resonance imaging (MRI) scheduling, and managing side effects due to treatment.⁸⁹ Box 2 provides details on the recommended approach to patient-centered care for older adults with AD.

Box 2 Recommended Approaches to Patient-Centered Care

Conclusions

AD is now recognized as a biological disease.⁹ ATTs with disease-modifying properties are available for the treatment of early symptomatic AD.^16,17 Two ATTs, donanemab and lecanemab, are currently FDA-approved for the treatment of MCI or mild dementia due to AD and available for use in the US.^16,17,76 While these treatments may slow cognitive and functional decline in the intended patient population,^15,74,83 they cannot reverse existing cognitive or functional deficits due to AD⁷³ and are associated with adverse events such as ARIA, infusion-related reactions, and headache.^16,17 The benefit versus risk balance and potential adverse reactions associated with ATT treatments should be carefully considered during shared decision-making between the PCP, the patient, and their care partner. ATTs for the treatment of early symptomatic AD have been granted Medicare coverage in the US through a National Coverage Determination under Coverage with Evidence Development.⁹⁰ This approach facilitates the clinical use of ATTs in appropriately selected patients while requiring ongoing collection of long-term outcomes and real-world evidence to determine treatment efficacy, safety, and impact on disease progression in routine clinical practice.

Ensuring diagnosis of early symptomatic AD is key to optimizing the benefits of available and emerging treatments as well as to alleviate symptoms and delay clinical decline in patients.^1,12 Additionally, an early diagnosis may also provide patients the opportunity to participate in care plans that can provide clinically meaningful reductions in cognitive, functional, and behavioral decline; make lifestyle changes to help maintain their quality of life; and reduce the burden on care partners as well as healthcare systems.^1,12

Providers should consider optimizing communication and coordination between the multi-disciplinary health care professionals including care navigators to ensure patient-centered care.¹ Geriatric-trained professionals should consider receiving supplemental training specific to AD including the detection, diagnosis, treatment, and monitoring of therapies for early symptomatic AD, as well as in caregiver education and support with the aim to improve outcomes for their patients.¹