Anti-Amyloid Monoclonal Antibodies in Alzheimer’s Disease Part 1: Patient Selection

Abstract

The availability of monoclonal antibodies directed against amyloid beta, as disease modifying therapies for Alzheimer’s disease (AD), represented a major shift in the field. The FDA approvals for both lecanemab, and more recently donanemab, provides clinicians two anti-amyloid therapy (AAT) options for targeting early symptomatic AD. The emergence of AAT has made careful biomarker-informed diagnosis of AD paramount, which was once reserved for highly specialized centers and research settings. Patient selection is complex, and while appropriate use recommendations have been published, clinicians caring for patients with AD across the country face uncertainty when trying to align clinical trial criteria, appropriate use recommendations, and “real world” patients in the clinic. Practical issues in patient selection as well as healthcare and systemic challenges in the implementation of AAT are considered in Part 1 and Part 2, respectively, of this two-part Treatment in Behavioral Neurology & Neuropsychiatry commentary on these therapies from the American Neuropsychiatric Association Dementia Special Interest Group.

Case Vignettes

Case 1: Amnestic Mild Cognitive Impairment (aMCI)

An 82-year-old woman presents to a memory disorders clinic for evaluation of two years of memory changes. She remains independent in instrumental activities of daily living. Her past medical history includes well-controlled hypertension and depression. Her elemental neurological examination is normal and her in-office Montreal Cognitive Assessment (MoCA) was 25 out of 30 points, with all five points missed for delayed recall (no benefit from cues), leading to a diagnosis of amnestic MCI. She is interested in being considered for the “new” medication for patients with AD. The potential benefits and risks of lecanemab are discussed with her and she is interested in pursuing this therapy. Given this history, four scenarios may follow on neuroimaging performed during her assessment for anti-amyloid therapy (AAT).

Scenario 1.

Magnetic resonance imaging (MRI) reveals mild bilateral medial temporal atrophy. There are no areas of microhemorrhage or superficial siderosis and a minimal degree of periventricular mild white matter disease. All other exclusionary criteria are considered and not observed. An amyloid positron emission tomography (PET) scan demonstrates amyloid deposition involving multiple cortical regions, and a diagnosis of MCI due to AD is made. Apolipoprotein (APOE) genotyping performed for personalized risk assessment of amyloid related imaging abnormality (ARIA) with edema (ARIA-E) or hemorrhage (ARIA-H) events that can occur with AAT (1; 2). It reveals an APOE ε3/ε3 genotype, which is associated with a much lower risk than having an ε4 allele, and the patient elects to start AAT infusions.

Scenario 2.

MRI reveals mild bilateral medial temporal atrophy. There is one area of superficial siderosis in the left frontal lobe and two cortical microhemorrhages, which renders the patient ineligible to receive lecanemab due to the likely comorbid diagnosis of cerebral amyloid angiopathy (CAA) (3), which is associated with a heightened risk of ARIA and cerebral hemorrhage. While the donanemab clinical trial did allow patients with one area of superficial siderosis to receive treatment, her treating physician feels that the risk of ARIA remains elevated due to convincing clinical and MRI evidence for CAA (3).

Scenario 3.

MRI reveals bilateral mild medial temporal atrophy with no foci of microhemorrhage or superficial siderosis. An amyloid-PET scan demonstrates deposition involving multiple cortical regions, and a diagnosis of MCI due to AD is made. Genetic testing returns an APOE ε4/ε4 genotype. Information about the increased risk for ARIA and symptomatic ARIA are discussed. A shared decision-making process between the provider and the patient is offered and, after addressing questions raised by the patient and her care partner, she decides to proceed with AAT infusions.

Scenario 4:

MRI reveals mild bilateral medial temporal atrophy and minimal periventricular white matter disease. There are no areas of microhemorrhage or superficial siderosis. Amyloid-PET scan is negative, making her ineligible for ATT. Given her age and negative AD biomarkers, her clinical presentation is determined to represent limbic-predominant age-related TDP-43 encephalopathy (LATE) (4; 5); accordingly, AAT is not offered.

Case 2: Logopenic Variant Primary Progressive Aphasia due to AD

A 61-year-old right-handed man presents to a memory clinic for evaluation of a two-year history of language decline. Progressive word finding difficulties interfered with his job, eventually leading to early retirement. He remains able to drive without difficulty, to shop independently, and to manage his own medications. His medical history is unremarkable, and his elemental neurological examination is normal. On office cognitive testing, he displays significant word finding difficulties in spontaneous speech and makes occasional phonemic paraphasic errors. His MoCA score is 14 out of 30 points, with points lost for naming, sentence repetition, phonemic fluency, digit span forward and backward, serial 7 subtractions, and delayed recall. MRI brain reveals left-sided predominant temporoparietal atrophy and minimal white matter disease. A diagnosis of logopenic variant primary progressive aphasia (lvPPA) is made. A lumbar puncture is obtained and confirms the etiologic diagnosis of AD, and genetic testing returns an APOE ε3/ε3 genotype.

Although this patient’s MoCA score is below the usual cut-off for lecanemab eligibility, his language impairment is likely contributing to his poor performance, and he exhibits only limited functional impairment, consistent with mild dementia. The clinical team reviews with both the patient and his spouse that the phase 3 trial of lecanemab included only patients with typical amnestic syndromes, but that treatment is felt to be appropriate in this case if they wish to pursue it. He decides to undergo treatment and is started on AAT.

Case 3: Posterior Cortical Atrophy plus Dementia with Lewy body Syndrome (Alzheimer’s Disease and Lewy Body Disease Co-Pathology)

A 72-year-old woman presents to a memory clinic with a three-year history of a decline in visuospatial perception after two local ophthalmologists found no evidence of ocular pathology. On evaluation, the patient and her spouse report dream enactment behaviors for the past six years and well-formed visual hallucinations of animals in their yard for the past year. Her husband reports that the patient has daytime episodes lasting several hours each in which she seems very confused and sleepy, after which she seems much more coherent and attentive. On her elemental neurological examination, she has optic ataxia and oculomotor apraxia but no other deficits. On bedside cognitive testing, she is unable to identify items on an overlapping figures test and is unable to draw a clock or a cube. Both a skin biopsy for alpha-synuclein and an amyloid PET scan are both positive, indicating the presence of both alpha-synuclein and AD neuropathologic change. Both she and her husband are interested in any treatments available, including the ‘new infusions’ they saw on television. Her case is reviewed by the clinical team and a diagnosis of Lewy body disease and AD co-pathology is made. Due to the prominence of clinical features suggesting a typical clinical syndrome of dementia with Lewy bodies (DLB), she is not felt to be an appropriate candidate for AAT despite the presence of positive AD biomarkers.

Discussion

Background

The amyloid cascade hypothesis, first proposed in 1992 by Hardy and Higgins (6) and modified over the intervening decades to align with experimental observations, is a dominant model of (AD) pathogenesis (7). The hypothesis states that amyloid β (Aβ) accumulation, through either increased production (as in dominantly inherited AD) or impaired clearance mechanisms (as in sporadic AD), is a necessary molecular antecedent of AD-related neurodegeneration (7).

Efforts to clear Aβ protein species is a prevailing framework underlying AD therapeutic development. Many previous attempts have failed to adequately reduce Aβ burden or meet primary endpoints in clinical trials (8). Aducanumab (Aduhelm^®), which received accelerated, but not full approval by the U.S. Food and Drug Administration (FDA)(9), was surrounded by controversies due to the conflicting results of two simultaneously conducted phase 3 trials (10) and was discontinued in 2024.

A potentially seismic shift in the clinical practice of AD in the United States began in July 2023, after the FDA granted full approval (11) of lecanemab (Leqembi^®) for the treatment of early symptomatic AD (12). Both the Veterans Health Administration and Centers for Medicaid and Medicare Services (CMS) indicated the drug would be included in their formularies and provide coverage. In July 2024, the FDA granted full approval to donanemab (Kisluna^™) (13), leaving to clinicians and health systems to the task of navigating the new and complex landscape of implementing AAT.

In some clinical centers, close adherence to clinical trial criteria and published appropriate use recommendations (14) are the standards for therapeutic decision-making. Others leave final treatment decisions to the individual clinicians and may allow for flexibility within reasonable clinical judgment (15).

The three case vignettes presented above are offered to highligh the complexity of assessment and decision-making associated with determining whether a particular patient is an appropriate candidate for AAT. The focus of these cases is clinical decision-making rather than cost effectiveness or the balancing of potential benefits (slowing the rate of disease progression) of AAT with potential adverse events, and particularly ARIA which, although most often asymptomatic, has been associated with serious adverse events; these issues are addressed in other publications (16; 17).

The determination of patient eligility for AAT requires consideration of multiple factors. The CLARITY-AD trial (lecanemab) criteria have been operationalized for clinical use (14). At the time of this writing, there are no published appropriate use recommendations for donanemab beyond the TRAILBLAZER-ALZ 2 (donanemab) trial protocol and the FDA-approved prescribing information; such peer-reviewed recommendations are forthcoming. Strictly following trial protocol or appropriate use recommendations is not required by FDA guidelines and practices will vary within the bounds of the FDA-approved indications. In the service of facilitating care aligned with the extant literature, steps for patient selection for AAT are offered here.

Diagnosis of Alzheimer’s Disease

While exclusionary criteria may be known prior to a biomarker-based diagnosis, the foundation of patient selection for AAT hinges on a biomarker-based diagnosis of cognitive symptoms caused by AD. This is more complicated than simply identifying that a patient has cognitive symptoms and a positive biomarker for AD. In cognitively normal individuals, amyloid positivity increases with age, with over 40% of typically cognitively aging individuals displaying amyloid PET positivity in their ninth decade (18).

The current diagnostic criteria for either MCI or dementia due to AD requires the identification of a clinical syndrome that has been associated with AD as well as presence of biomarkers to indicate the presence of AD neuropathologic change (19; 20). The typical clinical presentation of AD is a progressive amnestic syndrome, but several atypical AD clinical syndromes exist. These syndromes include posterior cortical atrophy (commonly with predominant visuospatial deficits), dysexecutive and behavioral variants, lvPPA (Case 2), and corticobasal syndrome.

Atypical presentations of AD are particularly common in patients under the age of 65 years, and they collectively represent approximately one third of cases (21). The inclusion criteria for the AAT trials, in which memory impairment was required, resulted in the enrollment of persons with predominantly amnestic variants of AD. In contrast, many groups offering AAT in clinical practice include patients with commonly recognized but nonetheless atypical patterns of cognitive impairment if demonstrated to be caused by AD. The benefits and risks of AAT for these atypically presentations are not yet known. Additionally, the cognitive screening tests that are used to gauge clinical severity are problematic for some atypical variants, especially those with lvPPA (Case 2) given the central role of language in performance on these tests.

Once a clinical syndrome that is compatible with AD as a cause is diagnosed, treatment with AAT requires a biomarker-based diagnosis, which is discussed in Part 2 of this commentary from the American Neuropsychiatric Association (ANPA) Dementia Special Interest Group (SIG). Both the clinical syndrome and biomarker profiles must be considered in determination of the likely underlying etiology of cognitive decline. For instance, a progressive dysexecutive syndrome can be due to AD, but could also be caused by DLB, frontotemporal lobar degeneration (FTLD), or vascular cognitive impairment. Many causes of executive dysfunction can be treatable, including obstructive sleep apnea, medication effects, and both primary psychiatric and medical conditions (22).

Etiologic consideration relies heavily on subtle differences in cognitive profile, presence or absence of non-cognitive symptoms (e.g., visual hallucinations or Parkinsonian motor signs), and findings on structural and/or functional neuroimaging (e.g., fluorodeoxyglucose PET scan). An individual patient meeting diagnostic criteria for mild DLB with parkinsonism, well-formed visual hallucinations, fluctuations in level of arousal/attention, and/or dream enactment (i.e., probable REM sleep behavior disorder) who has a positive amyloid PET scan may be given a diagnosis of AD. Familiarity with modern DLB diagnostic criteria (23), including proposed prodromal DLB criteria (24), is critical. One serious concern about treating patients with DLB with AAT is that episodes of altered arousal/attention can be misinterpreted as being due to ARIA, or conversely, that ARIA symptoms may be mistaken for a typical fluctuation (Case 3).

A singular neuropathology as the cause of late-life cognitive decline is remarkably rare, with comorbid neuropathology of multiple proteinopathies being the norm (25; 26). The possibility of co-pathology with AD and other neurodegenerative disorders is also a complex issue to be considered for AAT. Neuropathological studies frequently identify AD co-pathology in primary DLB cases (27) as well as Lewy body pathology in cases clinically considered primary AD cases (Case 3) (28). Even typical amnestic syndromes, frequently due to AD, can be diagnostically challenging. In octo- and nona-genarians with amnestic syndromes, biomarker assessment of amyloid status may be positive, yet LATE (4; 29) or even non-neurodegenerative conditions may represent the primary etiology. Appropriate use recommendations presently suggest excluding patients with “any medical, neurological, or psychiatric condition that may be contributing to the cognitive impairment or any non-AD MCI or dementia.”

In practice, many clinicians and treatment centers are open to offering AAT to patients with concomitant conditions that may be contributing to cognitive decline if the underlying AD pathology is suspected to be playing a significant role. This nuance of diagnostic consideration is unlikely to be applied evenly, which may lead to disparities in care. The benefits and risks of AAT in the setting of co-pathology are still unknown. Practicing clinicians, in conjunction with patients and their care partners, are left to decide whether to treat patients with suspected co-pathology based on clinical history, understanding that most cases do not have AD pathology in isolation.

MRI and Vascular Brain Injury

Structural brain imaging has long been recommended in the evaluation of cognitive decline with MRI preferred over CT scan when available; however, practices vary widely. For consideration of AAT, inability to undergo MRI (e.g., due to an implanted device such as a cardiac pacemaker) is an absolute contraindication because of the critical nature of this imaging for patient selection and ARIA monitoring (14). There are best practice recommendations for baseline and monitoring MRIs (30), which include a fluid attenuated inversion recovery (FLAIR) sequence for detection of ARIA-E and at least a T2*-gradient echo (GRE) sequence for detection of microhemorrhages and superficial siderosis (i.e., ARIA-H). While trial inclusion has been based on GRE rather than the more sensitive susceptibility weighted imaging (SWI) sequences, either can allow for comparison of scans during treatment. As microhemorrhages or regions of superficial siderosis may be identified more readily by SWI than by GRE, it cannot be assumed that newly identified microhemorrhages or superficial siderosis represent ARIA unless the same sequences are used. For instance, if a pre-treatment GRE sequence is utilized for eligibility and SWI sequences used for monitoring, the identification of microhemorrhages by SWI after treatment initiation may be misinterpreted as ARIA-H when they represent only enhanced detection relative to GRE. Finally, diffusion weighted imaging (DWI) is necessary to differentiate acute/subacute from chronic infarctions; additionally, ischemic changes may be another finding in ARIA (31).

Current lecanemab appropriate use recommendations (14) recommend exclusion from treatment when more than two lacunar infarcts, any single infarction involving a major vascular territory, or severe subcortical white matter disease are present. The donanemab clinical trial did not specifically exclude participants due to number of infarctions, instead excluding only patients with “severe white matter disease.” Some clinicians have expressed concern over the restrictive nature of these recommendations and may choose not to limit treatment based on number of lacunar infarctions or extent of subcortical small vessel disease. Individuals with a greater number of strokes are at an increased risk for future strokes, and receiving an AAT will limit the ability to receive thrombolytic therapy due to concern for fatal intracerebral hemorrhage (1) (see Medical Comorbidities).

Appropriate use recommendations for lecanemab recommend against AAT if a patient’s MRI reveals more than four microhemorrhages or any areas of superficial siderosis, while the exclusion criteria in the TRAILBLAZER-ALZ 2 phase 3 trial for donanemab (32) specified no more than four microhemorrhages or one area of superficial siderosis. Case 1, scenario 2, highlights a situation where patients may be offered one antibody but not the other. Clinical groups are likely to try to harmonize inclusion/exclusion criteria for AATs. The donanemab phase 3 trial did allow individual clinicians to consider SWI sequences in place of GRE, although this is more conservative than the trial enrollment criteria. These exclusions are meant to ensure that patients with CAA do not receive AAT due to increased risk of ARIA. Many experts view ARIA as iatrogenic CAA-related inflammation (CAA-ri), which can occur in patients with CAA who do not receive AAT (30).

Medical Comorbidities

Patients with certain medical comorbidities should be excluded from treatment with AAT. Anticoagulation (AC) has been the most discussed of such exclusory medical comorbidities. While the FDA prescribing information for both lecanemab and donanemab states that clinicians should use caution if individuals are receiving AC, this was not, in fact, an absolute contraindication: antithrombic medications, including both antiplatelet and AC, were permitted in the trials. Nevertheless, because of an increased risk of intracerebral hemorrhage, it has been recommended that patients on AC be excluded from treatment until more data are available, potentially from ongoing aftermarket registries, to guide decisions about safety are available (14). In the face of recommendations not to use an AAT in patients receiving AC, careful documentation of informed consent is paramount should clinicians decide with their patients to deviate from appropriate use recommendations.

Due to at least one high profile death (1), the current recommendation is to counsel patients that they should not receive thrombolytic therapy for ischemic stroke if they are on AAT (14). Additionally, use of thrombolytic therapy for other medical indications (e.g., pulmonary embolism, myocardial infarction) will undoubtedly arise in clinical practice. Ischemic stroke has garnered special consideration because the presentation of both ARIA and ischemic stroke overlap with focal neurological deficits. The presence of new ARIA-hemorrhage (ARIA-H) likely predisposes patients to potentially fatal consequences if not identified prior to thrombolytic administration. Many clinicians and treatment centers will not offer patients thrombolytics while on AAT. Some systems have opted to give thrombolytic therapy if an MRI can be obtained prior to administration to rule out the presence of ARIA, but this presumes that the risk is only elevated in the setting of active ARIA; this aspect of care coordination is addressed in Part 2 of this commentary from the ANPA Dementia SIG. Enrollment of patients into recognized registries is critical to answer these unknown and emerging questions.

Well-controlled immune-mediated diseases were permitted for both FDA-approved AAT trials unless they required immunoglobulins, systemic monoclonal antibody therapy, systemic immunosuppression, or plasmapheresis, presumably because of concerns related to reduced efficacy of AAT or increased risk of ARIA or posterior reversible encephalopathy syndrome. The lecanemab appropriate use recommendations (14) are similar, with the exception of a more strict recommendation against treatment in those with any prior history of an immune-mediated disease. Actual practice will vary, with some centers following the stricter recommendations and others opting for more flexibility such as stopping immunological therapy for the duration of AAT or limiting exclusionary criteria only to immunological therapy suspected to interfere with AAT mechanisms.

Apolipoprotein E Genotyping

APOE occurs in three common variants: ε2, ε3, and ε4. The ε4 allele is the most common genetic risk factor for sporadic AD (2). Despite this, previously there was no recommendation for the routine acquisition of APOE genotyping clinically in the diagnostic evaluation of AD. With AAT, it is now strongly recommended (and required with the Veterans Health Administration) to obtain APOE genotyping for personalized risk assessment due to the significantly increased risk of ARIA in patients with ε4 alleles, especially in those who are ε4 homozygotes (2). Although there is an increased risk, some practices are choosing to prescribe AAT for patients who are ε4 homozygotes (e.g., Case 1, Scenario 3), but others are not.

Choice of Anti-Amyloid Therapy

With the approval of a second AAT, patients and clinicians now face the additional task of choosing an agent. In some locations this may be limited by formulary decisions. The clinical trials produced roughly equivalent outcomes of modest reduction in clinical progression, although the primary outcome measures were different, with the Clinical Dementia Rating Sum of Boxes used in CLARITY-AD (12) for lecanemab and the integrated Alzheimer’s Disease Rating Scale used in TRAILBLAZER-ALZ 2 for donanemab (32).

Donanemab is administered every four weeks and lecanemab every two weeks, making donanemab more convenient. In the donanemab study, ARIA rates were higher, although it is not fully clear whether this difference was due to the slightly different trial populations versus inherently higher risk. A smaller TRAILBLAZER-ALZ 6 study, using a modified infusion titration schedule, reportedly demonstrated a lower risk of ARIA, especially for ε4 homozygote patients, but has not yet completed the peer review process. Additionally, subcutaneous administration of lecanemab has been proposed and submitted for a biologics license, though this has also not completed the peer review or approval process .

Strategies for when to stop infusions with these agents also require standardization. The available data for lecanemab indicate potential benefits of ongoing dosing for up to three years, transitioning to dosing every four weeks, rather than every two weeks, after 18 months of treatment (33). In the clinical trial, donanemab was stopped after either one amyloid PET scan that was less than 11 centiloids, or two consecutive scans below 25 but above 11 centiloids (32). However, the feasibility of using repeating amyloid PET scans, and the availability of centiloid measurement, in clinical practice remains unclear given the logistical challenges (see Part 2 of the ANPA Dementia SIG commentary).

Conclusions

Patient selection for AAT is critical to ensure that the most appropriate patients receive recently approved and costly treatments that carry a non-trivial degree of clinically meaningful risk. Subspecialists in behavioral neurology & neuropsychiatry, along with other dementia specialists in the health system, are called upon to assist with evaluation and patient selection. A nuanced understanding of neurodegenerative disease pathophysiology, neuroimaging, and biomarker performance is a prerequisite for offering AAT appropriately. Many clinical services already have extensive wait times, and due to the iterative nature of evaluation for appropriate use, multiple visits are likely required. Finally, the authors of this manuscript recognize that approaches to some of the issues raised here are likely to change as more data becomes available and clinical experience with these treatments accrues.