Amyloid-targeted therapies for the treatment of Alzheimer disease

INTRODUCTION — 

Alzheimer disease (AD) is a neurodegenerative disorder that primarily affects older adults and is the most common cause of dementia. The most essential and often earliest clinical manifestation of AD is selective memory impairment, although there are presentations where language, visuospatial, or executive functions are first affected. While treatments are available that can ameliorate some symptoms of the illness or slow progress of the disease to some extent, there is no cure currently available, and the disease inevitably progresses in all patients.

Deposition of the peptide beta-amyloid is a pathological hallmark of AD. Amyloid-targeted therapies are recombinant monoclonal antibodies directed against beta-amyloid. Two such therapies have been approved and are available in the United States: lecanemab and donanemab. Studies have consistently shown that these agents are highly effective in reducing amyloid plaque burden on positron emission tomography (PET) imaging [1-3]. Thus, they are considered to have a disease-modifying effect. However, their efficacy on clinical outcomes is modest, slowing progression by approximately 25 to 30 percent in carefully selected patients, and they are associated with risk for significant adverse effects. Thus, a choice to initiate therapy is an individual one requiring shared decision-making.

This topic discusses the amyloid-targeted therapies, lecanemab and donanemab, in the treatment of AD. Other aspects of the management of AD and other forms of dementia are discussed separately:

●(See "Treatment of Alzheimer disease".)

●(See "Management of the patient with dementia".)

●(See "Care of patients with advanced dementia".)

Other aspects of AD are discussed separately:

●(See "Clinical features and diagnosis of Alzheimer disease".)

●(See "Epidemiology, pathology, and pathogenesis of Alzheimer disease".)

●(See "Genetics of Alzheimer disease".)

CENTER REQUIREMENTS — 

In general, these therapies should be administered in centers with experience in evaluating and managing patients with dementia and administering these therapies.

A number of resources are required and/or are useful:

●Neurologist or other physician with specific education and experience in cognitive assessments and general neurologic evaluation. A formal cognitive assessment is required to determine study eligibility; in addition, we suggest that clinicians monitor cognitive change regularly throughout treatment.

●Neuroradiology expertise for baseline assessment and ongoing magnetic resonance imaging (MRI) monitoring. Those that interpret MRI scans should be knowledgeable about amyloid-related imaging abnormalities (ARIA).

●Ability to perform specialized testing including amyloid positron emission tomography (PET) and/or lumbar puncture and spinal fluid testing, as well as apolipoprotein E (APOE) genotyping. (See "Clinical features and diagnosis of Alzheimer disease", section on 'Role of biomarkers'.)

●Genetic counseling for patients undergoing genetic testing.

●Infusion setting with staff trained in evaluating and managing infusion reactions.

●Inpatient hospital resources and plan for management of severe adverse reactions.

●A nurse coordinator, while not essential, is extremely useful to ensure that protocols are being adhered to, including that patients are receiving infusions on schedule, which required MRI scans are completed and read, and that adverse effects are appropriately managed. They can also facilitate follow-up communications with patients and caregivers.

●Participation in a registry is required for all patients on Medicare; detailed instructions and a link to the portal are provided on the Centers for Medicare and Medicaid Services (CMS) website [4]. The Alzheimer's Association also sponsors a registry, ALZ-NET [5].

●Consensus group discussion within a center or among multiple centers is also helpful, in our experience, to review and discuss challenging cases.

PRETREATMENT CONSIDERATIONS — 

Prerequisites for initiating treatment with these therapies include:

●Mild cognitive impairment or mild AD

●Documented AD biomarkers, including amyloid pathology

Such patients are thereby defined to have early AD.

Testing — Before initiating treatment, the following tests should be obtained in order to confirm eligibility and exclude patients with contraindications [6]. We sequence the order as follows, reserving the more expensive testing for amyloid pathology for patients who meet other inclusion criteria and do not have contraindications (table 1):

●Cognitive assessment to confirm the presence of mild cognitive impairment or mild dementia. Cognitive decline should be mild, and testing cutoffs such as Mini-Mental State Examination (MMSE) score ≥22, Montreal Cognitive Assessment (MoCA) score ≥17, or Clinical Dementia Rating (CDR) score 0.5 to 1 can be used. Formal neuropsychological testing can be considered for quantification of deficits and changes over time. Neuropsychological testing can also confirm that the pattern of deficits is consistent with or is atypical for AD. (See "Evaluation of cognitive impairment and dementia", section on 'Neuropsychological testing'.)

●MRI of the brain to exclude patients with contraindications. A recent (within one year) brain MRI study utilizing T1-weighted fluid-attenuated inversion recovery (FLAIR) and T2*-weighted gradient recalled echo (GRE; or equivalent sequences) is required prior to initiating treatment. Imaging findings that contraindicate treatment are summarized in the table (table 1) and discussed below. (See 'Contraindications and safety concerns' below.)

●APOE genotyping to provide additional information regarding treatment risk, specifically of amyloid-related imaging abnormalities (ARIA). (See 'Contraindications and safety concerns' below and 'Amyloid-related imaging abnormalities (ARIA)' below.)

We provide genetic counseling to patients and families prior to testing. In general, APOE status provides information on treatment risk but does not otherwise impact the course of disease for patients. For family members, particularly children, it is important to know that APOE status is not determinative in regard to future risk of AD. The National Institute on Aging and the Alzheimer's Association provide useful guidance on genetic testing for AD [7,8]. (See "Genetic counseling: Family history interpretation and risk assessment".)

●Amyloid positron emission tomography (PET) or lumbar puncture to document amyloid pathology. (See "Clinical features and diagnosis of Alzheimer disease", section on 'Neuroimaging' and "Clinical features and diagnosis of Alzheimer disease", section on 'Role of biomarkers'.)

While blood testing for phosphorylated tau may be an alternative in the future, this is not currently approved for this indication. This test is also expensive and has the disadvantage of remaining elevated after treatment and thus cannot be used to determine treatment response or duration. (See "Clinical features and diagnosis of Alzheimer disease", section on 'Role of biomarkers'.)

Counseling

●Initiating treatment – The choice to initiate amyloid-targeted therapy is an important one usually shared by patients and their caregivers. We offer treatment to eligible patients and embark on shared decision-making.

Before initiating treatment, patients and caregivers should understand:

•Potential benefits – Treatment is not expected to improve cognition or function; rather, the goal is to slow progression of the disease and the rate of cognitive decline. Both therapies slow the rate of disease progression by approximately 25 to 30 percent; thus, the magnitude of this benefit is modest, and some experts dispute the degree to which it is clinically meaningful [9]. (See 'Efficacy of lecanemab' below.)

We believe that patients with mild cognitive impairment are most likely to benefit, and we are more likely to encourage such patients to initiate therapy.

•Potential harms – Amyloid-targeted therapies have substantial risks in regard to infusion reactions and ARIA, which can cause brain edema and microhemorrhages on MRI. While these are most often mild and asymptomatic, they can rarely be severe, with potential to cause morbidity and even death. (See 'Adverse events' below.)

•Burdens – Treatment is by intravenous (IV) infusion once monthly (donanemab) or twice monthly (lecanemab). These must be done in a hospital or infusion center; there is not currently an option for at-home infusions.

In addition, treatment requires periodic MRI scans, which are essential for mitigating the risk of ARIA. Additional pretreatment assessments are also required, as discussed above. (See 'Testing' above.)

●Choice of agent – The choice between the two available agents, lecanemab and donanemab, is also an individualized one. The efficacy of these two agents appears to be similar, although they have not been directly compared in a clinical trial. Considerations include:

•Risk factors for ARIA favor use of lecanemab over donanemab, as the incidence of ARIA is higher with donanemab treatment. Examples might include microhemorrhages seen on MRI that don't meet the criteria for contraindication to treatment and APOE epsilon 4 (ε4) heterozygotes. (See 'Contraindications and safety concerns' below.)

The modified titration schedule for donanemab may reduce the risk of ARIA. (See 'Donanemab' below.)

•Patients who find infusions particularly burdensome may favor donanemab, which is given once monthly, over lecanemab, which is given twice monthly.

Treatment with donanemab can be stopped once amyloid removal is complete, either after 6, 12, or 18 months. (See 'Treatment duration' below.)

Lecanemab is generally given for 18 months, although there is no clearly defined endpoint of therapy. (See 'Treatment duration' below.)

Contraindications and safety concerns — Contraindications to treatment with amyloid-targeted therapies are listed in the table (table 1) and discussed here [6,10]. Some of these contraindications are being reevaluated as more patients are treated with these therapies. At present, we adhere fairly closely to these in order to minimize risk to our patients.

●APOE ε4 homozygotes – Patients with an APOE ε4 allele have a greater risk of side effects of ARIA. Patients who are homozygous for APOE ε4 are at greatest risk; we do not treat such patients. However, at some centers, experts will treat such patients after a risk/benefit discussion with the patient. Heterozygotes are also at higher risk for adverse events compared with noncarriers. (See 'Amyloid-related imaging abnormalities (ARIA)' below.)

Some data also suggest that treatment may be less effective in APOE ε4 homozygotes compared with noncarriers [11].

●Brain pathology that increases risk of intracranial hemorrhage – Patients should not be offered these medications if they have a high risk of intracranial hemorrhage.

Risk factors that contraindicate treatment include hemorrhagic findings on brain MRI, including >4 microhemorrhages, any areas of superficial siderosis, prior macrohemorrhage (>10 mm), vasogenic edema, and underlying brain lesion or vascular malformation [6,10]. Also exclusionary are a history of, or brain MRI suggesting, cerebral amyloid angiopathy, significant white matter hyperintensities, multiple lacunar strokes, or any cerebral stroke involving a major vascular territory. We use Fazekas score of 3 to define significant white matter hyperintensities [12].

●Other risk factors for bleeding – Bleeding disorders or prescribed anticoagulants may increase the risk of a macrohemorrhage if the patient develops ARIA. If a patient develops an indication for anticoagulant treatment while on amyloid-targeted treatment, current guidance suggests discontinuing the amyloid-targeted treatment [6,10]; however, some experts will treat patients on anticoagulant treatment after discussing risks and benefits with patients and care partners.

Antiplatelet agents prescribed at standard doses are thought to be safe.

Note that these amyloid-targeted therapies are a contraindication to the use of antifibrinolytic therapy [6]. (See 'Concurrent medications' below.)

●Moderate to severe dementia – Efficacy and safety for these therapies have only been documented for patients with early AD (mild dementia or mild cognitive impairment). We generally do not treat patients with MMSE score <22, MoCA score <17, or CDR score >1 (table 2). However, we sometimes treat patients with a lower MMSE and/or MoCA score if other factors (language barrier, education level) are felt to contribute to the lower score.

●Non-AD pathologies – Patients with cognitive decline attributed to non-AD pathologies (eg, Lewy body disease, vascular dementia [VaD]) should not be offered treatment. At present, experts suggest against treating patients with AD in the setting of Down syndrome until more information is available [6].

●Unstable medical or psychiatric condition – Amyloid-targeted therapies should not be offered to patients with unstable medical or psychiatric conditions.

Examples include individuals with immunologic disorders that are not controlled or that are being treated with immunomodulatory therapy; such patients were excluded from the clinical trials. We also do not treat patients with moderate to severe depression (>8 on the Geriatric Depression Scale [GDS-15]) and those with a history of seizures in the previous 12 months.

●Body mass index >35 or <17 – The safety of medication in these patients has not been established.

●Age >90 years – The safety of medication in these patients has not been established.

●Inability to comply with MRI monitoring

●Pregnancy or breastfeeding

●Lack of a care partner – We strongly urge patients to have a designated care partner who can assist patients with the requirements of treatment and monitoring and to also provide some oversight in regard to monitoring for clinical changes that may signal adverse effects of treatment that require intervention. This may not be an absolute requirement to initiate therapy in patients with very mild deficits.

Concurrent medications — Current guidance states that patients should not take amyloid-targeted therapies if they are prescribed anticoagulants. This guidance may be modified in the future, and some experts are currently administering these therapies to patients on anticoagulants after discussion of risks and benefits with patients and care partners.

Antiplatelet agents prescribed at standard doses are thought to be safe.

These therapies are thought to be a contraindication to antifibrinolytic therapy.

Cholinesterase inhibitors and memantine as well as antiplatelet agents at standard doses can be prescribed concurrently.

Immune-modulating therapies are generally not given with antiamyloid therapies because of concern about reduced efficacy.

SPECIFIC AGENTS

Lecanemab — Lecanemab is a humanized monoclonal antibody targeting aggregated amyloid beta. The US Food and Drug Administration (FDA) has approved lecanemab for the treatment of patients with early-stage AD (mild cognitive impairment or mild dementia) with confirmed brain amyloid pathology.

Dosing and monitoring — Lecanemab is administered by a one-hour intravenous (IV) infusion: 10 mg per kg every two weeks.

We monitor for infusion reactions with each dose [6] (see 'Infusion reactions' below):

●First infusion – Observation for four hours; follow-up phone call later that day

●Second infusion – Observation for three hours

●Third infusion – Observation for two hours

●Subsequent infusions – Observation for 30 minutes (as long as no infusion reactions have occurred previously)

MRIs should be obtained before doses 5, 7, and 14 [6]. MRIs should also be obtained at week 52 (before the 26^th infusion), particularly in APOE ε4 carriers and in those who have had amyloid-related imaging abnormalities (ARIA) on prior MRI. Sequences should include fluid-attenuated inversion recovery (FLAIR), T2*, gradient recalled echo (GRE) or susceptibility-weighted imaging (SWI), and diffusion-weighted imaging (DWI).

Clinicians should assess patients at each infusion for symptoms of ARIA, which can be mild and/or nonspecific.

Unscheduled MRIs should be obtained for symptoms suggesting ARIA. (See 'Amyloid-related imaging abnormalities (ARIA)' below.)

Dosing should be suspended for some patients with moderate to severe radiographic ARIA or symptomatic ARIA, as discussed below. (See 'Management of ARIA' below.)

Efficacy of lecanemab — Lecanemab slows the progression of clinical decline in patients with mild AD.

In a randomized trial (Clarity AD), 1795 patients with mild cognitive impairment and evidence of AD with on a PET scan or cerebrospinal fluid (CSF) testing were treated with lecanemab or placebo and followed for 18 months [1]. Efficacy for lecanemab was demonstrated by a smaller decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SOB) compared with placebo. The CDR-SOB is an 18-point scale; the adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference -0.45, 95% CI -0.67 to -0.23). The degree to which this difference is clinically meaningful is uncertain, as the difference was less than what some consider a minimally clinically important difference [13-17]. Other clinical outcomes, including activities of daily living, the Zarit Burden Interview (a measure of carer burden), and the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; a measure of global cognition), also demonstrated reduced rates of decline in lecanemab- versus placebo-treated patients. One interpretation suggests that this benefit translates into approximately 5 fewer months of decline over 18 months, or approximately 30 percent slowing of decline [18]. Preliminary data with 24 months of follow-up suggest that the efficacy is sustained through that time point [19].

An earlier phase 2 trial involving 856 patients had also demonstrated that lecanemab slowed clinical decline over 12 to 18 months [2].

Adverse reactions with lecanemab

●Amyloid-related imaging abnormalities – In Clarity AD, ARIA was observed in 21 percent of participants on lecanemab; most cases were asymptomatic [1]. ARIA with edema (ARIA-E) occurred in 12.6 percent; most (78 percent) were asymptomatic. ARIA with hemosiderin deposition (ARIA-H) occurred in 17.3 percent. There were nine intracerebral hemorrhages, an overall rate of 0.5 percent. Two deaths, which occurred during the open-label extension of the study, may have been in part attributed to lecanemab; one patient also had received antifibrinolytic therapy and one patient was on anticoagulants [20].

ARIA is discussed in detail below. (See 'Amyloid-related imaging abnormalities (ARIA)' below.)

●Infusion reactions – These occurred in 26 percent of lecanemab-treated patients in Clarity AD and in 20 percent of patients in earlier studies [1,6]. Most infusion reactions were mild (56 percent) or moderate (44 percent) in severity, and serious adverse reactions occurred in <1 percent; all of these occurred with the first dose. Most reactions (88 percent) occurred at the time of the first infusion, and most (66 percent) were one-time events and did not recur. Infusion reactions can occur up to four hours after the infusion, hence the recommended observation times as noted above. (See 'Infusion reactions' below and 'Dosing and monitoring' above.)

●Other adverse outcomes – In Clarity AD, 18-month mortality was similar in lecanemab- and placebo-treated patients (0.7 versus 0.8 percent) [1]. Overall, the incidence of adverse events other than infusion reactions and ARIA was similar in both treatment groups.

Treatment duration — There is no clear guidance regarding duration of treatment. However, we would recommend stopping lecanemab once the patient has progressed to moderate dementia.

Some clinicians obtain amyloid positron emission tomography (PET) scans at 18 months (the duration of the double-blind phase of the clinical trial) and decrease the dose to once monthly for those who demonstrate amyloid clearance. Future guidance may advise that treatment be stopped once amyloid PET scan demonstrates amyloid clearance or after 18 months of treatment.

Donanemab — Donanemab is an immunoglobulin monoclonal antibody directed against the form of beta-amyloid present in brain amyloid plaques. It binds beta-amyloid and aids in plaque removal.

Dosing and monitoring — Donanemab is administered every four weeks by IV infusion.

The standard dosing (used in the clinical trial, TRAILBLAZER-ALZ 2) is:

●Months 1 through 3: 700 mg IV over 30 minutes

●Subsequent months: 1400 mg IV over 30 minutes

We are now using a modified titration schedule (as defined in TRAILBLAZER-ALZ 6), which has evidence of reduced risk of ARIA [21]:

●Month 1: 350 mg IV over 30 minutes

●Month 2: 700 mg IV over 30 minutes

●Month 3: 1050 mg IV over 30 minutes

●Month 4 and subsequent months: 1400 mg IV over 30 minutes

MRI should be obtained prior to the second, third, fourth, and seventh infusions [10]. Sequences should include FLAIR, T2*, GRE or SWI, and DWI.

Clinicians should assess patients at each infusion for symptoms of ARIA, which can be mild and/or nonspecific. For the initial five doses, observation should continue for one hour after the completion of the infusion. Unscheduled MRIs should be obtained for symptoms suggesting ARIA. (See 'Amyloid-related imaging abnormalities (ARIA)' below.)

Dosing should be suspended for some patients with moderate to severe radiographic ARIA or symptomatic ARIA, as discussed below. (See 'Management of ARIA' below.)

Efficacy of donanemab — Clinical trials of donanemab have demonstrated that treatment reduces the rate of functional and cognitive decline [3,22,23]. The efficacy appears similar to that observed for lecanemab.

In the larger trial (TRAILBLAZER-ALZ 2) of 1736 patients with mild AD treated over 76 weeks, donanemab-treated patients experienced less cognitive and functional decline as measured by least-squares mean change in the integrated Alzheimer Disease Rating Scale (iADRS) score of -6.0 versus -9.3 (absolute difference 3.25, 95% CI 1.88-4.62) [3]. The iADRS is an integrated assessment of cognition and daily function; scores range from 0 to 144, with lower scores indicating greater impairment. A similar reduction in decline in the CDR-SOB was also documented. Overall, the rate of clinical decline was slowed by 25 to 40 percent. An earlier phase 2 trial found a similar benefit in regard to the iADRS score [22,23].

Mortality was similar in both treated groups (1.9 versus 1.1 percent) [3].

Adverse reactions with donanemab — The following adverse reactions were reported in donanemab-treated patients in TRAILBLAZER-ALZ 2 [3]:

●Amyloid-related imaging abnormalities – ARIA in any form occurred in 36.8 percent [3]. ARIA-E occurred in 24 percent; symptomatic ARIA-E occurred in 6.1 percent. ARIA-H developed in 31.4 percent. Intracerebral hemorrhage developed in three patients (0.4 percent). These frequencies are approximately twice those observed for lecanemab. With a modified dosing titration used in TRAILBLAZER-ALZ 6, the rates of ARIA-E, symptomatic ARIA-E, and ARIA-H were 13.7, 2.8, and 20.3 percent, respectively [21]. Intracerebral hemorrhage developed in two patients (1 percent).

ARIA is discussed in detail below. (See 'Amyloid-related imaging abnormalities (ARIA)' below.)

●Infusion reactions – Infusion reactions occurred in 8.7 percent; serious reactions occurred in 0.4 percent [3]. Most (96 percent) of the infusion-related reactions were mild to moderate and occurred during or within 30 minutes of the end of the infusion and between the second and fifth infusions. Significant infusion reactions were not noted more than one hour after the infusion. Forty percent of patients with a first reaction experienced a second infusion reaction. (See 'Infusion reactions' below.)

Anaphylaxis occurred in three patients and was considered to be mild to moderate.

●Other – Three deaths in the donanemab group and one in the placebo group were considered treatment related, occurring in the setting of serious ARIA.

Treatment duration — Current guidance from the FDA suggests that donanemab may be stopped when amyloid clearance is demonstrated on amyloid PET but does not suggest a specific timing of this assessment [10].

In the clinical trial of donanemab, treatment was stopped when amyloid clearance was demonstrated on scheduled amyloid PET scan [3]. Approximately 30 percent of patients reached this goal at 24 weeks, and 76 percent reached it at 76 weeks. It is likely that future guidance will suggest that amyloid PET be performed at one year, when over 50 percent of patients will be able to discontinue treatment.

Aducanumab — Aducanumab is no longer available; it is a recombinant monoclonal antibody directed against amyloid beta. The FDA had approved aducanumab for the treatment of mild AD using the accelerated approval pathway [24]. Its approval was controversial, as observed benefits on clinical endpoints were small and inconsistent.

The manufacturer discontinued production of the drug in 2024.

ADVERSE EVENTS

Infusion reactions

Incidence — Infusion reactions were somewhat more commonly seen in clinical trials of lecanemab than in those of donanemab (26 versus 9 percent). The timing of when these occurred and the risk of recurrent reactions also varied in studies of the two agents; reactions occurred primarily in the first 30 minutes after donanemab infusion but up to four hours after infusion with lecanemab. (See 'Adverse reactions with lecanemab' above and 'Adverse reactions with donanemab' above.)

Regardless of the agent, the vast majority (>95 percent) were mild to moderate in severity.

Clinical manifestations — Signs and symptoms of infusion-related reactions include fever, chills, rash, nausea and vomiting, dyspnea, sweating, low or elevated blood pressure, headache, and abdominal or chest pain [3,6].

Hypersensitivity reactions can include anaphylaxis and angioedema [3].

Management — For severe reactions that occur during the infusion, the infusion should be stopped.

Reactions are treated with cetirizine or diphenhydramine and/or acetaminophen every four to six hours as needed. More severe reactions are treated with oral glucocorticoids (dexamethasone 0.75 mg/day or methylprednisolone 80 mg twice per day) for two to three days [6].

In future infusions, regimens employed as treatment can be used for pretreatment. As examples: cetirizine 10 mg and acetaminophen 650 mg administered 30 minutes prior to infusion; for severe reactions, methylprednisolone 80 mg given six hours prior to infusion [6]. However, it is not known if pretreatment minimizes the incidence or severity of the reaction.

Severe reactions are rare, but clinics should have bronchodilators, epinephrine, and oxygen to use as needed. Individuals with severe symptoms or those with moderate to severe symptoms that are prolonged should discontinue lecanemab [6].

Amyloid-related imaging abnormalities (ARIA) — Monoclonal antibodies directed against aggregated forms of beta-amyloid, such as lecanemab and donanemab, can cause ARIA, characterized as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H).

Incidence and risk factors

●Amyloid-targeted therapy – ARIA is more frequent with donanemab than with lecanemab treatment (37 versus 21 percent). (See 'Adverse reactions with lecanemab' above and 'Adverse reactions with donanemab' above.)

ARIA can also occur in untreated patients with AD, but the incidence is very low. In the clinical trials of lecanemab and donanemab, 2 percent of placebo-treated patients developed ARIA [1,3]. Those patients with MRI findings suggesting cerebral amyloid angiopathy (eg, microhemorrhage, superficial siderosis) were at higher risk.

●Timing – ARIA can occur at any time; however, the majority occur within the first three to six months during treatment [6]. In the lecanemab trial and open-label extension, ARIA-E occurred early in treatment, while isolated ARIA-H and intracerebral hemorrhage occurred at a consistent frequency throughout [20].

●APOE ε4 – The risk of ARIA is greater in patients with an APOE ε4 allele compared with noncarriers; homozygotes for APOE ε4 have a higher risk than heterozygotes.

In the Clarity AD trial (lecanemab), the rates of ARIA-E in APOE ε4 noncarriers, APOE ε4 heterozygotes, and APOE ε4 homozygotes were 5.4, 10.9, and 32.6 percent, respectively [1,6]. Rates of symptomatic ARIA were 1.4, 1.7, and 9.2 percent, respectively. In TRAILBLAZER-ALZ 2 (donanemab), the corresponding rates of ARIA-E by APOE ε4 status were 16, 23, and 41 percent [3]. In both trials, the corresponding rates according to APOE ε4 status in placebo-treated patients were <1, 2, and 3 to 4 percent.

●Anticoagulation – Anticoagulation increases the risk of macrohemorrhage associated with ARIA-H.

The rate of intracerebral hemorrhage with lecanemab was higher with anticoagulation than in the group overall (2.7 versus 0.5 percent) [20].

Clinical and neuroimaging features — ARIA can take the form of edema (ARIA-E) and/or microhemorrhage (ARIA-H). A severe/serious form is also recognized. These may coexist.

●ARIA-E is characterized by focal vasogenic edema with fluid-attenuated inversion recovery (FLAIR) hyperintensity [25]. The radiologic findings of ARIA-E are graded as mild, moderate, or severe (table 3).

Most patients (70 percent) with ARIA-E are asymptomatic, but others have fatigue, headache, confusion, dizziness, falls, vision change, or nausea. Some patients present with seizure. Focal neurologic signs can develop and suggest acute stroke; it is important to note that thrombolytic therapy is contraindicated in patients treated with lecanemab or donanemab.

In most patients (>80 percent), ARIA-E resolves over a few months without long-term side effects; however, some patients experience a recurrence if treatment is restarted [6,25].

●ARIA-H usually manifests as microhemorrhage and/or superficial siderosis, which can vary in number and extent (table 3) [25]. ARIA-H often, but not always, occurs concurrently with ARIA-E in the affected brain region; isolated ARIA-H is rare. Microhemorrhage will continue to show up on follow-up MRI even after stability.

Intracerebral hemorrhage (macrohemorrhage) can complicate ARIA-H; this occurred very infrequently in the clinical trials but was fatal in some cases. Intracerebral hemorrhage also occurred in a patient who was treated with antifibrinolytic therapy for acute ischemic stroke; this patient was not known to have ARIA before this treatment. However, MRI after intracerebral hemorrhage did reveal severe ARIA-E and ARIA-H. Symptomatic ARIA can mimic ischemic stroke symptoms; extreme caution is required in differentiating these conditions.

Isolated ARIA-H is rare; antithrombotic medication did not appear to increase risk.

●Severe/serious ARIA is characterized by larger areas of edema on FLAIR MRI, with mass effect and often numerous microhemorrhages [6]. This form of ARIA resembles the syndrome of cerebral amyloid angiopathy-related inflammation (CAA-ri) and often manifests with seizures, status epilepticus, encephalopathy, and/or focal neurologic deficits. At least one death was thought to result from this complication. (See "Cerebral amyloid angiopathy", section on 'Cerebral amyloid angiopathy-related inflammation'.)

Management of ARIA — Clinical signs or symptoms suggesting ARIA should prompt an MRI; sequences should include FLAIR, T2*, gradient recalled echo (GRE) or susceptibility-weighted imaging (SWI), and diffusion-weighted imaging (DWI). If a brain MRI shows ARIA, the patient should be evaluated clinically.

●Asymptomatic patients with mild MRI findings – Patients who are asymptomatic and who have mild MRI changes (table 3) may be able to continue treatment with close clinical monitoring and monthly MRI scans until findings resolve or stabilize [6].

●Symptomatic patients or moderate to severe MRI findings – Treatment should be held for moderate or severe ARIA (table 3) and/or symptomatic ARIA of any severity and/or a macrohemorrhage [6].

Monthly follow-up MRI scans are required to determine resolution of ARIA-E and documented stability of any hemorrhages.

Resuming treatment can be considered after such resolution and/or stabilization but requires careful discussion of risks and benefits with the patient and caregivers. Across clinical trials of amyloid-targeted therapies, the rate of ARIA-E recurrence after dose reinitiation or dose adjustment was 14 to 26 percent [26].

●Severe/serious ARIA – Patients with severe/serious ARIA should be admitted [6]. Severe cerebral edema and signs of increased intracranial pressure may be treated with glucocorticoids: methylprednisolone 1 g intravenous (IV) per day for five days followed by a gradual oral glucocorticoid taper over six to eight weeks. Seizures should be treated.

We would not resume treatment in such patients.

Prognosis — Typically, ARIA resolves over several weeks. At 12 weeks, 62 percent of ARIA had resolved, and at 21 weeks, 81 percent had resolved. Post-ARIA cognitive assessments suggest that ARIA did not lead to worse cognitive or functional outcomes [20].

However, manifestations of severe ARIA may not completely resolve and may produce substantial morbidity or death.

Loss of brain volume — Volumetric MRI studies demonstrate that both donanemab and lecanemab produce a loss of whole brain volume that manifests primarily as increased ventricular size [3,27]. Reduction of volume of the hippocampus is proportionately less than that of the brain as a whole. The clinical significance of this finding is uncertain and requires further study.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cognitive impairment and dementia".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Dementia (including Alzheimer disease) (The Basics)" and "Patient education: Dementia – ED discharge instructions (The Basics)" and "Patient education: Caring for someone with Alzheimer disease or dementia (The Basics)")

●Beyond the Basics topics (see "Patient education: Dementia (including Alzheimer disease) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Background – Amyloid-targeted therapies are recombinant monoclonal antibodies directed against amyloid beta, the pathological hallmark of Alzheimer disease (AD). Two such therapies have been approved and are available in the United States: lecanemab and donanemab. (See 'Introduction' above.)

These therapies should be administered in centers with experience in evaluating and managing patients with dementia and administering these therapies. (See 'Center requirements' above.)

●Indications – Eligible patients for amyloid-targeted therapy include those with mild cognitive impairment or early dementia in the setting of documented amyloid pathology (ie, those with early AD). (See 'Counseling' above.)

We offer treatment to such patients and embark on shared decision-making, counseling patients on:

•Potential benefits – The efficacy of these agents on clinical outcomes is modest, slowing progression by approximately 25 to 30 percent. Thus, patients with very early-stage disease (ie, mild cognitive impairment) may be more likely to benefit than those with established dementia.

Treatment does not improve cognition or function.

•Potential harms – These therapies have substantial risks, causing infusion reactions and amyloid-related imaging abnormalities (ARIA). These are usually mild and asymptomatic; however, they can be severe, with the potential to cause morbidity and even death.

•Burdens of therapy – Treatment requires monthly or twice-monthly intravenous (IV) infusion in a hospital or infusion center for 6 to 18 months; there is not currently an option for at-home infusions.

In addition, periodic MRI scans are essential for mitigating the risk of ARIA.

●Pretreatment testing – Before initiating treatment, the following tests should be obtained in order to confirm eligibility and exclude contraindications (see 'Testing' above):

•Cognitive assessment to confirm the presence of mild cognitive impairment or mild dementia

•MRI of the brain to exclude contraindications (table 1)

•Apolipoprotein E (APOE) genotyping to provide additional information regarding treatment risk, specifically of ARIA

•Amyloid positron emission tomography (PET) or lumbar puncture to document amyloid pathology

●Contraindications – Contraindications to treatment with amyloid-targeted therapies are listed in the table (table 1). Some of these are being reevaluated as more patients are treated with these therapies. At present, we adhere fairly closely to these in order to minimize risk to our patients. (See 'Contraindications and safety concerns' above.)

●Specific agents – The efficacy of lecanemab and donanemab appears to be similar, although they have not been directly compared in a clinical trial. Differentiating considerations include:

•A higher incidence of ARIA with donanemab compared with lecanemab (see 'Contraindications and safety concerns' above)

•A higher frequency of administration (twice monthly) with lecanemab compared with donanemab (once monthly)

Aducanumab has been withdrawn from the market. (See 'Specific agents' above.)

●Infusion reactions – Infusion reactions were somewhat more commonly seen in clinical trials of lecanemab than in those of donanemab (26 versus 9 percent). The timing of when these occur also varies with the agent. For both agents, the majority of reactions are mild and are unlikely to occur with later doses. (See 'Infusion reactions' above.)

●Amyloid-related imaging abnormalities – ARIA can occur at any time during treatment; however, the majority occurs within the first three to six months.

The risk of ARIA is greater with donanemab than with lecanemab (37 versus 21 percent); however, a modified dose titration for donanemab may reduce this risk. The risk of ARIA is higher in patients with an APOE epsilon 4 (ε4) allele compared with noncarriers; homozygotes for APOE ε4 have the highest risk. (See 'Incidence and risk factors' above.)

Subcategories of ARIA include (see 'Clinical and neuroimaging features' above):

•ARIA with edema (ARIA-E) is characterized by focal vasogenic edema on MRI (table 3). Most patients are asymptomatic, but others have fatigue, headache, confusion, dizziness, falls, vision change, or nausea. Symptoms and imaging features typically resolve over a few months without long-term side effects.

•ARIA with hemosiderin deposition (ARIA-H) usually manifests as microhemorrhage and/or superficial siderosis, which can vary in number and extent (table 3). ARIA-H often occurs concurrently with ARIA-E in the affected brain region. Intracerebral hemorrhage can infrequently complicate ARIA-H.

•Severe/serious ARIA is characterized by larger areas of edema on MRI with mass effect and often numerous microhemorrhages; it often manifests with seizures, status epilepticus, encephalopathy, and/or focal neurologic deficits. Such patients require hospital admission and management with glucocorticoids and/or other treatments.

Clinical signs or symptoms suggesting ARIA should prompt an MRI evaluation. While the clinical signs of ARIA can overlap with acute stroke, it is important to note that thrombolytic therapy is contraindicated in patients taking one of these medications. (See 'Management of ARIA' above.)

•Treatment should be held for symptomatic ARIA and for moderate or severe radiologic ARIA (table 3). Resuming treatment after clinical and radiographic stabilization requires discussion of risks and benefits with patients and caregivers. We would not resume treatment after severe/serious ARIA.

•Asymptomatic patients with mild MRI findings may continue treatment with close clinical and MRI monitoring.