Appropriate use recommendations of the Spanish Society of Neurology’s Behavioural Neurology and Dementia Study Group on anti-amyloid antibodies in the treatment of Alzheimer disease

Abstract

Introduction

Two anti-amyloid monoclonal antibodies (mAb) have recently been approved by the European Commission for the treatment of Alzheimer disease (AD). In this context, the Spanish Society of Neurology’s Behavioural Neurology and Dementia Study Group decided to issue a consensus statement gathering the recommendations of national experts on the appropriate use of anti-amyloid mAb. The document provides recommendations on practical aspects of the use of these drugs in Spain, which are intended to complement the indications described by regulators.

Development

Fifty-seven members of the study group participated in the consensus process (January-September 2025), which includes recommendations on criteria for selecting candidates, adverse reactions, monitoring, criteria for suspension of treatment, shared physician-patient decision-making, and requirements of prescribing centres. All participants were invited to revise the complete document, specifically asked whether they agreed with the content of each section, and invited to share their comments.

Conclusions

The introduction of the first anti-amyloid mAb represents a paradigm shift in the management of AD, but is not free of challenges. The participating experts showed a high level of consensus on basic clinical and practical considerations, with the requirements of prescribing centres and criteria for treatment suspension being the areas that generated the most debate. Participants noted concerns about equity of access and implementation into current care, particularly if insufficient resources are allocated to this implementation. This document will require updates in line with new knowledge and/or approval of new drugs in this class.

Resumen

Introducción

Dos anticuerpos monoclonales dirigidos contra Aβ (mAbs antiamiloide) han sido recientemente aprobados en la Comisión Europea para la enfermedad de Alzheimer (EA). En este contexto, el Grupo de Estudio (GE) de Conducta y Demencias de la Sociedad Española de Neurología se propuso realizar un documento con recomendaciones de buen uso de mAbs antia-miloides escrito por neurólogos expertos nacionales. El objetivo complementar las indicaciones de las agencias reguladoras con recomendaciones sobre aspectos prácticos de aplicación en nuestro medio.

Desarrollo

Cincuenta y siete miembros del GE participaron en el documento (enero-septiembre del 2025) que incluye recomendaciones sobre criterios de selección y exclusión de candidatos, efectos adversos, monitorización, criterios de discontinuación, decisiones compartidas médico-paciente y requerimientos de los centros prescriptores. Todos los participantes fueron invitados a revisar el documento completo, a mostrar su acuerdo o discrepancia con cada una de las recomendaciones y a compartir comentarios.

Conclusiones

La introducción de los primeros mAbs antiamiloide suponen un cambio en el paradigma del manejo de la EA, no exento de dificultades. Los expertos participantes mostraron un alto consenso en aspectos operativos y clínicos básicos, siendo las áreas que generaron más debate los requerimientos de los centros prescriptores y la discontinuación de los mAbs antiamiloide. Los participantes revelaron preocupaciones sobre la equidad de acceso y el encaje en la asistencia actual, especialmente si no hay una adecuada dotación de recursos para su implementación. Este documento habrá de ser actualizado a medida que se disponga de nuevos conocimientos o/y se aprueben nuevos fármacos de esta clase.

Introduction

Alzheimer disease (AD) is the most prevalent neurodegenerative disease. Studies following different methodologies have estimated that there are currently between 400 000 and 800 000 patients with AD in Spain, although up to 30% of cases go undiagnosed in early stages. Dementia was the fourth leading cause of death in Spain (with AD being the seventh) in 2023, and is one of the diseases causing the greatest loss of quality of life and dependence.¹

The Spanish National Health System currently funds 4 symptomatic drugs approved to treat AD: donepezil, galantamine, rivastigmine, and memantine; though these drugs have been shown to be cost-effective, they do not modify the disease course.²

In recent years, several clinical trials have shown that various anti-amyloid monoclonal antibodies (mAb) are able to eliminate cerebral deposits of this protein, to differing extents. Two drugs, lecanemab and donanemab, have been shown not only to eliminate amyloid plaques, but also to slow disease progression in phase 3 randomised clinical trials.^3,4 The results of these clinical trials have led to the approval of both drugs by different regulatory agencies, with the United States Food and Drug Administration approving lecanemab in 2023 and donanemab in 2024. The European Commission approved their commercialisation in the European Union in April 2025 and September 2025, respectively, in accordance with the recommendations of the European Medicines Agency.^5,6 At the time of writing, the Spanish Ministry of Health has not announced whether these drugs will be funded by the Spanish National Health System. Other members of this class of drugs, and new formulations, are expected to be approved for clinical use in the coming years.

In this context, the Spanish Society of Neurology’s Behavioural Neurology and Dementia Study Group decided to issue a consensus statement gathering the recommendations of national experts on the appropriate use of anti-amyloid mAb. The document provides expert recommendations on practical aspects of the use of these drugs, which are intended to complement the indications included in the summaries of product characteristics and described by regulators. This is intended as a “living document,” which will incorporate modifications in accordance with new evidence and experience and the incorporation of new drugs in the same class.

Fifty-seven members of the study group responded to an email invitation to participate in the drafting of the document (Appendix 1). The working group was established in January 2025, and the document was written between March and September 2025. The draft of each section was written by 2 experts. Every participant was invited to revise the complete document, specifically asked whether they agreed with the content of each section, and invited to share their comments. The corresponding author gathered all the comments received, and the drafting group reviewed points of disagreement in order to reach a recommendation endorsed by the majority of members; where this was not possible, recommendations were not included.

The consensus recommendations of the working group are presented below.

Clinical criteria for the selection of patients eligible for anti-amyloid monoclonal antibody treatment

Anti-amyloid mAb should be restricted to patients meeting the following clinical criteria:

• -

  Diagnosis of mild cognitive impairment (MCI) or mild dementia due to AD (“early AD,” corresponding to stages 0.5-1 on the Clinical Dementia Rating [CDR] scale or stages 3-4 on the Global Deterioration Scale [GDS]), with biomarker confirmation of amyloid deposition (summary of product characteristics). Some data suggest that patients with MCI benefit more than those with mild dementia.

• -

  Diagnosis should be based on the presence of progressive cognitive symptoms confirmed by the patient, informant, or the patient’s usual physician, in addition to objective cognitive deficit affecting at least one cognitive domain and compatible with suspected AD. Cognitive deficit must be confirmed by a test or battery of tests validated for use in the Spanish population. It is also advisable to use functional scales to evaluate the level of involvement of daily living activities.

• -

  Atypical forms of AD (particularly logopenic aphasia and posterior cortical atrophy) are also considered eligible, if the cognitive deficit is thought to be caused by AD.

• -

  Cognitive and/or functional deficits must not be attributable to another medical, neurological, or psychiatric disorder.

• -

  A broad age range was used in pivotal trials (50-90 years for lecanemab³; 60-85 years for donanemab⁴). Little experience is available for extreme ages, and the decision to use anti-amyloid mAb outside this age range is subject to clinical judgement.

• -

  Although the clinical trials used additional selection criteria based on Mini–Mental State Examination scores of 22-30 points, the treatment may also be indicated in patients falling outside this range, provided that symptoms are confirmed to be due to AD and progression is in the MCI or mild dementia stage. In patients with intellectual or sensory disabilities, some tests and scales used in the general population are not applicable, and instruments validated for those populations should be used.

• -

  Limited safety and efficacy data are available on the use of these drugs in autosomal dominant forms; while a baseline increase of cerebral amyloid angiopathy (CAA) is observed, treatment with anti-amyloid mAb seems not to present greater risk of adverse effects.⁷

• -

  No data are available on patients with Down syndrome, as this population was excluded from the clinical trials.

• -

  It is helpful for patients to have sufficient social, family, and professional support to guarantee safe treatment.

Diagnosis of amyloidosis

Biomarker confirmation of amyloidosis is obligatory for a patient to be considered eligible for treatment with anti-amyloid mAb (summary of product characteristics).^5,6 Negativity for a validated biomarker of cerebral amyloidosis is an exclusion criterion for these treatments.

Positivity for cerebral amyloidosis can currently be established with any of the following examinations:

• -

  Brain positron emission tomography (PET) with an amyloid tracer approved for use in Spain. Amyloid positivity by visual read is sufficient to start treatment.

• -

  Cerebrospinal fluid (CSF) biomarkers of AD: the Aβ42/Aβ40 and Aβ42/pTau-181 ratios show the greatest concordance with amyloid PET results. The specific cut-off point may vary between laboratories or platforms. Each centre should have a protocol indicating how inconclusive or conflicting results should be handled.

• -

  Blood markers: the plasma marker showing the best correlation with cerebral amyloid deposition to date is phosphorylated tau 217 (pTau-217). Most commercial platforms for pTau-217 determination present very similar diagnostic yields to CSF studies.^8,9 Using a classification system with 2 cut-off points, plasma pTau-217 values in the upper range may be sufficient to begin treatment, although local determination of the biomarker would be required, at least until a summary of product characteristics is approved in the European Union. Results in the intermediate range would require confirmation with a CSF or brain amyloid PET study. Results in the lower range would be considered an exclusion criterion for anti-amyloid mAb treatment.

Patient evaluation should take into account the fact that amyloid pathology may present concomitantly with another neurodegenerative disease; therefore, the presence of this pathology alone is not sufficient to indicate treatment if symptoms are not attributable to AD.

Currently, biological confirmation of the presence of neurofibrillary tangles and quantification of the distribution of tau pathology are not required for anti-amyloid mAb treatment; however, amyloid PET imaging may be useful for differential diagnosis in some cases.

Clinical exclusion criteria and the use of concomitant medications

The summary of product characteristics for each drug lists exclusion criteria based on the available evidence, some of which may be generic for the family of drugs and others of which are specific to each drug. However, certain aspects that are not addressed in this document may be subject to controversy, and are discussed in appropriate use recommendations.^10–12

One controversial issue is the use of these drugs in patients with haemorrhagic disorders or receiving treatment with anticoagulants, given the increased risk of cerebral haemorrhage. Inadequately controlled haemorrhagic disorders and anticoagulant treatment constitute exclusion criteria for anti-amyloid mAb treatment (summary of product characteristics).⁵ If a patient receiving this treatment requires anticoagulant treatment, the mAb treatment should be interrupted. Thrombolytics should be avoided, except in the event of imminently life-threatening indications for which no alternative treatment exists.⁵ In this case, wherever possible, brain MRI with diffusion-weighted sequences should be performed to rule out baseline alterations and amyloid-related imaging abnormalities (ARIA), and to determine the risk-benefit ratio of thrombolytic treatment. In the event of recanalisable cerebral vascular occlusion, endovascular therapy is recommended. Standard therapeutic doses of antiplatelet drugs seem not to increase the risk of haemorrhage, and would be appropriate as complementary treatments. No data are available on the effect of dual antiplatelet therapy.

Cholinesterase inhibitors and memantine may be used concomitantly with anti-amyloid mAb. They may be started before or after anti-amyloid mAb therapy.

No evidence is currently available to support the use of anti-amyloid mAb in the event of adverse effects or lack of response. No evidence is available on the use of anti-amyloid mAb in patients who have participated in clinical trials with other anti-amyloid or anti-tau mAb or other drugs under research; however, this should not be considered a contraindication in patients meeting inclusion criteria, including the presence of amyloid pathology.

Other situations in which anti-amyloid mAb should be avoided include:

• 1)

  Recent history (last 12 months) of stroke, transient ischaemic attack, or epileptic seizures.

• 2)

  Uncontrolled immune system disease or active systemic immunotherapy (corticosteroids are not contraindicated). In patients under treatment with anti-amyloid mAb and requiring systemic immunotherapy, mAb therapy should be interrupted.

• 3)

  Medical or psychiatric disorder interfering in understanding of the treatment and its potential benefits/adverse effects and/or monitoring of treatment.

• 4)

  Any other unstable or inadequately controlled medical condition (including poorly controlled hypertension, according to clinical judgement) that may exacerbate or interfere in anti-amyloid mAb therapy.

The clinical trials did not include women who were pregnant or breastfeeding; therefore, no information is available on the use of anti-amyloid mAb in these situations. We also lack data on patients with body mass index below 17 or above 35; therefore, caution should be exercised when prescribing the drugs to these patients.

The published data on differences in the effect of anti-amyloid mAb according to sex, age, and ethnic group are from post-hoc analyses without adjustment; therefore, these results should not currently be used as the basis for clinical decision-making.

APOE genotyping

The ε4 allele of the APOE gene (APOE ε4) represents the main genetic risk factor for sporadic AD, with greater APOE ε4 allele numbers being associated with increased risk.¹³ Approximately 50%-70% of patients with AD carry at least one APOE ε4 allele,¹⁴ with 10%-15% of these carrying the variant in homozygosis.¹⁵ This percentage may be even greater among patients with family history of AD, although APOE genotyping is not currently recommended for diagnostic or genetic counselling purposes.

The safety of anti-amyloid mAb is influenced by APOE genotype. Specifically, the incidence of ARIA shows a clear relationship with APOE ε4 status.¹⁶Table 1 shows the frequency of ARIA in relation to APOE genotype in the pivotal clinical trials of lecanemab and donanemab.

Table 1.

Percentage of patients presenting ARIA during treatment with anti-amyloid drugs.

	Lecanemab^3	Donanemab^4	Donanemab (modified titration, at 52 weeks)^19
ARIA-E	12.6%	24%	16%
Non-carriers of APOE ε4	5.4%	15.7%	13%
1 APOE ε4 allele	10.9%	22.8%	16%
2 APOE ε4 alleles	32.6%	40.6%	24%
Symptomatic ARIA-E	2.8%	6.1%	3%
Non-carriers of APOE ε4	1.4%	4.1%	3%
1 APOE ε4 allele	1.7%	6.1%	3%
2 APOE ε4 allele	9.2%	7.7%	0%
ARIA-H	17.3%	31.4%	25%
Microhaemorrhage	14%	26.8%	23%
Superficial siderosis	5.6%	15.7%	8.5%
Macrohaemorrhage	0.6%	0.5%	0.9%
Symptomatic ARIA-H	0.7%	–	0.5%

ARIA: amyloid-related imaging abnormalities; ARIA-E: ARIA with parenchymal vasogenic oedema or sulcal effusions; ARIA-H: ARIA with such haemorrhagic changes as microhaemorrhages, superficial siderosis, or macrohaemorrhages.

The European Medicines Agency recommends that homozygosis for APOE ε4 be considered an exclusion criterion for treatment with lecanemab or donanemab, and the drugs cannot be administered in this patient group. Therefore, APOE genotyping is essential to assessing whether a patient is eligible for treatment. As this is a genetic study, patients must be informed in advance of the reason for the test; of the risk of developing ARIA, depending on the genotype; and of the implications of the results for family risk. APOE genotyping exclusively for genetic counselling purposes is not currently recommended.

APOE studies should be performed with a CE-marked test or a product with similar validity. As of September 2025, no test quantifying protein levels has received CE certification; therefore, genotyping is the recommended methodology.

Exclusion criteria according to baseline neuroimaging

Potential candidates for anti-amyloid mAb must undergo brain MRI in the 6 months prior to treatment onset to rule out any findings that may contraindicate the treatment (summary of product characteristics). Therefore, these treatments would be ruled out for patients with contraindications for this test, such as those with severe claustrophobia or carrying pacemakers, defibrillators, or other devices incompatible with MRI. Head CT is not appropriate for detecting contraindications or monitoring ARIA, and cannot substitute MRI.

MRI should preferably be performed in a 3 T scanner, but 1.5 T systems are also acceptable.^10,11 The study should include at least the following sequences: T2 FLAIR, T2*/gradient echo, and diffusion-weighted imaging (DWI). Susceptibility-weighted imaging (SWI) is an improved version of the T2* sequence, and may be used optionally as a complementary sequence. As SWI is more sensitive for detecting blood breakdown products, and the available safety data are based on findings from T2* sequences, the exclusive use of findings from SWI sequences may lead to the exclusion of patients who might be classified as eligible according to T2* findings.

Baseline MRI findings that constitute exclusion criteria are presence of > 4 microhaemorrhages, one macrohaemorrhage, foci of superficial siderosis or vasogenic oedema, or other findings indicative of CAA (summary of product characteristics); extensive white matter lesions (Fazekas score of 3); or > 2 lacunar infarcts or large vessel ischaemic stroke.¹¹ Other lesions (aneurysm, vascular malformations, encephalomalacia, contusions, brain tumour) with potential to increase the risk of intracerebral haemorrhage must be excluded while safety data are not available. Small meningiomas, arachnoid cysts, or small venous malformations do not constitute exclusion criteria per se.

Monitoring of adverse reactions to anti-amyloid monoclonal antibodies

Infusion reactions

Infusion reactions have been reported frequently both in clinical trials^3,4 and in post-authorisation safety studies,¹⁷ and are particularly frequent during the first infusion.

According to their severity, these reactions are classified as follows: grade 1: mild and transient; grade 2: interruption indicated but responds promptly to symptomatic treatment; grade 3: prolonged, potentially even needing hospitalisation for proper control; grade 4: life-threatening; urgent intervention indicated; and grade 5: death.

Most infusion reactions are mild or moderate, but their recurrence may justify discontinuation of treatment. In the event of an infusion reaction, depending on severity, infusion should be slowed or stopped and appropriate treatment should be started according to the clinical indication. For grade 1-2 reactions, prophylactic treatment with antihistamines (eg, diphenhydramine), paracetamol 30 minutes before infusion, or oral corticosteroids 6 hours before infusion should be considered for 2-4 infusions; however, the efficacy of these pretreatments is controversial, and some centres prefer not to administer pretreatment, using paracetamol to treat any reactions that do occur. In any case, it is important that both the patient and their family, as well as the professionals involved in treatment, are aware of these reactions and their management, according to the centre’s protocols.

Monitoring of ARIA

The main adverse effect of anti-amyloid mAb treatment is ARIA. Two types of ARIA exist: ARIA with parenchymal vasogenic oedema or sulcal effusions (ARIA-E), and ARIA with such haemorrhagic changes as microhaemorrhages, superficial siderosis, or macrohaemorrhages (ARIA-H). ARIA tend to be mild to moderate from a radiological perspective; clinically, they are typically asymptomatic or present with mild symptoms. The most frequently described symptoms are mild and non-specific, and include headache, confusion, visual disorders, dizziness, nausea, and gait disorders. However, severe symptomatic ARIA have been reported, and include epileptic seizures, encephalopathy, stupor, and focal neurological deficits mimicking stroke. ARIA-E typically occur in the first 3 months of treatment, disappearing within 3-4 months after detection. ARIA-H, on the other hand, are usually associated with ARIA-E, but may also appear in isolation at any time during treatment. As noted above, the incidence of ARIA depends on APOE genotype (Table 1).

Monitoring of patients during treatment aims to promptly detect ARIA in order to minimise the risk of worsening or recurrence.^3,4,10,11 Depending on the mAb, slightly different protocols are recommended during the first year (see specific sections on lecanemab and donanemab), even in patients without symptoms of ARIA. To facilitate follow-up, each patient should be monitored using the same imaging system, with the same sequences, for the duration of treatment. No data are available to recommend follow-up MRI beyond 12 months in asymptomatic patients.

If signs or symptoms suggestive of ARIA are detected, patients should not receive additional doses of anti-amyloid mAb until ARIA are ruled out with a brain MRI study. In the event of focal neurological signs, differential diagnosis of ARIA and stroke should be performed with emergency MRI including diffusion sequences (restricted diffusion will be observed in acute stroke, but not in ARIA). Such non-specific symptoms as headache or confusion require MRI study before the next infusion if they are moderate (impacting daily life) or if relevant changes in headache pattern are observed (in patients with history of headache). In some patients, infusion reactions present with non-specific, flu-like symptoms, including headache; in this case, given the immediacy after infusion, it is very unlikely that the cause is ARIA, and MRI is not needed in the absence of other warning signs.

Other common adverse effects

Other common adverse effects (≥1/100 and <1/10 patients) observed in clinical trials^3,4 that should be considered in clinical monitoring are hypersensitivity reactions, atrial fibrillation, and nausea.

Although anti-mAb antibodies frequently appear in patients receiving these drugs, insufficient data are currently available to draw conclusions on the clinical relevance of this finding.

Management of ARIA

The therapeutic management of ARIA (Fig. 1) depends on their radiological severity and the presence or absence of associated symptoms (Table 2). In patients with mild, asymptomatic ARIA, administration of the drug need not be suspended, but closer clinical supervision is needed, with monthly MRI studies until resolution of ARIA-E or stabilisation of ARIA-H. In symptomatic patients, or in asymptomatic patients with moderate or severe radiological findings, treatment should be interrupted (Table 3). According to the patient’s clinical situation, high-dose glucocorticoid treatment may be considered (for instance, intravenous methylprednisolone at 1 g/day for 5 days, with tapering of oral steroids over several weeks). Status epilepticus or epileptic seizures should be monitored and treated in accordance with the protocols in place.

Figure 1.

Monitoring and management of ARIA.

Flow diagram of recommendations for management of ARIA, according to the presence or absence of symptoms and the severity of MRI findings (mild/moderate/severe). In the event that, during monitoring, ARIA becomes symptomatic or radiological classification worsens, it must be managed according to the new situation.

ARIA: amyloid-related imaging abnormalities; ARIA-E: ARIA with parenchymal vasogenic oedema or sulcal effusions; ARIA-H: ARIA with such haemorrhagic changes as microhaemorrhages, superficial siderosis, or macrohaemorrhages.

Table 2.

ARIA classification criteria.

		Intensity
Type of ARIA	Mild	Moderate	Severe
ARIA-E	FLAIR hyperintensity confined to sulcus and/or cortex/subcortical white matter in one location < 5 cm	FLAIR hyperintensity 5-10 cm on the longest single dimension, or more than one site of involvement, each measuring < 10 cm	FLAIR hyperintensity measuring < 10 cm, with oedema affecting gyri and sulcal effacement; may involve one or more separate sites
ARIA-H	≤ 4 new microhaemorrhages, or 1 focal area of superficial siderosis	5 to 9 new microhaemorrhages, or 2 focal areas of superficial siderosis	≥ 10 new microhaemorrhages, or > 2 focal areas of superficial siderosis, or 1 macrohaemorrhage (≥ 1 cm)
According to symptoms	Symptoms do not interfere in the patient’s daily life.	Symptom intensity is sufficient to affect daily life.	Disabling: patient is unable to work or function in daily life. Requires hospitalisation.

ARIA: amyloid-related imaging abnormalities; ARIA-E: ARIA with parenchymal vasogenic oedema or sulcal effusions; ARIA-H: ARIA with such haemorrhagic changes as microhaemorrhages, superficial siderosis, or macrohaemorrhages.

Table 3.

Therapeutic management of ARIA according to the severity of symptoms and neuroimaging findings.

	Asymptomatic	Mild symptoms	Moderate symptoms	Severe symptoms
ARIA-E
Mild	Continue	Pause	Pause	Suspend
Moderate	Pause	Pause	Pause	Suspend
Severe	Suspend	Suspend	Suspend	Suspend
ARIA-H
Mild	Continue	Pause	Pause	Suspend
Moderate	Pause	Pause	Pause	Suspend
Severe	Suspend	Suspend	Suspend	Suspend

ARIA: amyloid-related imaging abnormalities; ARIA-E: ARIA with parenchymal vasogenic oedema or sulcal effusions; ARIA-H: ARIA with such haemorrhagic changes as microhaemorrhages, superficial siderosis, or macrohaemorrhages.

After resolution of ARIA-E or stabilisation of ARIA-H in asymptomatic cases with moderate radiological findings, or in symptomatic cases with mild to moderate radiological findings, treatment may be resumed after discussion with the patient and their family of the associated risks and benefits. In cases with severe symptoms and/or severe radiological findings, definitive suspension of treatment is recommended (Fig. 1).

Criteria for definitive suspension of treatment

Treatment with anti-amyloid mAb should be suspended definitively in several situations:

• a

  Related to adverse reactions and/or treatment safety:

• b

  Adverse effects related to ARIA:

• -

  ARIA-E or ARIA-H: symptomatic cases or asymptomatic with severe radiological findings.

• -

  ARIA-E: recurrence of ARIA-E with symptoms or with moderate radiological findings, independently of symptoms (summary of product characteristics).

• c

  Adverse effects related to infusion reactions: definitive suspension of treatment is recommended in patients with infusion reactions of grade 3 or higher. Recurrent grade 2 reactions may also be considered an exclusion criterion if pretreatment is poorly tolerated or ineffective.

• d

  Medical conditions or concomitant medication

• lowerRomane

  Need to start anticoagulant treatment

• lowerRomanf

  Need to start immunosuppressive or immunomodulatory treatment (with the exception of corticosteroids)

• lowerRomang

  Any other new medical condition or concomitant medication that, in the opinion of the treating physician, may significantly increase the risk of complications or limit the benefits of the treatment.

• h

  Related to efficacy and/or clinical progression: During treatment with anti-amyloid mAb, clinical and cognitive evaluation should be performed periodically, at intervals of approximately 6 months (summary of product characteristics).⁵

Although no criteria have been established for clinical inefficacy, treatment should be interrupted if the patient progresses to moderate dementia (GDS ≥ 5 or CDR ≥ 2) (summary of product characteristics).

In the opinion of the expert group, there is no evidence (as of October 2025) to establish a recommendation regarding the continuation of mAb treatment beyond the double-blind period in the published trials,^3,4 especially if it is not known whether neuritic plaques persist. If amyloid PET or other valid biomarkers of amyloid plaque progression cannot be performed, this progression may be estimated according to the published data.

Shared physician-patient decision-making

Anti-amyloid mAb treatment is indicated for patients with early AD, a phase in which patients are generally competent for health-related decision-making, although given the complexity of managing these drugs and/or progression of the disease to stages in which this competence is compromised, it is advisable for the patient to be supported by a formal and/or informal caregiver during decision-making and treatment.

The shared decision-making process includes:

• 1

  Learning about the patient and their vision of their disease. It is essential to understand the patient’s expectations, values, and preferences about the management of their disease, to ensure that the decision about anti-amyloid mAb treatment is in line with their wishes and lifestyle.

• 2

  Active participation of the patient’s family/caregivers in decision-making. Patients’ family members and caregivers should be involved in decision-making and receive the information necessary for this process.

• 3

  Personalised risk/benefit assessment. The potential benefits and risks of treatment should be analysed on an individual basis, considering the patient’s comorbidities, concomitant treatments, quality of life, and caregiver support.

• 4

  Complete, clear transmission of information. It is essential to provide patients and their families with clear, accessible information about the fundamental aspects of anti-amyloid mAb treatment. Explanations must also be offered about the tests needed for administration and monitoring of the treatment, as well as potential secondary effects and their management.

• 5

  Development of tools to support decision-making. Educational materials or infographics should be developed to help patients and their families to better understand the treatment and make informed decisions.

• 6

  Communication skills training and education for healthcare professionals. It is crucial for professionals to be trained in communication skills, enabling effective, empathetic interaction.

The shared decision-making process must be reflected in the patient’s clinical records, either as a clinical note or as an informed consent document.

A patient information card should be provided.

Requirements of prescribing centres

In accordance with the approval criteria for the anti-amyloid mAb currently available in the European Union, the drugs must be prescribed within a controlled access programme to minimise and record risks, ensuring that the centre, prescribing physician, and patient meet the approved criteria for the administration of anti-amyloid mAb.

This section presents the study group’s recommendations on the requirements of participating centres (Fig. 2).

Figure 2.

Staff, devices, and protocols needed at prescribing centres.

Multidisciplinary team

• -

  The prescription, administration, and monitoring of anti-amyloid mAb treatment should be conducted at hospitals with cognitive disorders units experienced in the assessment and treatment of AD and other neurodegenerative dementias. The multidisciplinary team should include at least 2 neurologists specialising in cognitive disorders, preferably dedicated to this subspecialty; nurses trained in intravenous drug administration, professionals trained in the administration of cognitive tests, and neuroradiology specialists. Inclusion of such other professionals as nuclear medicine specialists, advanced practice nurses, case managers, and social workers is also recommended. All candidate patients should be evaluated by a multidisciplinary committee, which would also be responsible for monitoring safety.

• -

  The multidisciplinary team must be properly trained in administration of the treatment and management of complications.

• -

  The working group should coordinate with vascular neurologists, the emergency department, radiologists, and intensive or critical care teams for the management of potential complications.

Structural resources

• -

  The prescribing centre should have access to validated methods for amyloid pathology determination (CSF biomarkers and/or amyloid PET). We recommend advancing with the implementation of plasma biomarkers to streamline candidate selection pathways at centres in which these tests are not yet available.⁹

• -

  Centres must have the means to perform APOE genotyping with CE-marked in vitro diagnostic tests. If CE-marked tests are not available, an alternative validated test must be used (summary of product characteristics).

• -

  Centres must have access to MRI for baseline and follow-up assessment, as well as urgent/priority access in the event of adverse reactions. Studies with 3T MRI systems are preferred, though 1.5T scanners are also acceptable.

• -

  The centre must have facilities for infusion of the drug and management of adverse reactions (medical day hospital, or similar).

• -

  Centres must have an emergency department, 24/7 on-call neurology service with code stroke care, stroke unit or semi-critical neurology care unit, and intensive care unit. Availability of emergency brain MRI with diffusion sequences is also recommended for differential diagnosis between stroke and ARIA, as well as endovascular interventional treatment for ischaemic stroke in patients under mAb treatment, either at the centre itself or through referral pathways to centres with these capacities.

Protocols, procedures, and pathways

Each prescribing centre should have specific protocols for:

• a)

  Agile referral pathways from primary care to cognitive disorders units for potentially eligible patients.

• b)

  Procedure for implementation of the therapies, with inclusion/exclusion criteria that are reviewed periodically.

• c)

  Protocol for the monitoring and detection of ARIA.

• d)

  Procedures and urgent care pathways for incidents or potential adverse effects of the drugs at the centre where the patient is receiving treatment.

• e)

  Notification plan for events with potential implications for clinical safety and/or quality in the use of anti-amyloid mAb.

• f)

  Development of an information procedure for shared physician-patient decision-making, with information cards and/or infographics.

• g)

  Anti-amyloid mAb therapy should be correctly identified in patients’ medical records.

At the state or regional level, the following elements are recommended:

• a)

  Specific multiprofessional training programmes on anti-amyloid mAb.

• b)

  A register of patients under treatment for the longitudinal assessment of clinical benefit and safety. It is strongly recommended that this register be homogeneous at the national level, led by a scientific expert committee, endorsed by scientific societies, and integrated into patient clinical records.

• c)

  Care pathways to ensure that potentially eligible patients attended at non-prescribing centres are quickly referred to prescribing centres, with total population coverage at the state level. The development of code stroke networks in Spain may be an example to follow.

Regarding the amount of resources needed, no published data are available on mAb prescription at centres belonging to a system like the Spanish National Health System. Data from specialised centres in the United States suggest that in the first 14 months after prescription of the drug, only 6% of the total patients and 16% of patients with mild dementia or MCI received mAb treatment¹⁷; the reasons for this low prescription rate are not reported. A communication from the SEN’s Study Group on Clinical Management and Care Quality, based on data from 2023, estimated that there are 46-181 candidates for mAb treatment per 100 000 population, with 17-115 patients per 100 000 population ultimately receiving the treatment.¹⁸

Specific considerations on lecanemab^3,5

Lecanemab is a monoclonal IgG1 antibody that specifically recognises soluble Aβ protofibrils and insoluble Aβ aggregates and reduces amyloid plaques.³

The primary efficacy outcome in the phase 3 Clarity AD trial was the change in the CDR-Sum of Boxes (CDR-SB) score at 18 months. In the total study population, patients treated with lecanemab showed a 27% reduction in cognitive and functional decline.³ In the population meeting the European Medicines Agency criteria for indication (non-carriers and heterozygotes for APOE ε4),⁵ a 31% reduction was observed at 18 months of treatment.

The recommended dose is 10 mg/kg body weight, with no need for dose escalation, administered by intravenous infusion over 1 hour.¹ The administration schedule currently approved in the European Union is one infusion every 2 weeks.¹ However, other administration schedules and formulations are being evaluated.

In accordance with the summary of product characteristics, cognitive function and clinical symptoms should be assessed approximately every 6 months during lecanemab treatment.⁵ Lecanemab treatment must be permanently suspended if the patient progresses to moderate AD.⁵

With regard to MRI monitoring, patients under treatment with lecanemab should undergo studies before the third, fifth, seventh, and fourteenth infusions, in addition to the baseline study (within 6 months prior to treatment onset) or in the event of symptoms suggestive of ARIA.^5,10 MRI should generally be performed approximately a week before the scheduled infusion, and reviewed prior to administration.

Specific considerations on donanemab^4,11

Donanemab is a monoclonal antibody targeting Aβ aggregates, which reduces amyloid plaques.

The primary efficacy endpoint in the TRAILBLAZER-ALZ 2 pivotal trial was the change in Integrated Alzheimer’s Disease Rating Scale (iADRS) score at 76 weeks. Patients treated with donanemab showed a reduction in clinical decline, as measured with the iADRS, of 22% in the total sample and 35% in the low/medium tau pathology group.⁴ The European Medicines Agency requested more restrictive complementary studies than those established for the pivotal trial, excluding patients homozygous for APOE ε4. According to the approval document, the subgroup of 1447 treated patients showed a change of 1.73 in CDR-SB, compared to 2.42 in untreated individuals (–0.69; 29%).

In pivotal trials, patients underwent follow-up amyloid PET studies every 6 months; donanemab treatment was definitively suspended in patients meeting established criteria for amyloid clearance, which occurred in approximately 69% of patients by week 76. Amyloid deposition after treatment suspension was estimated at 2.80 centiloids/year.

Donanemab is administered as an intravenous infusion lasting approximately 30 minutes, every 4 weeks. Dose is not adjusted for body weight. It is available in vials of 350 mg/20 mL; a full dose is 4 vials (1400 mg), although progressive dose escalation is recommended. Recently, the results of the TRAILBLAZER-ALZ 6 clinical trial showed that slower dose escalation, with 1 vial in the first dose, 2 in the second dose, 3 in the third dose, and 4 from the fourth dose, presented a better safety profile, with lower incidence of ARIA and similar levels of amyloid plaque reduction.¹⁹

The maximum duration of donanemab treatment is 18 months (summary of product characteristics). Clearance of amyloid plaques or clinical progression to moderate dementia constitute criteria for suspension of donanemab treatment before 18 months.

Regarding MRI monitoring, imaging should be performed before the second, third, fourth, and seventh infusions, in addition to the baseline study (performed in the 6 months prior to treatment onset). An additional study should be performed at one year of treatment (before the twelfth dose) in patients with risk factors for ARIA, such as heterozygosis for APOE ε4 or history of ARIA, and at any time in the event of compatible symptoms.^5,10 MRI should generally be performed approximately a week before the scheduled infusion, and reviewed prior to administration.

Conclusions

The approval of the first potentially disease-modifying drugs for AD represents a paradigm shift in the management of this fatal, disabling, and incurable disease. However, their introduction in clinical practice is not free of challenges, controversies, and unknowns.

During the revision of the document, quantitative analysis of the responses of the participating experts showed high levels of consensus regarding the basic clinical and practical aspects addressed; however, open-ended questions revealed concerns about equity of access and how the structural requirements might be applied and implemented into current care systems, particularly if insufficient resources are available. Areas generating greater debate were the practical implementation of these treatments, the requirements of prescribing centres, and suspension of treatment. The document was intended to be comprehensive; however, we recommended simplification and clarification of some sections of the initial version to facilitate its use in clinical practice.

The working group hopes that this document might support clinical neurologists and other professionals in starting this new era; we are conscious that the recommendations may have to be updated in the light of new data on the approved drugs, practical experience with their use, new approvals, and changes in the approved summaries of product characteristics.

Funding

This study has received no specific funding.

Ethical considerations

No patient data or animal experiments are reported. This is a consensus statement in which all members of the Spanish Society of Neurology’s Behavioural Neurology and Dementia Study Group were invited to participate.

Declaration of Generative AI and AI-assisted technologies in the writing process

The CoPilot application (Microsoft 365 package) was used to revise the Spanish-language manuscript and identify typographical and grammatical errors.