Dementia with Lewy bodies and amyloid pathology: Eligible for anti‐amyloid treatment or not?

Abstract

In the future, treatment of dementia will be personalized, targeted to contributing pathologies, rather than the clinical syndrome. Anti‐amyloid drugs for Alzheimer's disease are the first approved drugs; however, the impact of co‑pathology on the treatment effects remains incomplete. Currently, only patients with a clinical diagnosis of Alzheimer's disease are eligible for these new drugs, but could they also be beneficial when amyloid is present in other neurodegenerative diseases? For example, roughly 50% of patients with dementia with Lewy bodies are amyloid‐positive. In this perspective, we discuss the theoretical benefits and challenges of anti‐amyloid drugs in patients with a clinical diagnosis of dementia with Lewy bodies and concomitant Alzheimer's disease pathology. We show that a significant portion of newly diagnosed dementia with Lewy bodies patients could be eligible. We advocate for the systematic collection of efficacy and safety data using innovative strategies to achieve adequate statistical power.

Highlights

• Amyloid removal as a potential therapeutic approach in amyloid‐positive dementia with Lewy bodies is of specific interest as the amyloid co‐pathology is associated with increased cognitive decline.

• In a real‑world clinical cohort, we found that roughly one in five newly diagnosed patients with dementia with Lewy bodies could be eligible for lecanemab treatment based on key appropriate use criteria.

• Robust, systematically collected evidence regarding the efficacy and safety of anti‑amyloid therapies in amyloid‑positive patients with dementia with Lewy bodies is warranted.

• There is a clear need to explicitly account for co‐pathologies in the design and interpretation of future dementia clinical trials.

1. ANTI‐AMYLOID TREATMENT

The first generation of anti‐amyloid treatments (AAT) as a therapeutic option for patients with early symptomatic Alzheimer's disease is now entering the market worldwide. The antibodies lecanemab and donanemab both showed amyloid removal and clinical efficacy in phase 3 studies. ¹ , ² These approvals mark a significant first step in the treatment of Alzheimer's disease. Treatment benefits are heterogeneous and must be weighed against potential risks, including amyloid‐related imaging abnormalities (ARIA), treatment burden, monitoring requirements, and substantial healthcare costs. ³ , ⁴ , ⁵ In addition, emerging evidence suggests that AAT might have differential effect by sex, ⁶ as well as across patient subgroups defined by genetic and biological factors, highlighting the importance of careful patient selection and individualized risk–benefit assessment.

The availability of these medications challenges our thinking about diagnosing dementia, as mixed pathology is the rule rather than the exception, with amyloid frequently present as co‐pathology in other neurodegenerative diseases. For example, roughly 50% of patients with dementia with Lewy bodies have evidence of amyloid co‐pathology with relevant clinical impact. ⁷ This raises the question whether only patients with a clinical diagnosis of Alzheimer's disease are eligible for the new drugs, or eligibility could be possible when amyloid is present in other neurodegenerative diseases. The current prescribing information of both lecanemab and donanemab, specifies it is indicated for the treatment of mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease. ³ , ⁴ In this perspective, we aim to discuss the opportunity and challenges of prescribing AAT in patients with a clinical diagnosis of dementia with Lewy bodies and concomitant Alzheimer's disease pathology.

2. AMYLOID POSITIVITY IN DEMENTIA WITH LEWY BODIES

Dementia with Lewy bodies is defined as an alpha‐synuclein disorder, leading to a dementia syndrome with the core symptoms of cognitive fluctuations, recurrent visual hallucinations, rapid eye movement sleep behaviour disorder and parkinsonism with alpha‐synuclein deposition as underlying aetiology. ⁸ Dementia with Lewy bodies is the second most common form of neurodegenerative dementia after Alzheimer's disease. ⁹ There is no disease‐modifying treatment targeting alpha‐synuclein currently available. ¹⁰ At the time of diagnosis, about 50% of subjects with dementia with Lewy bodies have amyloid co‐pathology, based on cerebrospinal fluid (CSF) and/or positron emission tomography (PET) biomarkers. ⁷

The presence of amyloid co‐pathology in dementia with Lewy bodies patients is associated with a poorer prognosis in terms of greater cognitive decline, worse daily functioning, and increased mortality. ¹¹ More specifically, amyloid‐positive dementia with Lewy bodies patients decline almost one point per year faster on the Mini‐Mental State Examination (MMSE) compared to dementia with Lewy bodies patients with normal Alzheimer's disease biomarkers. ⁷ There are several theoretical mechanisms that could explain this. ¹² , ¹³ Alzheimer's disease co‐pathology might be an independent driver of neuronal dysfunction and cell death in dementia with Lewy bodies next to alpha‐synucleinopathy. There could be a synergistic effect of alpha‐synucleinopathy and aggregation of beta‐amyloid and phosphorylated tau (pTau), which has been suggested to reflect a more severe disease process. The relationship between these pathologies has yet to be further elucidated but the clear detrimental clinical impact of Alzheimer's disease co‐pathology suggests that this group could benefit from amyloid removal treatment.

3. AAT ELIGIBILITY BASED ON APPROPRIATE USE CRITERIA

Appropriate Use Recommendations (AURs) for lecanemab ⁴ , ⁵ and donanemab ³ guide the clinical use of these new drugs. Several versions have been published considering local health care, but with comparable key eligibility criteria. In short, they highlight the clinical diagnosis of MCI or mild dementia with Alzheimer's disease as suspected etiology. The presence of Alzheimer's disease pathology is operationalized by positive amyloid PET or CSF biomarkers. To capture MCI or mild dementia, cognitive screening instrument scores should be compatible with these disease stages, such as MMSE 22–30. ⁵ To reduce the risk of ARIA, several exclusion criteria are specified: (1) vascular damage on brain MRI, especially MRI evidence of cerebral amyloid angiopathy such as more than four microhemorrhages or superficial siderosis; (2) anticoagulant use or bleeding disorders; (3) in the European Union (EU) and United Kingdom (UK), apolipoprotein E (APOE) ε4/ε4 carriers. In other geographies, APOE ε4 genotyping is encouraged to inform discussions on risk of side effects with treatment candidates and their care partner(s). ⁴ To monitor ARIA, the AURs recommend periodic brain MRI assessments; hence, patients with contraindications for MRI are not eligible.

We applied the key AUR criteria of lecanemab described by Mummery et al. ⁵ to all patients diagnosed with dementia with Lewy bodies (n = 347) from the Amsterdam Dementia Cohort who visited the memory clinic between January 2010 and May 2025. Patients underwent a standardized diagnostic work‐up consisting of a visit to a neurologist, including physical and neurological examination during which medical history and current medications were systematically recorded, standardized neuropsychological testing, brain MRI, laboratory investigations, and CSF biomarker testing as described elsewhere. ⁷ , ¹⁴ Some patients underwent amyloid PET imaging either as part of research protocols or for diagnostic purposes; these data were used when CSF was missing.

Figure 1 shows the eligibility funnel for AAT of patients with dementia with Lewy bodies based on the information of the first diagnostic visit. In 196 of the 347 dementia with Lewy bodies patients seen between January 2010 and May 2025, amyloid status in CSF or PET was available. Overall, 44% were amyloid positive (23% negative), defined as β‐amyloid_1‐42 below the local laboratory cutoff or local visual rating of the PET images. ⁷ , ¹⁴ Additionally, applying the MMSE score between 22 and 30 reduced eligibility to 28%. In the next step of eligibility, fewer than four microbleeds on MRI, 22% remained. One more subject was excluded due to anticoagulant use. When considering APOE ε4/ε4 as exclusion criterion, 19% remained eligible. Our data show that about one in five newly diagnosed dementia with Lewy bodies patients would be eligible for AAT according to the key AUR criteria.

FIGURE 1.

How many dementia with Lewy bodies patients would fulfill the appropriate use criteria? We applied the key appropriate use criteria of lecanemab described by Mummery et al. ⁵ to all patients diagnosed with dementia with Lewy bodies (n = 347) from the Amsterdam Dementia Cohort who visited the memory clinic between January 2010 and May 2025.

4. AAT IN DEMENTIA WITH LEWY BODIES

Removing amyloid by using AAT may be beneficial in amyloid‐positive dementia with Lewy bodies for several reasons. As already discussed, amyloid co‐pathology in dementia with Lewy bodies patients is associated with a poorer prognosis in terms of greater cognitive decline and worse daily functioning. ⁷ , ¹¹ Furthermore, evidence is emerging that a greater benefit of AAT may occur in patients with low pTau levels, representing early‐stage Alzheimer's disease in biological terms. ¹ , ¹⁵ When present, pTau levels are lower in dementia with Lewy bodies patients compared to Alzheimer's disease patients. ¹⁶ In their respective trials, lecanemab and donanemab slowed cognitive decline by approximately 25% and 35%, respectively, compared with placebo. ¹ , ² If we assume a 30% reduction in the rate of decline, what would this imply for amyloid‐positive dementia with Lewy bodies patients? Average decline in the MMSE in the amyloid‐positive dementia with Lewy bodies group is 1.3 points per year, and 0.4 point per year in the dementia with Lewy bodies group with normal Alzheimer's disease biomarkers. ⁷ This would represent a 0.9‐point difference in decline. Assuming a stable decline in the dementia with Lewy bodies group with normal Alzheimer's disease biomarkers, a 30% reduction in decline would lower the difference to 0.6 point per year. The amyloid‐positive group would still decline faster compared to the amyloid‐negative group (see Figure 2). A similar effect, 30% reduction, seems a reasonable theoretical assumption since the decline in amyloid‐positive dementia with Lewy bodies is comparable to what has been reported in Alzheimer's disease. In a memory clinic setting, 1.7 points ¹⁷ and in the donanemab phase 3 study population 1.4 points per year. ² At the same time, it must be acknowledged that our understanding of the impact of co‑pathology on the treatment effects of AAT remains incomplete. The effect could be smaller or larger. A critical and as yet unresolved question is whether amyloid removal indeed confers clinical benefit in patients with dementia with Lewy bodies. Given the substantial costs and treatment burden associated with AAT, the identification of dementia with Lewy bodies subgroups most likely to benefit from treatment will be essential to optimize the benefit–risk and cost‐effectiveness profile of these interventions.

FIGURE 2.

Estimated cognitive decline in amyloid‐positive dementia with Lewy bodies versus amyloid‐negative. Plotted regression lines are based on data presented by van de Beek et al. ⁷ and represent estimated Mini‐Mental State Examination (MMSE) scores based on linear mixed models corrected for age and sex in subjects with amyloid‐positive and ‐negative dementia with Lewy bodies. Anti‐amyloid treatment (AAT) represents estimated MMSE scores with 30% less decline if the amyloid‐positive group is treated.

Limited preclinical evidence provides biological support for targeting amyloid in dementia with Lewy bodies with concomitant amyloid pathology. In an amyloid precursor protein (APP)/α‐synuclein double‐transgenic mouse model exhibiting features of mixed Alzheimer and Lewy body pathology, active immunization with the Aβ‐directed peptide vaccine AD02 generated anti‐Aβ antibodies, reduced Aβ burden, phosphorylated tau, and α‐synuclein pathology, and showed improvements in selected behavioral measures. ¹⁸ These findings suggest that antibody‐mediated targeting of Aβ may attenuate both amyloid‐related injury and interactions between Aβ, tau, and α‐synuclein. However, this evidence derives from an active‐immunization paradigm in an APP/α‐synuclein overexpression model and cannot be directly extrapolated to passive monoclonal‐antibody treatment in sporadic dementia with Lewy bodies. To our knowledge, direct preclinical studies of lecanemab‐, donanemab‐, or aducanumab‐like passive Aβ clearance in validated dementia with Lewy bodies models have not yet been reported.

It is currently unlikely that AAT will be used in clinical care of subjects with the clinical diagnosis of dementia with Lewy bodies, even the amyloid‐positive subjects. Both the label and the AUR highlight the clinical diagnosis of MCI and mild Alzheimer's disease dementia. Real‐world experience with these treatments is still limited; hence off‐label use is unlikely. Proof of concept of AAT in amyloid‐positive dementia with Lewy bodies patients is needed. Ultimately, a clinical trial is considered the gold standard for determining efficacy and safety. The currently available dementia treatments in dementia with Lewy bodies were also first studied in large trials in Alzheimer's disease patients, followed by small‐sized trials with dementia with Lewy bodies patients that were often not adequately powered. For instance, rivastigmine was approved for Alzheimer's disease in 2000 based on a pivotal study including 699 Alzheimer's disease patients, while a later dementia with Lewy bodies trial included 55 participants. ¹⁹ This creates a lack of support for evidence‐based treatment of dementia with Lewy bodies. In our opinion, it is important to conduct adequately powered studies on the effectiveness and safety of AAT in dementia with Lewy bodies, especially because a significant portion of new dementia with Lewy bodies patients could be eligible for AAT. Innovative, well‐designed strategies will be necessary, given that recruiting a large number of patients with dementia with Lewy bodies into a phase 3 trial will require substantial time and effort.

5. FORWARD‐LOOKING STATEMENT

In the future, treatment of dementia will be personalized, targeted to contributing pathologies, rather than the clinical syndrome. Hence, the time is now to start thinking about co‐pathologies in dementia drug development. As the field moves toward precision medicine, the systematic evaluation of co‐pathologies from preclinical development onward will become increasingly necessary. A better understanding of the presence of co‐pathology in trial participants is in reach. With the recent developments of biomarkers, it becomes possible to include co‐pathology analyses in dementia trial design. This can inform about the potential influence of the presence/absence of specific co‐pathologies on efficacy and safety in early stages. Is it possible to include amyloid‐positive dementia with Lewy bodies patients in an AAT trial? A method of supporting proof‐of‐concept of an agent's activity in two or more disorders sharing key biological or clinical features is a basket trial design. In oncology, these basket trials are common, while in neurodegenerative neurology this is rather new. ²⁰ Cummings et al ²⁰ showed that the most common combinations were trials with alpha‐synucleinopathies, including Parkinson's disease & dementia with Lewy bodies (12 trials) and Parkinson's disease & Multiple System Atrophy (11 trials). Basket trials avoid the cost and operational challenges of implementing separate trials for each indication but come with different operational challenges of coordinating multiple disease groups, sites, and eligibility rules. It has been postulated that basket trials, combined with biomarkers, can be a powerful means of advancing precision drug development and precision medicine for patients with dementia. ²⁰ Furthermore, basket trial designs may be particularly valuable for evaluating combination therapies in patients with mixed pathologies. As treatments become increasingly pathology‐specific, patients may receive multiple disease‐modifying therapies simultaneously. This introduces additional complexity related to pharmacokinetic interactions, overlapping toxicities, and synergistic or antagonistic pharmacodynamic effects. Incorporating biomarker‐guided assessments and combination therapy cohorts within basket trials may provide an efficient means of evaluating these interactions while determining whether targeting multiple pathological pathways yields greater clinical benefit than single‐agent approaches.

In this perspective, we showed that, in a real‐world setting, one in five of newly diagnosed dementia with Lewy bodies patients could be eligible for lecanemab based on key AUR. AAT in dementia with Lewy bodies could, in theory, be effective and safe, comparable to Alzheimer's disease, but there are no clinical trial data supporting that. Given the burden, costs, and risks, structurally gathered information on efficacy and safety of AAT in amyloid‐positive dementia with Lewy bodies patients is warranted.

CONFLICT OF INTEREST STATEMENT

L.G.E. is part‐time employed by Julius Clinical as scientific officer, a CRO that is involved in Alzheimer's disease trials. As an employee of the Brain Research Center, she was Principal Investigator (PI) of studies by Treeway, EIP Pharma, and GemVax; via her university affiliation, she is PI of studies of Novartis. F.B. has research agreements with ADDI, Merck, Biogen, GE Healthcare, Roche. He has received consulting fees from Roche, Celltrion, Rewind Therapeutics, Merck, and Bracco. He is on the steering committee or Data Safety Monitoring Board member for Biogen, Merck, Eisai, and Prothena. He is on the advisory board member for Combinostics, Scottish Brain Sciences, and Alzheimer Europe. He is co‐founder and shareholder of Queen Square Analytics LTD. C.T. has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, and performed contract research or received grants from AC Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, and Vivoryon. C.T. serves on editorial boards of Medidact Neurologie/Springer, Alzheimer's Research & Therapy, and Neurology: Neuroimmunology & Neuroinflammation and is editor of a Neuromethods book (Springer). She had speaker contracts for Roche, Grifols, and Novo Nordisk. E.G.B.V. has received consultancy fees (paid to the university) for New Amsterdam Pharma, Treeway, ReMynd, Vivoryon, Biogen, Vigil Neuroscience, ImmunoBrain Checkpoint, Muna Therapeutics, Eisai, Eli Lilly, CogRX, Therini, UCB and Roche. Within his university affiliation he is PI of studies of DIAN, AC Immune, Alnylam, CogRX therapeutics, New Amsterdam Pharma, Janssen, UCB, Roche, Vivoryon, ImmunoBrain, GSK, MSD, Biogen, Alector, Eli Lilly, AriBio, FUJIFILM Toyama, and GemVax. E.G.B.V. is co‐founder of the CANDIDATE Center Amsterdam UMC. E.G.B.V. collaborates on scientific projects with the Dutch Soccer Association (KNVB). E.G.B.V. is recipient of ABOARD, which is a public‐private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). D.A. has received research support and/or honoraria from AstraZeneca, H. Lundbeck, Novartis Pharmaceuticals, Evonik, Roche Diagnostics, GE Health, Bioarctic and Sanofi; and served as a paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura, Eli Lilly, Cognetivity, Enterin, Acadia, EIP Pharma, Biogen, and Takeda. J.L.vA. and A.F.L. report no competing interests. Author disclosures are available in the Supporting Information.

Supporting information

Supporting Information

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request. The data from the Amsterdam Dementia Cohort are not publicly available due to privacy restrictions.