Slovenian Memory Clinic Organization with the Introduction of Potential New Alzheimer’s Disease Treatment

INTRODUCTION

In 2018, there were over 34,000 individuals living with dementia in Slovenia, and projections suggest that this number will double by 2050 [1]. Dementias represent a global health challenge, accompanied by substantial economic costs. Global economic costs of dementia were estimated at US $1313.4 billion in 2019 [2]. In Slovenia, all expenses related to dementia, covering medical, formal and informal home assistance, and nursing home placements, are estimated at 377 million euros [3]. Mitigating the severity of dementia or postponing its onset could significantly alleviate this financial burden. For instance, an intervention capable of delaying the onset of dementia by five years today has the potential to reduce costs by 36% by the year 2050 [4].

Presently, in Europe, there are no approved disease-modifying treatments (DMT) for Alzheimer’s disease (AD). The current approach involves symptomatic treatments such as acetylcholinesterase inhibitors or memantine. However, following two decades marked by clinical trial setbacks, there is finally uplifting news regarding the long-awaited positive outcomes of a potential DMT for AD.

On July 6, 2023, lecanemab, an anti-amyloid monoclonal antibody, transitioned from an accelerated pathway to traditional approval by the US Food and Drug Administration (FDA). Currently, it is undergoing evaluation by the European Medicines Agency (EMA) [5, 6]. In an 18-month study involving participants with mild AD, lecanemab demonstrated a noteworthy 27% reduction in the rate of cognitive decline [7]. Another DMT, donanemab, demonstrated 35% slowing of cognitive decline compared to placebo and is under consideration for traditional approval by FDA [8].

The prospective approval of lecanemab and donanemab is anticipated to generate significant demand from the general population for both diagnosis and eventual treatment. Potential candidates for treatment are expected to include individuals aged 65 years or older presenting with mild cognitive impairment (MCI) or mild Alzheimer’s dementia, along with AD positive biomarkers [9].

Our aim was to determine the number of potential candidates for DMT currently under the care of the Centre for Cognitive Impairments at the Department of Neurology, Ljubljana University Medical Centre, Slovenia. Lecanemab was chosen as a representative for DMT, given its potential imminent approval by the EMA. Additionally, we sought to determine the national count of potential candidates and provide an estimate of the costs associated with potential DMT.

METHODS

All cerebrospinal fluid (CSF) biomarker results for all referrals from the Center for Cognitive Impairments at the Department of Neurology, University Medical Center Ljubljana, Slovenia, for the evaluation of dementia biomarkers were systematically analyzed for the years 2021–2022. During the initial outpatient visit to the memory clinic, a comprehensive assessment is conducted, involving a detailed history, a general neurological examination, and a screening cognitive assessment. Subsequently, patients are directed for extensive laboratory testing and a structural brain scan. Additional examinations are indicated on a case-by-case basis. For potential lecanemab candidates, the requirement includes positive AD biomarkers. Given the unavailability of amyloid-PET imaging in Slovenia, patients with low Aβ₄₂/Aβ₄₀ ratio (locally validated cut-off <0,077) in CSF were included. CSF biomarker analyses were performed in a standardized way, using INNOTEST^® (Fujirebio) immunoassays according to manufacturers’ instructions.

Clinical data, encompassing details such as date of birth, MCI/dementia type diagnosis, results of screening cognitive tests [Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA)], specific comorbidities (diabetes, arterial hypertension), treatments (anticoagulant therapy), and results of structural (CT, MRI), functional brain imaging tests (FDG-PET), and neuropsychological evaluations, were extracted from hospital records in April/May 2023. Patients potentially eligible for lecanemab treatment were individuals aged 65 years or older, diagnosed with MCI or mild Alzheimer’s dementia, scoring a minimum of 21 points on the MMSE and 16 points on the MoCA, who underwent MRI and had no contraindications (e.g., hemosiderosis, microhemorrhages) and were not receiving anticoagulation treatment. This study was approved by the National Medical Ethics Committee (no 0120-539/2020/10).

The total costs were estimated using a bottom-up calculation method, factoring in the costs of examinations, diagnostic procedures, and the current unit costs of DMT, referencing the Medical Centre Ljubljana price list for 2021 as the primary source. Presently, the US annual treatment cost with lecanemab is estimated at €24,000 ($26,500, exchange rate $1 =€0.945) [10].

To predict potential lecanemab candidates on a national level, we relied on approximations from other publications. The reported estimates of MCI prevalence exhibit heterogeneity due to variations in criteria, differences in study populations, and methodologies. Prevalence estimates for MCI range from 1/3 in a US study (>65 years) [11], 15.4% in a Chinese meta-analysis (>55 years) [12], 15.4.% in a German study (>75 years) [13], and 6.6%–21.4% in a Swedish study (>60 years) [14]. Additionally, the concept of MCI aims to capture the prodromal stage of dementia from various causes, not solely AD, with approximately 55% of MCI case attributed to AD [15]. Using the middle estimate from a European country, such as Sweden (14%), the estimated MCI due to AD would be 7.7%. In Slovenia, with a population 2.1 million people, there are 451,915 individuals aged 65 or above [16] and this translates to 34,720 people with MCI due to AD. Assuming that about 40% of cases in the AD continuum are as mild Alzheimer’s dementia and Alzheimer’s dementias account for roughly 70% [15] of the total 34,137 ‘general dementia’ cases [1], this calculation results in an estimated 9,558 mild AD patients. Therefore, total potential eligible population for DMTs in Slovenia is 44,278.

RESULTS

In the years 2021–2022, there were a total of 1,461 initial visits, 3,133 follow-up visits, and 657 lumbar punctures for individuals presenting with cognitive complaints in the Centre of Cognitive Impairments. Among them, 246 exhibited an AD characteristic pathological CSF biomarker profile. However, less than half of this group, comprising 114 individuals, were identified at the stage of MCI or mild AD, making them potential candidates for lecanemab. The characteristics of these patients are detailed in Table 1. The diagnostic costs for the 114 potential lecanemab candidates amounted to €80,118, as outlined in Table 2.

If the prevalence of MCI due to AD and mild Alzheimer’s dementia in Slovenia is estimated at 44,278, the projected costs for a neurological assessment with a screening cognitive test, lumbar puncture with CSF analyses for dementia biomarkers, and MRI would be approximately €471 per person, totaling around €20.9 million (excluding control visits and other diagnostic tests). The consideration of APOE4 homozygote state as an exclusion criterion due to higher chances of amyloid-related imaging abnormalities (ARIA), with an additional test cost of €21 per test (as per internal communication), would elevate the total costs to nearly €21.8 million.

Given the annual costs of Leqembitrademark amount to €24,000, the expenses associated with treating all potential candidates in Slovenia would be estimated at approximately €1.06 billion.

DISCUSSION

The introduction of DMT for AD will likely augment the demand for diagnosing and addressing cognitive concerns. This surge in demand is not only anticipated among potential candidates for treatment but also among individuals at advanced stages of the disease, those with other dementias and those concerned about their risk to develop dementia. Consequently, this will intensify the strain on primary care physicians and dementia specialists, who are already managing heavy workloads.

Outpatient facilities specialized in addressing cognitive impairment in Slovenia are scarce, and their capabilities are limited. If lecanemab attains regulatory approvals by the EMA and Agency for Medicinal Products And Medical Devices of the Republic of Slovenia (JAZMP), the question of funding arises, often contingent on cost-effectiveness studies. These studies evaluate anticipated clinical benefits in light of potential side effects and costs. Eisai determined the societal value of Leqembitrademark at $37,600 (€34,470) annually but has set the pricing at €24,000 to promote broader patient access and alleviate overall financial burden [10]. Despite this reduction, treating all 44,278 potential candidates in Slovenia would incur costs amounting to €1.06 billion, surpassing the entire 2022 annual medication cost in Slovenia (€743 million) [17], making it unsustainable [18]. An additional €21.8 million would be necessary for conducting essential assessments for all potential candidates.

It is clearly unrealistic to recognize and treat all the potential candidates. Given the relatively small size of Slovenia and the fact that Ljubljana is positioned in the center of the country, the Centre for Cognitive Impairments could potentially cover the entire country [3]. However, in Slovenia, aside from the Centre for Cognitive Impairments in Ljubljana, only University Psychiatric Clinic Ljubljana and University Medical Centre Maribor have subspecialized outpatient facilities for patients with cognitive impairment, but their capacities do not surpass those in Ljubljana. The approval of lecanemab would inevitably heighten the burden on these centers, leading to increased waiting times, during which patients may advance beyond the point of eligibility. Moreover, even with regulatory approval, the high cost may prompt the national agency to restrict the number of treated patients or potentially deny reimbursement altogether. The Institute for Clinical and Economic Review (ICER), an independent non-profit research organization assessing expected clinical benefits against potential side-effects and costs, has determined that lecanemab’s price would require a substantial 66% to 19% discount to be deemed cost-effective [9]. Therefore, at current capacity, the Slovenian healthcare system is insufficient to diagnose and identify eligible patients for DMT in AD. Substantial investments in personnel, infrastructure and medication alone will be required to provide timely diagnosis and enable treatment with lecanemab (Fig. 1). Firstly, the facility should possess diagnostic capabilities to identify potential candidates for treatment. Secondly, it must be equipped to administer infusions, conduct safe patient monitoring through clinical assessments and regular MRI scans, and effectively manage any potential complications. This entails having sufficient space, personnel, and other necessary resources. While most patients currently undergo an MRI scan as part of the diagnostic process, the introduction of lecanemab treatment necessitates a minimum of three additional scans (Fig. 1, prior to the 5th, 7th, and 14th infusion). This heightened frequency not only amplifies the demand for MRIs but also raises concerns about the potential emergence of another significant bottleneck.

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Fig. 1

Flowchart illustrating the post-approval management pathway for patients receiving lecanemab. BBB, blood-based biomarkers; DMT, disease modifying therapy; LP, lumbar puncture; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging.

Biomarker analyses costs actually exceed €2,000 per person, covering outpatient clinic admission, procedure, CSF analyses, and hospital stay. This results in potential diagnostic expenses increase from €21.8 to €126 million.

At the present time, there are no reliable blood-based biomarkers established in routine practice that could substitute CSF analysis. In scenario where such biomarkers become available, a combination of blood-based biomarkers and cognitive testing could be conducted at a primary level, potentially serving as a gatekeeping mechanism. However, implementing this strategy would require additional resources and capacities at the primary level, which, even at present, is facing critical understaffing challenges.

Given the retrospective nature of our investigation of real-life data, we relied on physicians’ documentation of comorbidities, medications (including anticoagulation), and diagnostic tests performed on an outpatient basis (e.g., CT and MRI). Additionally, we examined available MRI reports, excluding patients with microbleeds or hemosiderosis, however, it is essential to clarify that these MRIs were conducted as part of the dementia diagnosis process, aimed at ruling out reversible causes rather than selecting patients eligible for DMT treatment. In some instances, reports were not accessible. Lecanemab was employed as a representative for DMT; however, the discussion is also pertinent to donanemab and other potential DMTs. Furthermore, APOE testing was not consistently carried out, potentially leading to more patients being considered ineligible for treatment due to these data gaps.

The advent of DMTs for AD will invariably challenge health systems globally. Yet, it also serves as a unique opportunity to reshape the perception of dementia, enhance diagnostic processes, refine dementia subtyping, and elevate care standards for all patients, extending beyond those eligible for DMT treatment. Finally, it is also an undeniable fact that the accessibility of DMTs and the associated logistics, along with potential complications, will represent a new and significantly changed societal, professional, and patient approach to the treatment of AD. From the patient and their caregiver’s perspective, a significantly increased commitment will be required, which, given the fact that these are older patients with similarly aged partners, can pose a substantial or even insurmountable burden. Ultimately, this may lead to a decision against the introduction of DMT.

AUTHOR CONTRIBUTIONS

Eva Zupanic (Conceptualization; Formal analysis; Investigation; Methodology; Visualization; Writing – original draft; Writing – review & editing); Andreja Emersic (Data curation; Validation; Writing – review & editing); Anders Wimo (Conceptualization; Methodology; Writing – review & editing); Bengt Winblad (Conceptualization; Methodology; Writing – review & editing); Andreja Speh (Conceptualization; Data curation; Methodology; Writing – review & editing); Milica Gregoric Kramberger (Conceptualization; Data curation; Investigation; Methodology; Supervision; Writing – review & editing).