Anti-amyloid therapies for Alzheimer’s disease (AD) are associated with amyloid-related imaging abnormalities (ARIA), with apolipoprotein E ε4 (APOE4) homozygosity conferring the highest risk. Given the new clinical need, novel plasma proteotyping assays may offer a rapid and high-throughput alternative to existing methods.

We evaluated proteotyping performance against real-time polymerase chain reaction (PCR) genotyping in a cohort of 104 participants. Plasma samples were analyzed using apoE4 and total apoE assays on the Fujirebio Lumipulse G1200. APOE4 allelic status (non-carrier, heterozygote or homozygote) was determined from the apoE4-to-total apoE ratio. Analytical validation assessed precision, matrix interference and freeze/thaw stability.

Proteotyping correctly identified all non-carriers (n = 53) and all E4/E4 homozygotes (n = 6). Among 45 heterozygotes, 4 were misclassified as homozygotes, yielding 40% misclassification rate for homozygosity but 100% negative predictive value (NPV). Overall accuracy was 96.2%. The assay performed robustly in the presence of hemolysate and lipemia, with consistent results up to 4 freeze/thaw cycles.

Proteotyping reliably rules out E4/E4 homozygosity (100% NPV), enabling rapid eligibility screening for anti-amyloid therapies. Positive homozygosity results require confirmatory testing due to the potential for error. Among non-homozygous results, the assay discriminates E4 carriers from non-carriers, supporting ARIA risk stratification. As plasma phospho-tau217 testing is more commonly used, the ability to run plasma apoE4 testing on the same automated clinical immunoassay analyzer (and the same sample) enables a reflexive testing workflow, supporting more efficient treatment decision-making in the era of disease-modifying therapies.

Pharmacological treatment options for patients with dementia owing to Alzheimer's disease are limited to symptomatic therapy. Recently, the US Food and Drug Administration approved the monoclonal antibody lecanemab for the treatment of amyloid-positive patients with mild cognitive impairment (MCI) and early Alzheimer´s dementia. European approval is expected in 2024. Data on the applicability and eligibility for treatment with anti-amyloid monoclonal antibodies outside of a study population are lacking.

This study examined eligibility criteria for lecanemab in a real-world memory clinic population between 1 January 2022 and 31 July 2023.

We conducted a retrospective, single-centre study applying the clinical trial eligibility criteria for lecanemab to out-patients of a specialised psychiatric memory clinic. Eligibility for anti-amyloid treatment was assessed following the phase 3 inclusion and exclusion criteria and the published recommendations for lecanemab.

The study population consisted of 587 out-patients. Two-thirds were diagnosed with Alzheimer's disease (probable or possible Alzheimer's disease dementia in 43.6% of cases, n = 256) or MCI (23%, n = 135), and 33.4% (n = 196) were diagnosed with dementia or neurocognitive disorder owing to another aetiology. Applying all lecanemab eligibility criteria, 11 (4.3%) patients with dementia and two (1.5%) patients with MCI would have been eligible for treatment with this compound, whereas 13 dementia (5.1%) and 14 (10.4%) MCI patients met clinical inclusion criteria, but had no available amyloid status.

Even in a memory clinic with a good infrastructure and sufficient facilities for dementia diagnostics, most patients do not meet the eligibility criteria for treatment with lecanemab.