With this study we aimed to evaluate how CSF AD biomarker changes unfold according to clinical presentation, and whether combining early biomarker assessment with neuropsychological evaluation could help identifying a higher number of patients likely to benefit from AMABs.

Considering the correspondence between these neuropsychological categories and CSF biomarker changes, we first observed that the condition of aMCI-SD was invariably associated with Aβ pathology (100%), confirming a virtually perfect concordance with an A + status. When amnestic impairment was present in the context of multiple domain impairment (aMCI-MD), the prevalence of Aβ pathology was also very high, as it was detected in almost 90% of patients. Instead, in the absence of memory deficit (naMCI-MD) A + status was found only in around 60% of patients, who still represent the majority within this category. Interestingly, the prevalence of Aβ pathology was different across the three MCI categories, while tau pathology (T+) was found in equal proportions whenever an A + status was confirmed. This is consistent with the notion that the presence of Aβ pathology primarily leads to the onset of memory dysfunction, typical of AD, while tau pathology might be more linked to disease progression [10].

Moreover, in our cohort we found an A-T + status in 20 patients (15%), all belonging to the multidomain MCI categories (aMCI-MD and naMCI-MD), while only 7 patients (5%) showed normal CSF biomarkers (A-T-). Both these CSF profiles are held indicative of non-AD pathology, and the clinical progression of these subjects should be carefully evaluated considering other possible forms of dementia [4].

These results show a high concordance between amnestic syndrome and Aβ pathology [11], which in turn may also underscore other neuropsychological phenotypes not including or not limited to memory impairment. In our sample, these patients constitute approximately one-third of A + subjects, suggesting that biomarkers assessment may expand the cohort that could be addressed to AMABs. The increase in this percentage– from 60 to 80%– seems crucial considering that exclusion criteria could further narrow the eligible population. On the other hand, clinical studies have not been conducted in non-amnestic patients with amyloidopathy, who are hypothetically encompassed within the drug approval criteria. This raises challenges in predicting the efficacy and potential side effects in this subgroup and, notably, it remains unclear whether the favorable benefit-to-risk ratio that led to the approval of AMABs is confirmed in this population.

This study has limitations, for instance the sample size which affected the proportion of patients within the single MCI subgroups. In particular, the number of patients with aMCI-SD was lower with respect to the other two categories, potentially impacting the results of the analyses. Broader evaluations should be performed, considering the limitations coming from the restricted time-window that we applied to our retrospective study. Longitudinal data would also clarify the clinical progression of patients with atypical presentations and indeterminate CSF biomarkers. Furthermore, following the very recent approval of lecanemab in the European Union, it should be appropriate to evaluate how a real-world cohort aligns with the full treatment indication outlined in the Summary of the Product Characteristics (“adult patients with a clinical diagnosis of mild cognitive impairment and mild dementia due to Alzheimer’s disease (Early Alzheimer’s disease) who are apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes with confirmed amyloid pathology”). In this regard, our study only focused on patients with MCI, not including individuals with mild AD dementia. Additionally, ApoE genotyping was not systematically available for all patients, limiting our ability to stratify the sample accordingly. Nonetheless, our findings reveal how the choice of selection criteria—particularly when accounting for non-amnestic clinical profiles—can significantly affect the proportion of individuals potentially eligible for treatment with AMABs.

In conclusion, in a hypothetical workflow designed to optimize the prescription of AMABs, we suggest that biomarker assessment not subordinated to the presence of memory deficits could expand the pool of patients eligible according to current guidelines. Conversely, this approach would include patients without clear memory impairment, who were not evaluated in the initial clinical trials, and for whom it is not yet possible to determine whether the benefits outweigh the risks. Further research is needed to confirm the clinical benefits across different neuropsychological profiles. Additionally, while the presence of overt cognitive decline is currently held pivotal to consider treatment, growing evidence advocates that the benefit of AMABs could be even greater in the earliest stages of AD. This is particularly relevant in the era of blood-based biomarkers, that as soon as clinically available would provide a less invasive and reliable method for early diagnosis and for the prediction of clinical progression.