Early and accurate diagnosis of Alzheimer's disease (AD) is crucial for effective intervention. Cognitive challenge tests, such as the Loewenstein Acevedo Scales for Semantic Interference and Learning (LASSI-L), have shown promise in previous studies using amyloid or FDG PET. However, their relationship with CSF biomarkers, which can be altered before neuroimaging changes, remains unexplored. This study aimed to evaluate the association between LASSI-L scores and CSF biomarkers (Aβ1-42/Aβ1-40 and ptau181) in patients with SCD and MCI to determine the test's capacity to detect amyloid and tau deposition. Early detection is particularly critical given the recent development of disease-modifying therapies whose efficacy depends on early intervention before extensive neurodegeneration. Amnestic MCI (aMCI) patients are at higher risk for AD, but even within this group, the underlying causes are heterogeneous, and a substantial proportion do not exhibit amyloid deposition. Traditional neuropsychological measures have yielded mixed results in accurately detecting early AD, necessitating refinement of clinical and cognitive assessment tools. Cognitive challenge tests, including the LASSI-L, offer a novel approach by assessing cognitive performance under controlled conditions to maximize sensitivity. The LASSI-L, in particular, utilizes a semantic interference paradigm, assessing learning, cued recall, and recovery from proactive semantic interference. Previous studies have demonstrated the LASSI-L's association with brain structure, metabolism, and amyloid load in various populations, supporting its potential as an early diagnostic tool. This study hypothesized that LASSI-L would detect early pathophysiological events related to amyloid and/or tau deposition in individuals with memory complaints but without functional impairment.

The existing literature highlights the challenges in early AD diagnosis and the limitations of traditional neuropsychological tests. Studies have shown that cognitive challenge tests are more sensitive in detecting subtle cognitive impairments compared to standard tests. The LASSI-L has previously shown promise in detecting aMCI and AD dementia, demonstrating associations with brain structure and metabolism in AD-vulnerable regions. Furthermore, LASSI-L scores have been linked to amyloid load in community-dwelling elders and in individuals from an Alzheimer's Disease Research Center. However, no prior research has directly examined the relationship between LASSI-L performance and CSF biomarkers, a crucial step in validating its biological relevance for early AD detection.

This study enrolled 179 Spanish-speaking patients consulting for memory loss but without significant functional impairment. Participants were assessed using a comprehensive neuropsychological battery including the Addenbrooke's Cognitive Examination III (ACE-III), and the LASSI-L. The LASSI-L was administered to assess learning, cued recall, and recovery from proactive interference using two lists of semantically related words. The Free and Cued Selective Reminding Test (FCSRT) was used to categorize patients into aMCI (those with at least one -1.5 SD below the age and education-adjusted norm in learning or delayed recall scores) and SCD (those without such deficits). CSF biomarkers (Aβ1-42, Aβ1-40, ptau181, t-tau) were measured using a commercially available Lumipulse® assay. Statistical analysis included Mann-Whitney U tests for group comparisons, Spearman's correlation coefficients for assessing associations between LASSI-L scores and CSF biomarkers, logistic regression models to predict biomarker abnormalities, and ROC curve analysis to evaluate diagnostic accuracy. The study used established cutoff points for CSF biomarkers based on manufacturer guidelines and previous literature. The researchers also calculated the Aβ1-42/Aβ1-40 ratio and Aβ1-42/ptau181 ratio, which are known to have superior diagnostic properties.

LASSI-L scores showed significant correlations with CSF biomarkers. Specifically, Cued A2 (maximal storage), Cued B2 (recovery from proactive interference), and Delayed Recall (DR) showed moderate correlations with Aβ1-42, Aβ1-42/ptau181, and the Aβ1-42/Aβ1-40 ratio. Patients with amyloid deposition (reduced Aβ1-42/Aβ1-40 ratio) exhibited lower scores on Cued A2, Cued B1, Cued B2, and DR, and higher intrusion error rates. In the aMCI group, patients with reduced amyloid ratios performed worse on LASSI-L measures reflecting learning, interference effects, and delayed recall. Similar patterns were observed for ptau181 levels and Aβ1-42/ptau181 ratio. In the SCD group, impaired amyloid ratios correlated with lower scores on Cued B2 and DR. Logistic regression models demonstrated that DR, age, and PIE-B2 (intrusion errors in Cued B2) were significant predictors of amyloid deposition, increased ptau181, and abnormal Aβ1-42/ptau181 ratio. The model for predicting amyloid deposition (using Aβ1-42/Aβ1-40 ratio) had an accuracy of 0.749 and an AUC of 0.785. The corresponding AUCs for MCI and SCD were 0.742 and 0.799 respectively. Models predicting abnormal ptau181 and Aβ1-42/ptau181 ratio achieved similar accuracies and AUCs.

This study provides strong evidence for the biological validity of the LASSI-L in the early detection of AD-related pathophysiology. The significant correlations between LASSI-L scores and CSF biomarkers, particularly amyloid measures, confirm that the test's semantic interference paradigm captures cognitive processes impaired in the early stages of AD. The superior performance of DR in the logistic regression models underscores the importance of delayed recall in assessing early memory deficits. Notably, the similar performance of the models across aMCI and SCD suggests that LASSI-L may be sensitive even in pre-MCI stages. The test's potential as a clinical tool is highlighted by its acceptable diagnostic accuracy and the potential to guide the use of more invasive or expensive diagnostic procedures. The findings are consistent with prior research indicating that semantic interference challenges are particularly sensitive to early AD-related changes. The results suggest the utility of LASSI-L as a screening tool to identify individuals at risk for AD and to inform the selection of patients for more definitive diagnostic tests such as CSF analysis or amyloid PET.

This study demonstrates the biological validity of the LASSI-L as a sensitive tool for detecting early AD-related changes. The significant correlations between LASSI-L scores and CSF biomarkers, along with the high accuracy of the logistic regression models, suggest its potential as a clinical screening tool and for patient selection before expensive or invasive testing. Further research using longitudinal designs and larger sample sizes could refine the test’s diagnostic capabilities and explore its role in predicting disease progression.

The study employed statistical models that assume linearity, which may not fully capture the complex relationship between CSF biomarkers and LASSI-L performance. The cross-sectional design limits the ability to assess the test’s longitudinal predictive value. The sample consisted of patients from a memory clinic, which may limit the generalizability of the findings to other settings. The use of neuropsychological examination (except LASSI-L) as one of the criteria for CSF testing needs to be further examined for potential bias.