Symptomatic clusters related to amyloid positivity in cognitively unimpaired individuals

Abstract

Background: The NIA-AA Research Framework on Alzheimer’s Disease (AD) proposes a transitional stage (stage 2) between the fully asymptomatic stage 1 and mild cognitive impairment (stage 3) in the evolution of symptoms over the disease course. Proposed features of stage 2 include subtle cognitive dysfunction, subjective cognitive decline (SCD) and mild neurobehavioral symptoms. Here, we aimed to identify specific clusters of participants based on these features and assess the association with amyloid positivity in cognitively unimpaired individuals. Methods: We used baseline data of n=338 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study without objective evidence of cognitive impairment and with available data on cerebrospinal fluid biomarkers for AD. Specifically, healthy controls (n=90), participants with SCD (n=202) and first-degree relatives of AD patients (n=46) were included. Classification into the Alzheimer’s continuum (i.e., amyloid positivity, A+) was based on Aß42/40 status. Neuropsychological test data were used to assess subtle objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess neurobehavioral changes (NPS). A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analysed. Results: We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6%) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6%) and a cluster of participants with overall few symptoms (A+:19.7%) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aß42/ptau181 ratio compared to those with neither SCD nor OBJ. Conclusion: In this study, we identified three distinct clusters of participants based on symptoms associated with the NIA-AA stage 2. The cluster characterized by OBJ and concomitant SCD was associated with an increased A+ frequency, suggesting that this combination is enriched for stage 2 of the Alzheimer’s continuum. Trial registration German Clinical Trials Register DRKS00007966. Registered 4 May 2015.