Clinical Manifestations.

Background: In cognitively unimpaired (CU) older adults, the presence of a subjective cognitive decline (SCD) combined with evidence of abnormal b-amyloid (Ab) is proposed as stage 2 of Alzheimer's disease (AD) by the NIA-AA framework (Jack et al., 2018). However, the associations found between SCD and preclinical AD are inconsistent across studies, highlighting the importance of better understanding which specific SCD features are associated with either Ab or tau burden.

Methods: The present study includes cross-sectional data from 9 independent cohorts with a total of 7217 CU older adults (57% female), aged 69.34 (1.20) years, recruited from general and memory-clinic populations. Ab and tau biomarkers were measured by positron emission tomography (PET) or cerebrospinal fluid (CSF). Using established cut-offs, 28% of participants were Aβ+, and 12% were Aβ+T+ (approximately one-third of the sample had available tau data). We examined four SCD-plus criteria as well as the mean number of SCD criteria met (i.e., mean SCD-severity) in relation to both biomarker status and levels in logistic/linear regressions adjusted for age and sex for each cohort. Summary statistics were extracted for meta-analyses.

Results: The overall frequency of stage 2 AD varied from 7-16% [4-26%] according to each SCD-plus criterion endorsement. Only 1-5% [0-8%] of participants meeting the SCD-plus criteria also had both high Aβ and tau burden (Fig.1). The presence of self-reported memory decline (SMD), an associated concern/worry, and a higher mean SCD-severity were each associated with high Ab (status and continuous). Only the latter was associated with high tau status (Fig.2). Onset of SCD within the last 5 years, and feeling of worse performance than same-age peers, were not associated with AD biomarkers at a Bonferroni-corrected threshold.

Conclusions: Our results suggest that widespread endorsement of multiple SCD features is more powerful than a single criterion alone in identifying both Aβ and tau in CU older adults. We found that the isolated SCD criterion was particularly sensitive to elevated Aβ, even after adjustment for tau, supporting the power of SCD as a very early behavioral marker of preclinical AD.