Background: Emerging evidence suggests that subjective cognitive concerns (SCC) may herald initial cognitive decline at the preclinical stage of Alzheimer's disease (AD). While previous studies have investigated the relationship between SCC and amyloid (A b ) burden and neurodegeneration (ND) separately, it remains unclear if increased SCC correlates with successive stages of preclinical AD.
      Methods: We studied 186 CN individuals from the Harvard Aging Brain Study (Clinical Dementia Rating Scale = 0, Geriatric Depression Scale <11). A b status was determined with PIB-PET imaging and ND was measured using two a priori imaging markers: hippocampus volume and glucose metabolism extracted from AD-vulnerable regions. A subjective cognitive concerns composite was calculated using subscales from three questionnaires. Linear regression models with A b and ND status as simultaneous predictors were used to predict SCC, controlling for age, education, and gender. A secondary analysis included APOE ε4 carrier status as a predictor. SCC were also examined across groups based on joint A b and ND status (Stage 0: A b -/ND-; Stage 1: A b +/ND-, Stage 2: A b +/ND+, and SNAP: A b -/ND+).
      Results: SCC was not related to age, gender or education. Both A b (p=0.002) and ND (p=0.036) were independently associated with greater SCC. APOE ε4 carrier status was not related to SCC and did not impact results from the initial model. Examination across groups revealed that SCC was greater in stage 2 compared to stage 0 (p<0.001), stage 1 (p=0.20) and SNAP (p=0.03). Furthermore, Stage 0 had lower SCC than both SNAP (p = 0.07) and stage 1 (p=0.03). There was no difference between Stage 1 and SNAP (p=0.45).
      Conclusions: We demonstrate independent and additive contribution of A b and ND status in predicting SCC, unaffected by APOE ε4 carrier status, such that individuals who are positive on both biomarkers show the greatest SCC, while individuals positive for a single biomarker show intermediate levels of SCC. This pattern is consistent with the hypothesis that the combination of A b and ND markers increases likelihood of cognitive decline.