AbstractBackgroundSubjective cognitive decline (SCD) may be an early risk factor for dementia, particularly in highly educated individuals and women. This study examined the effect of education and sex on the association between SCD and Alzheimer’s disease (AD) biomarkers in non‐demented older adults.MethodVanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n = 129, 73±7 years, 33% mild cognitive impairment, 28% female) completed fasting lumbar puncture, SCD assessment, and Wide Range Achievement Test 3rd edition Reading subtest to assess reading level at baseline. Cerebrospinal fluid (CSF) biomarkers for AD (β‐amyloid42 (Aβ42), Aβ42/40 ratio, phosphorylated tau, tau, neurofilament light) were analyzed in batch. Linear mixed effects models related SCD to CSF AD biomarkers adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE)‐e4 status, cognitive diagnosis, and Geriatric Depression Scale scores (minus points for cognition). Follow‐up models assessed SCD x reading level, SCD x education, and SCD x sex interactions on AD biomarkers.ResultIn main effect models, higher SCD was associated with lower Aβ42 and Aβ42/40 ratio (p‐values<0.005) but not associated with tau, p‐tau, or NfL levels (p‐values>0.38). SCD score interacted with education on Aβ42 and Aβ42/40 ratio (p‐values<0.005), such that associations were stronger in individuals with higher education. In stratified models, no significant associations were observed in any individual educational tertile (p‐values>0.07). SCD score interacted with sex on Aβ42/40 ratio (p = 0.03). In stratified models, higher SCD was associated with lower Aβ42/40 ratio in men (p = 0.002) but not in women (p = 0.89). Reading level did not interact with SCD score on any biomarker (p‐values>0.19), though significant associations between SCD score and Aβ42 and Aβ42/40 ratio were observed in the higher reading level (p‐values<0.005), but not the lower reading level group (p‐values>0.11).ConclusionAmong community‐dwelling older adults free of clinical dementia, higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD may be most useful in detecting early AD pathology in individuals of higher education and men. SCD was not associated with CSF markers of tau or neurodegeneration. These findings suggest that considering sex and education is important when assessing SCD in older adults.