Background Stage 1 of the NIA-AA’s proposed Alzheimer’s disease (AD) continuum is defined as β-amyloid (Aβ) positive but cognitively normal. Identifying at-risk individuals before Aβ reaches pathological levels could have great benefits for early intervention. Although Aβ levels become abnormal long before severe cognitive impairments appear, increasing evidence suggests subtle cognitive changes may begin early, potentially before Aβ surpasses the threshold for abnormality. We examined whether baseline cognitive performance would predict progression from normal to abnormal levels of Aβ.Methods We examined the association of baseline cognitive composites (Preclinical Alzheimer Cognitive Composite [PACC]; ADNI memory factor score [ADNI_MEM]) with progression to Aβ-positivity in 292 non-demented, Aβ-negative Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants. Additional analyses included continuous CSF biomarker levels to examine the effects of subthreshold pathology.Results Forty participants progressed to Aβ-positivity during follow-up. Poorer baseline performance on both cognitive measures was significantly associated with increased odds of progression. More abnormal levels of baseline CSF p-tau and subthreshold Aβ were associated with increased odds of progression to Aβ-positivity. Nevertheless, baseline ADNI\_MEM performance predicted progression even after controlling for baseline biomarker levels and APOE genotype (PACC was trend level). Survival analyses were largely consistent: controlling for baseline biomarker levels, baseline PACC still significantly predicted progression time to Aβ-positivity (ADNI\_MEM was trend level).Conclusions The possibility of intervening before Aβ reaches pathological levels is of obvious benefit. Low cost, non-invasive cognitive measures can be informative for determining who is likely to progress to Aβ-positivity, even after accounting for baseline subthreshold biomarker levels.

Aβ-Positivity Predicts Cognitive Decline but Cognition Predicts Progression to Aβ-Positivity