Amyloid-ß Positivity Predicts Cognitive Decline but Cognition Predicts Progression to Amyloid-ß Positivity.

BACKGROUND: Stage 1 of the National Institute on Aging-Alzheimer's Association's proposed Alzheimer's disease continuum is defined as amyloid-ß (Aß) positive but cognitively normal. Identifying at-risk individuals before Aß reaches pathological levels could have great benefits for early intervention. Although Aß levels become abnormal long before severe cognitive impairments appear, increasing evidence suggests that subtle cognitive changes may begin early, potentially before Aß surpasses the threshold for abnormality. We examined whether baseline cognitive performance would predict progression from normal to abnormal levels of Aß. METHODS: We examined the association of baseline cognitive composites (Preclinical Alzheimer Cognitive Composite, Alzheimer's Disease Neuroimaging Initiative (ADNI) memory factor composite) with progression to Aß positivity in 292 nondemented, Aß-negative ADNI participants. Additional analyses included continuous cerebrospinal fluid biomarker levels to examine the effects of subthreshold pathology. RESULTS: Forty participants progressed to Aß positivity during follow-up. Poorer baseline performance on both cognitive measures was significantly associated with increased odds of progression. More abnormal levels of baseline cerebrospinal fluid phosphorylated tau and subthreshold Aß were associated with increased odds of progression to Aß positivity. Nevertheless, baseline ADNI memory factor composite performance predicted progression even after controlling for baseline biomarker levels and APOE genotype (Preclinical Alzheimer Cognitive Composite was trend level). Survival analyses were largely consistent: controlling for baseline biomarker levels, baseline Preclinical Alzheimer Cognitive Composite still significantly predicted progression time to Aß positivity (ADNI memory factor composite was trend level). CONCLUSIONS: The possibility of intervening before Aß reaches pathological levels is of obvious benefit. Low-cost, noninvasive cognitive measures can be informative for determining who is likely to progress to Aß positivity, even after accounting for baseline subthreshold biomarker levels.