Progression to dementia in memory clinic patients with mild cognitive impairment and normal β-amyloid

Background: Determination of beta-amyloid (A beta) positivity and likelihood of underlying Alzheimer's disease (AD) relies on dichotomous biomarker cut-off values. Individuals with mild cognitive impairment (MCI) and A beta within the normal range may still have a substantial risk of developing dementia, primarily of Alzheimer type. Their prognosis, as well as predictors of clinical progression, are not fully understood. The aim of this study was to explore the associations of cerebrospinal fluid (CSF) biomarkers (A beta 42, total tau, phosphorylated tau) and other characteristics, including modifiable vascular factors, with the risk of progression to dementia among patients with MCI and normal CSF A beta 42. Methods: Three hundred eighteen memory clinic patients with CSF and clinical data, and at least 1-year follow-up, were included. Patients had normal CSF A beta 42 levels based on clinical cut-offs. Cox proportional hazard models with age as time scale and adjusted for sex, education, and cognition (Mini-Mental State Examination) were used to investigate predictors of progression to dementia and Alzheimer-type dementia. Potential predictors included CSF biomarkers, cognitive performance (verbal learning and memory), apolipoprotein E (APOE) epsilon 4 genotype, medial temporal lobe atrophy, family history of dementia, depressive symptoms, and vascular factors, including the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score. Predictive performance of patient characteristics was further explored with Harrell C statistic. Results: Lower normal A beta 42 and higher total tau and phosphorylated tau were associated with higher dementia risk, and the association was not driven by A beta 42 values close to cut-off. Additional predictors included poorer cognition, APOE epsilon 4 genotype, higher systolic blood pressure, and lower body mass index, but not the CAIDE dementia risk score. A beta 42 individually and in combination with other CSF biomarkers improved the risk prediction compared to age and cognition alone. Medial temporal lobe atrophy or vascular factors did not increase the predictive performance. Conclusions: Possibility of underlying AD pathology and increased dementia risk should not be ruled out among MCI patients with CSF A beta 42 within the normal range. While cut-offs may be useful in clinical practice to identify high-risk individuals, personalized risk prediction tools incorporating continuous biomarkers may be preferable among individuals with intermediate risk. The role of modifiable vascular factors could be explored in this context.