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

This study investigated whether cerebrospinal fluid (CSF) biomarkers—specifically beta-amyloid 1-42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau)—can predict the progression to dementia in patients diagnosed with mild cognitive impairment (MCI) who are categorized as having normal Aβ42 levels. In current clinical practice, a binary cut-off value often dictates who is considered to have underlying Alzheimer’s pathology. This research challenges that dichotomy by analyzing 318 memory clinic patients to determine if continuous biomarker levels or other clinical factors (such as vascular risk scores, APOE ε4 genotype, and medial temporal lobe atrophy) provide a more nuanced prognosis for those currently labeled as 'amyloid-negative'.

The researchers found that even among patients within the normal range, lower Aβ42 levels and higher t-tau and p-tau levels are significant predictors of progression to Alzheimer-type dementia. These associations remained robust even when applying more lenient, data-driven cut-offs for amyloid positivity. Interestingly, while the study identified APOE ε4 status, higher systolic blood pressure, and lower body mass index as additional predictors of progression, the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score failed to predict conversion. The study concludes that biomarkers are most informative when treated as continuous variables rather than relying solely on arbitrary threshold values.

These results suggest that 'normal' amyloid levels do not rule out the risk of underlying Alzheimer’s pathology. For clinicians, the current practice of binary classification may be overly reductive for patients at intermediate risk. The authors propose that personalized risk-prediction models incorporating continuous biomarker data would significantly improve prognostic accuracy. Furthermore, because these patients fall outside the typical inclusion criteria for amyloid-focused trials, their identification is a crucial step toward developing targeted secondary prevention and intervention strategies.