Defining SNAP by cross-sectional and longitudinal definitions of neurodegeneration

Introduction: Suspected non-Alzheimer's pathophysiology (SNAP) is a biomarker driven designation that represents a heterogeneous group in terms of etiology and prognosis. SNAP has only been identified by cross-sectional neurodegeneration measures, whereas longitudinal measures might better reflect “active” neurodegeneration and might be more tightly linked to prognosis. We compare neurodegeneration defined by cross-sectional ‘hippocampal volume’ only (SNAP/L−) versus both cross-sectional and longitudinal ‘hippocampal atrophy rate’ (SNAP/L+) and investigate how these definitions impact prevalence and the clinical and biomarker profile of SNAP in Mild Cognitive Impairment (MCI). Methods: 276 MCI patients from ADNI-GO/2 were designated amyloid “positive” (A+) or “negative” (A−) based on their florbetapir scan and neurodegeneration ‘positive’ or ‘negative’ based on cross-sectional hippocampal volume and longitudinal hippocampal atrophy rate. Results: 74.1% of all SNAP participants defined by the cross-sectional definition of neurodegeneration also met the longitudinal definition of neurodegeneration, whereas 25.9% did not. SNAP/L+ displayed larger white matter hyperintensity volume, a higher conversion rate to dementia over 5 years and a steeper decline on cognitive tasks compared to SNAP/L− and the A- CN group. SNAP/L− had more abnormal values on neuroimaging markers and worse performance on cognitive tasks than the A- CN group, but did not show a difference in dementia conversion rate or longitudinal cognition. Discussion: Using a longitudinal definition of neurodegeneration in addition to a cross-sectional one identifies SNAP participants with significant cognitive decline and a worse clinical prognosis for which cerebrovascular disease may be an important driver.