Differential Progression of White Matter Hyperintensities in Early-Onset compared to Late-Onset Alzheimer’s Disease: a Longitudinal MRI Study (P5.017)

OBJECTIVE: To compare the rates of progression of cerebral white matter disease burden in early vs late-onset Alzheimer’s disease (AD). BACKGROUND: Early-onset AD, with symptom-onset before age 65, often presents without a genetic basis, necessitating further research into its pathogenesis. White matter hyperintensities (WMH) correspond to varying degrees of cerebral ischemia and are frequently found in AD. However, unlike Medial Temporal Lobe Atrophy (MTA), the clinical significance of WMH is still unclear. We hypothesized that the rates of progression of WMH may be different in early compared to late-onset AD, which may reflect differences in their pathophysiology. DESIGN/METHODS: 115 patients (70 late-onset AD [LOAD], 45 early-onset AD [EOAD]) with two temporally separated MRI scans were studied: at each time point, T2-weighted MRI images were scored for WMH burden on the Fazekas scale and the ARWMC (Age-Related White Matter Changes) scale, while T1-weighted MRI images were scored for MTA using Schelten’s criteria. Multivariable linear regressions were used to compare associations with demographic and vascular risk factors. RESULTS: The mean age of diagnosis was 58.57 in EOAD and 77.04 in LOAD. WMH burden at baseline was significantly higher in the older patients (ARWMC, LOAD = 10.85 (SD=4.33), EOAD = 7.9 (SD=5.75), p-value = 0.0005). Despite lower burden of baseline WMH, progression of WMH burden was significantly greater in the EOAD group compared to the LOAD group, in total Fazekas score (OR = 2.25, p-value = 0.002) and total ARWMC score (OR = 1.55, p-value = 0.001). No difference in MTA progression was noted (OR = 1.10, p-value = 0.49). CONCLUSIONS: White matter disease burden progresses more rapidly in early-onset AD patients, indicating novel insights into its differing pathophysiology. Genetic and neuroinflammatory mechanisms will need to be explored. Disclosure: Dr. Oey has nothing to disclose. Dr. Zainal has nothing to disclose. Dr. Cenina has nothing to disclose. Dr. Kandiah has received personal compensation for activities with Lundbeck Research USA, Inc., Novartis, and Eisai Inc.