White matter hyperintensities and amyloid are independently associated with entorhinal cortex volume among individuals with mild cognitive impairment.

BACKGROUND Current hypothetical models of Alzheimer's disease (AD) pathogenesis emphasize the role of β-amyloid (Aβ), tau deposition, and neurodegenerative changes in the mesial temporal lobe, particularly the entorhinal cortex and hippocampus. However, many individuals with clinical AD who come to autopsy also exhibit cerebrovascular disease. The relationship between AD and vascular pathology is unclear, especially whether they represent additive and independent effects on neuronal injury. We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to (1) confirm whether entorhinal cortex and hippocampal volume are associated with memory among individuals with amnestic mild cognitive impairment (MCI) who are at risk for AD; and (2) determine whether regional white matter hyperintensity (WMH) volume, a radiological marker of small-vessel cerebrovascular disease, is associated with entorhinal cortex and hippocampal volume independent of putative AD biomarkers in this group. METHODS Cognitive test scores, entorhinal cortex volume, hippocampus volume, intracranial volume, and cerebrospinal fluid-derived phosphorylated tau and Aβ1-42 protein levels were measured in 199 subjects with amnestic MCI (mean age = 74.89 ± 7.47). Lobar WMH volumes were derived from T1-, proton-density-, and T2-weighted magnetic resonance imaging scans. We examined the association between entorhinal cortex volume and cognition. Next, we examined the association of tau and Aβ1-42 with entorhinal cortex volume and between lobar WMH and entorhinal cortex volume. Finally, tau, Aβ1-42, and regional WMH volumes were entered simultaneously to predict entorhinal cortex volume. We repeated the analyses with hippocampal volume instead of entorhinal cortex volume. The analyses were also repeated with the sample restricted to those MCI patients who transitioned to AD on subsequent ADNI follow-up visits (n = 86). RESULTS Larger entorhinal cortex volume was associated with better memory but not with performance on a task of executive functioning. Lower levels of Aβ1-42 and higher temporal WMH volumes were associated with smaller entorhinal cortex volume. When entered simultaneously, temporal lobe WMH volume was more reliably associated with entorhinal cortex volume than was Aβ1-42. The findings were similar for hippocampus volume and when the sample was restricted to MCI patients who subsequently transitioned to AD. CONCLUSIONS The findings confirm the role of entorhinal cortex and hippocampus volume in influencing memory decline in amnestic MCI, and emphasize that even in this nominally AD prodromal condition, WMH may be influencing regional neurodegeneration.