Abstract

INTRODUCTIONCognitive decline in Alzheimers disease is associated with amyloid-{beta} accumulation, neurodegeneration and cerebral small vessel disease, but the temporal relationships between these factors is not well established. METHODSData included white matter hyperintensity (WMH) load, grey matter (GM) atrophy and Alzheimers Disease Assessment Scale-Cognitive-Plus (ADAS13) scores for 720 participants and cerebrospinal fluid amyloid (A{beta}1-42) for 461 participants from the Alzheimers Disease Neuroimaging Initiative. Linear regressions were used to assess the relationships between baseline WMH, GM, and A{beta}1-42 to changes in WMH, GM, A{beta}1-42, and cognition at one-year follow-up. RESULTSBaseline WMHs and A{beta}1-42 predicted WMH increase and GM atrophy. Baseline WMHs, GM, and A{beta}1-42 predicted worsening cognition. Only baseline A{beta}1-42 predicted change in A{beta}1-42. DISCUSSIONBaseline WMHs lead to greater future GM atrophy and cognitive decline, suggesting that WM damage precedes neurodegeneration and cognitive decline. Baseline A{beta}1-42 predicted WMH increase, suggesting a potential role of amyloid in WM damage. Research in ContextO_LISystematic Review: Both amyloid {beta} and neurodegeneration are primary pathologies in Alzheimers disease. White matter hyperintensities (indicative of presence of cerebrovascular disease) might also be part of the pathological changes in Alzheimers. However, the temporal relationship between white matter hyperintensities, amyloid {beta}, neurodegeneration, and cognitive decline is still unclear. C_LIO_LIInterpretation: Our results establish a potential temporal order between white matter hyperintensities, amyloid {beta}, neurodegeneration, and cognitive decline, showing that white matter hyperintensities precede neurodegeneration and cognitive decline. The results provide some evidence that amyloid {beta} deposition, in turn, precedes accumulation of white matter hyperintensities. C_LIO_LIFuture Directions: The current findings reinforce the need for future longitudinal investigations of the mechanisms through which white matter hyperintensities impact the aging population in general and Alzheimers disease patients, in particular. C_LI