Contemplating Alzheimer's disease and the contribution of white matter hyperintensities

Abstract

As the older adult segment of the population increases, Alzheimer's disease (AD) has emerged as a significant public health epidemic. Over the past 3 decades, advances in the understanding of the biology of AD have led to a somewhat unified hypothesis of disease pathogenesis that emphasizes the precipitating role of beta amyloid protein. However, several lines of evidence suggest that multiple pathologies are necessary for clinical manifestation of the disease. Our focus over the past several years has been on the contribution of small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on magnetic resonance imaging, to AD. White matter hyperintensity volume, particularly in parietal regions, is elevated among individuals with and at risk for AD, predicts future diagnosis of AD, predicts the rate of progression of cognitive symptoms among individuals with AD, and increases over time among individuals destined to develop AD. White matter hyperintensities may represent an independent source of impairment and/or may interact more fundamentally with "primary" AD pathology. Future work should focus on more inclusive models of that better define "normal" vs "pathological" aging.

Figure 1

Framework for understanding contributors to the Alzheimer’s disease phenotype. By defining AD as a syndrome, we are able to identify structural and functional brain changes that predict onset of symptoms, severity of symptoms, and progression of symptoms. Scrutiny of structural and functional alterations associated with the AD syndrome can occur at multiple levels using a variety of disciplines (e.g., cell biology, neuroimaging) and across species. The extent to which age is a necessary or causative factor in AD has not been established entirely but it is noteworthy that symptom onset occurs after age 65 for the vast majority of “sporadic” forms of the disease, which comprise over 90% of AD cases. Mediating factors—the mechanisms that underlie the relevant structural and functional brain changes or through which aging impacts those changes—and moderating factors—those factors that mitigate the effects of relevant structural and functional brain changes on their clinical outcomes—can be identified as reasonable targets for treatment or prevention strategies. The model stipulates that treatment or prevention strategies target factors that ultimately impact the AD syndrome either directly (i.e., through the mediators) or indirectly (i.e., through the moderators). The line connecting the moderators and mediators is to indicate that these factors may interact with each other and are not necessarily independent.

Figure 2

An axial slice from a T2-weighted FLAIR image. A, This image shows the unlabeled MRI scan. B, This image shows WMH labeled in red and a lobar atlas superimposed on the image. Frontal lobe is labeled in green, parietal lobe is labeled in brown, and occipital lobe is labeled in blue (temporal lobe is not visible at this level).

Figure 2

An axial slice from a T2-weighted FLAIR image. A, This image shows the unlabeled MRI scan. B, This image shows WMH labeled in red and a lobar atlas superimposed on the image. Frontal lobe is labeled in green, parietal lobe is labeled in brown, and occipital lobe is labeled in blue (temporal lobe is not visible at this level).