Two to tango? Do cerebrovascular disease + amyloidosis make for Alzheimer’s?

The combination of white matter hyperintensities and cerebral amyloidosis may result in the clinical manifestation of Alzheimer’s disease (AD), according to a study published Feb. 18 in JAMA Neurology. The researchers suggested treatment of risk factors involved in the development of white matter hyperintensities (WMHs) may help prevent or mitigate Alzheimer’s disease.

Although amyloid deposition plays a role in Alzheimer’s, its presence alone is insufficient for the disease as approximately 30 percent of older adults have elevated amyloid levels. Data suggest small-vessel cerebrovascular disease, demonstrated as WMHs on MRI exams, is involved in the disease process.

Frank A. Provenzano, MS, from the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University in New York City, and colleagues devised a study to determine the impact of WMH and PET-derived amyloid positivity on clinical expression of AD.

The researchers focused on data from the Alzheimer’s Disease Neuroimaging Initiative database and included 21 normal control subjects, 59 with mild cognitive impairment and 20 with clinically defined Alzheimer’s. They aimed to answer three questions: does the severity of WMHs discriminate between those with Alzheimer’s disease and normal controls independently of beta amyloid; does WMHs severity discriminate between Alzheimer’s and normal controls among those who are Pittsburgh Compound B (PIB) positive; and does the severity of WMHs provide prognostic information.

Provenzano et al reviewed data from C-11 PIB PET scans to determine amyloid deposition and structural MRI data were used to estimate WMHs volume.

Among the 100 participants, 28 were PIB positive, and 17 of these met clinical criteria for AD. Among the 13 PIB-negative participants, three met Alzheimer’s criteria. Although total WMHs volume did not differ among PIB-positive and PIB-negative individuals, the researchers found a significant negative association between cortical PIB uptake values and total WMHs volume among all participants.

Logistic regression demonstrated higher WMHs volume and PIB positivity were each independently associated with a diagnosis of AD.

The researchers followed subjects with mild cognitive impairment (MCI) for a mean of 30 months from baseline evaluation to AD or last assessment. A total of 22 of 59 individuals with MCI converted to AD. Both PIB and WMHs status were significant predictors of conversion, according to Provenzano et al.

“The findings suggest a role of small-vessel cerebrovascular disease in the clinical presentation of AD and point to the importance of incorporating WMH into the formulation of pathogenic models of the disease. … Our findings suggest that WMHs contribute to AD presentation in addition to beta-amyloid and that WMHs may be a factor that provides a second hit necessary for dementia in the context of amyloidosis,” wrote Provenzano and colleagues.

The researchers noted that treatment or prevention of vascular risk factors may help delay or mitigate Alzheimer’s.

“Knowing if cerebrovascular disease plays an early and initiating role in the formation of AD neuropathology may have a significant impact on strategies to treat or even prevent the disease since vascular diseases are often highly responsive to treatment,” added Karen M. Rodrigue, PhD, from the University of Texas at Dallas, in an accompanying editorial. Understanding a patient’s white matter health may help identify those at highest risk for conversion to AD, she added.

Additional research and replication in larger samples are needed to confirm the role of WMHs in AD, according to Provenzano et al. Rodrigue suggested longitudinal studies that track vascular health risk factors and measure the development of key biomarkers for AD over time.