White Matter Changes Could Predict Cognitive Decline in Alzheimer’s Disease

Alzheimer’s disease is diagnosed based on abnormal pathology of two proteins in the brain: amyloid and tau. Research suggests, however, that other factors may also play a role. In a paper published online this week in the journal Neurology, a team of investigators at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital explore the contributions of white matter damage in the brain. Such damage could serve as a biomarker to help both in classifying clinical diagnoses of Alzheimer’s and in predicting changes in cognition over time.

“There is a good deal of evidence linking white matter damage to Alzheimer’s,” says Emily Lindemer, first author of the Neurology study. Lindemer, currently a researcher at IBM Watson Health, was a graduate student at the Martinos Center when the study was conducted. “White matter signal abnormalities seen on MRI, which reflect white matter damage, have been tied to cognitive decline and dementia. Until this study, though, we still didn’t know how prominent a role they played. Nor did we fully understand the relationship between white matter signal abnormalities and the biomarkers amyloid and tau. We set out to study this relationship and the combined impact of the three on cognitive decline.”

To this end, the researchers examined data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, a University of Southern California-based initiative established to provide researchers with access to imaging findings from this ongoing, large-scale study. They included data from 236 individuals in the database: 61 with an Alzheimer’s diagnosis, 56 cognitively healthy age-matched controls, and 119 with a diagnosis of mild cognitive impairment.

The study compared brain imaging measures from two groups of patients with clinical diagnoses of Alzheimer’s disease. The groups differed in the extent to which the biomarkers amyloid and tau were present: one had levels of the biomarkers typical for Alzheimer’s disease and the other had lower-than-usual levels. The researchers observed a greater amount of white matter damage in the patients with lower-than-usual biomarker levels and found that the damage was a stronger predictor of a patient’s future clinical status. The damage itself was presumed to be the result of deterioration of blood flow to the brain, likely due to vascular disease.

Beyond the ability to predict changes in cognition, the white matter findings have two important implications for clinical care. First, they show that a subset of individuals with a clinical diagnosis of Alzheimer’s disease may have a primary vascular etiology as opposed to a classical Alzheimer’s pathology. Also, in certain patients, the damage to the white matter presumed to be due to vascular disease may be an important therapeutic target for future clinical trials.

The researchers hope to follow up the findings in future work. “The white matter damage examined here has been described in several prior studies of Alzheimer’s disease, yet is not considered a primary feature of the disease,” Lindemer says. “It is most often considered a simple independent comorbidity. We are interested in better understanding the etiology of this tissue damage in Alzheimer’s disease and specifically how this damage fits in with the classical understanding of the disease.”

The authors of the study also include Douglas Greve, Bruce Fischl and David Salat of the Martinos Center and Teresa Gomez-Isla of the MGH Department of Neurology.

Gary Boas