An Emerging Role for Imaging White Matter in the Preclinical Risk for Alzheimer Disease: Linking β-Amyloid to Myelin.

Over the past 2 decades, advances in brain imaging have enhanced our ability to detect and evaluate the changes that occur as we age and in relation to the developing pathology of Alzheimer disease (AD). Because age is the greatest risk factor for developing Alzheimer dementia and the prevalence of AD is expected to grow rapidly,1 identifying the earliest effects of AD on the brain and the associated molecular mechanisms that lead to cognitive decline and dementia has profound implications for patient care and public health.1,2 The research community’s consensus has widely recognized the need to intervene early before the cascade of pathological events in AD is fully under way.2 Yet, effective early interventions have proven highly elusive. Much work has focused on identifying early risk factors, such as genetic or familial risk, that can be evaluated in the preclinical stages of AD before the development of clinical symptoms. This research effort not only depends on applying sensitive and novel brain imaging biomarkers critical for identifying the earliest effects of developing AD, but also on addressing the complexity of how brain aging interacts with incipient disease pathology. Over the years, this work has led to researchers applying a variety of imaging modalities, including positron emission tomography and magnetic resonance imaging (MRI), to show alterations in brain glucose metabolism, morphology, and functional connectivity in relation to the preclinical risk for AD.3-5 New and emerging imaging techniques are providing exciting opportunities to evaluate the in vivo deposition of brain β-amyloid and tau pathologies,6,7 as well as brain alterations that have not been traditionally linked to the preclinical effects of AD. One such emerging, but relatively understudied, area of research addresses how white matter myelin content is affected by aging and the developing pathology of AD. Although a potential role has previously been proposed for white matter and its vulnerability to the early development of AD pathology,8 a direct association between alterations in white matter myelin content and markers of β-amyloid and tau pathology in asymptomatic older adults has only been recently suggested. In this issue of JAMA Neurology, Dean and colleagues9 report on an application of a novel brain imaging approach with the goal of determining whether well-established cerebrospinal fluid (CSF) markers of AD β-amyloid and tau pathology are related to brain white matter myelin content in a cohort of cognitively asymptomatic late-middle–aged to older adults. This group included 71 community-dwelling participants who were enriched for a family history and genetic risk for late-onset AD, ranging from 48 to 72 years of age. Leveraging the use of a new MRI method, the Multicomponent Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT),10 they were able to directly evaluate the concurrent relation between CSF markers of developing AD β-amyloid and tau pathology and MRI relaxometry-based measures of myelin content in the brain. The authors considered factors such as sex, apolipoprotein E ε4 status, white matter hyperintensity lesion volume, and a cardiovascular risk score by statistically controlling for their potential influence in the sample. Notably, the results showed that age was not associated with the CSF markers of AD pathology in this enriched healthy aging cohort, but widespread regional reductions in MRI myelin content were observed with increasing age. This finding is consistent with prior work showing that alterations in white matter microstructure reflect an important part of the effect of aging on the brain.8 The authors additionally found that after they controlled for sample age, lower β-amyloid and higher tau and tau levels relative to β-amyloid CSF markers were related to regional decreases in the brain MRI myelin measures. These novel and important findings were further enhanced by observing that the degree of AD pathology interacted with age to moderate differences in brain myelin content in the sample. In this case, higher levels of CSF tau relative to β-amyloid led to greater reductions in myelin with increasing age compared with those having lower values of this AD pathology index. Interestingly, the authors noted that their strongest relation was between myelin reductions and CSF concentrations of the soluble amyloid precursor protein, particularly in brain regions known to be preferentially affected in AD, including white matter in the frontal, temporal, corpus callosum, and cingulum regions. Together, these new findings point to early brain alterations of myelin content in relation to the developing pathology of AD and occurring without the presence of overt cognitive symptoms. These results suggest that brain myelin may have a key role in the preclinical stages of this age-related, neurodegenerative disease. Related article Opinion