A Twin Analysis of AD Brain Signatures and Abnormal White Matter

Abstract

AbstractBackgroundAlzheimer’s disease (AD) and vascular disease frequently co‐occur and may interact additively or synergistically on risk for cognitive decline, though the degree of shared overlap between these pathologies remains unclear. Our group has demonstrated the utility of AD signatures, or composite MRI metrics in brain regions associated with AD pathology, for prediction of AD‐related changes beginning in midlife. Our novel signature based on gray matter mean diffusivity (MD) aided 12‐year prediction of incident mild cognitive impairment among cognitively unimpaired adults in their 50s, captured unique phenotypic and genetic variance not otherwise explained by an AD signature based on cortical thickness/volume or general brain aging, and robustly predicted thickness/volume signatures over a decade later. Here, we leveraged twin data from the Vietnam Era Twin Study of Aging (VETSA) to delineate shared and unique genetic and environmental influences on two AD signatures and white matter hyperintensities (WMHs), which have been consistently linked to vascular origin.MethodParticipants were 512 men from the VETSA (age = 67.52, SD = 2.60). Our validated thickness/volume signature, novel MD signature based on the same brain regions as the thickness/volume signature, and WMH volume were used in biometrical twin analyses to examine their phenotypic, genetic, and environmental relationships. We adjusted each AD signature for an MRI‐based measure of brain age to detect associations with WMH that were specific to AD‐related brain regions versus general brain aging. We also examined regional WMH parcellations.ResultPhenotypic and genetic correlations demonstrated significant associations between the MD signature and WMH (rp = 0.26 [95% CI: 0.15, 0.36]; rg = 0.34 [95% CI: 0.10, 0.57]). In contrast, phenotypic and genetic correlations between the thickness/volume signature and WMHs were nonsignificant. Environmental correlations between each AD signature and WMH were similarly nonsignificant. Results were similar for each WMH parcellation, suggesting global WMH effects.ConclusionA gray matter MD signature and WMHs share significant genetic influences, whereas a thickness/volume signature was not associated with WMHs. AD signatures based on brain microstructure, such as the MD signature, may capture very early AD‐related and vascular‐related changes that are not captured by a macrostructural signature at the same timepoint.