Higher cortical thickness/volume in Alzheimer’s‐related regions: Protective factor or risk factor?

Abstract

AbstractBackgroundNeuroimaging signatures based on cortical thickness or volume in regions vulnerable to Alzheimer’s disease (AD) pathology are tools developed to identify brain changes specific to mild AD. Lower thickness/volume signatures (indicating comparatively thinner cortex) are commonly associated with risk of future decline. In contrast, some evidence suggests a biphasic pattern of changes wherein higher, rather than lower, cortical thickness is associated with very early AD pathology. Understanding the difference between high cortical thickness indicating a risk versus a protective factor carries important implications for early identification of AD. We examined whether integrating information from a novel AD brain signature based on gray matter mean diffusivity (MD)—previously shown by our group to be sensitive to early AD‐related changes and predictive of thickness/volume‐based signatures over a decade later—can aid in the interpretation of when high cortical thickness/volume is a risk versus a protective factor for future AD‐related changes.MethodParticipants were 572 men in the Vietnam Era Twin Study of Aging (VETSA) who were cognitively unimpaired (CU) at baseline (mean age = 56 years; range = 51‐60). A validated thickness/volume signature and novel gray matter MD signature, each a weighted average of MRI‐based morphometry in eight AD‐related brain regions, were used in longitudinal mixed models predicting brain and cognitive outcomes. Subgroup analyses included all CU participants with high baseline thickness/volume signatures, regardless of subsequent cognitive status (n = 147).ResultAmong individuals with high thickness/volume signature scores at baseline, those that additionally had high values on MD signature scores showed significantly lower thickness/volume signatures and lower episodic memory performance 12 years later compared to the high thickness/volume‐low MD group. In contrast, group differences in global mean cortical thickness remained stable across waves. Groups did not differ in level of young adult cognitive reserve.ConclusionGray matter MD differences may capture heterogeneous subgroups among individuals with high cortical thickness/volume. Findings are in line with a biphasic model in which increased cortical thickness in AD‐related regions may precede future decline. An AD signature based on cortical MD can be used alongside cortical thickness to identify subgroups with differential risk for poorer brain and cognitive outcomes.