Early Cortical Microstructural Changes in Aging Are Linked to Vulnerability to Alzheimer’s Disease Pathology

Early identification of Alzheimer's disease (AD) risk is critical for improving treatment success. Cortical thickness is a macrostructural measure used to assess AD neurodegeneration. However, cortical microstructural changes appear to precede macrostructural atrophy and may improve early risk identification. Currently, whether cortical microstructural changes in aging are linked to vulnerability to AD pathophysiology remains unclear in non-clinical populations, who are precisely the target for early risk identification. In 194 adults, we calculated MRI-derived maps of changes in cortical mean diffusivity (microstructure) and cortical thickness (macrostructure) over 5-6 years (meanage: Time1=61.82; Time2=67.48). Episodic memory was assessed using three well-established tests. We obtained PET-derived maps of AD pathology deposition (beta-amyloid, tau) and neurotransmitter receptors (cholinergic, glutamatergic) implicated in AD pathophysiology. Spatial correlational analyses were used to compare pattern similarity among maps. Spatial patterns of cortical macrostructural changes resembled patterns of cortical organization sensitive to age-related processes (r=-0.31, p<0.05), whereas microstructural changes resembled the patterns of tau (r=0.39, p=0.015) deposition in AD. Individuals with patterns of microstructural changes that more closely resembled stereotypical tau deposition exhibited greater memory decline (β=0.21, p=0.036). Microstructural changes and AD pathology deposition were enriched in areas with greater densities of cholinergic and glutamatergic receptors (ps<0.05). Patterns of cortical microstructural changes were more AD-like than patterns of macrostructural changes, which appeared to reflect more general aging processes. Microstructural changes may better inform early risk prediction efforts as a sensitive measure of vulnerability to pathological processes prior to overt atrophy and cognitive decline.