BOLD amplitude correlates of preclinical Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by a long preclinical stage during which molecular markers of amyloid beta and tau pathology rise, but there is minimal neurodegeneration or cognitive decline. Previous literature suggests that measures of brain function might be more sensitive to neuropathologic burden during the preclinical stage of AD than conventional measures of macrostructure, such as cortical thickness. Among studies that used resting-state functional Magnetic Resonance Imaging (fMRI) acquisitions with Blood Oxygenation Level Dependent (BOLD) contrast, most employed connectivity-based analytic approaches. Consequently, little is known about the effects of amyloid and tau pathology on amplitude of intrinsic BOLD signal fluctuations. To address this knowledge gap, we characterized the effects of preclinical and prodromal AD on the amplitude of low-frequency fluctuations (ALFF) of the BOLD signal both at the whole-brain level and at a more granular level focused on subregions of the medial temporal lobe. We observed reduced ALFF in both preclinical and prodromal AD. In preclinical AD, amyloid positivity was associated with a spatially diffuse ALFF reduction in the frontal, medial parietal, and lateral temporal association cortices. In contrast, tau pathology was negatively associated with ALFF in the entorhinal cortex. These ALFF effects were observed in the absence of observable macrostructural changes in preclinical AD and remained after adjusting for structural atrophy in prodromal AD, indicating that ALFF offers additional sensitivity to early disease processes beyond what is provided by traditional structural imaging biomarkers of neurodegeneration. We conclude that ALFF may be a promising imaging-based biomarker in preclinical AD. • AD pathology adversely a1ects both cortical and subcortical BOLD ALFF. • ALFF e1ects in early AD are detectable in the absence of macrostructural atrophy. • Amyloidpositivity is linked to widespread ALFF reduction in preclinical AD. • Tau burden in the medial temporal lobe has a local, not global, e1ect on ALFF. • ALFF may be a promising metric in the context of preclinical and prodromal AD.