Abstract

BackgroundMechanisms of functional compensation throughout the progression of Alzheimers disease (AD) remain largely underspecified. By investigating functional connectomics in relation to cerebrospinal fluid (CSF) biomarkers across the pathophysiological continuum of AD, we identify disease-stage-specific patterns of functional degradation and functional compensation.\n\nMethodsData from a sample of 96 participants, comprised of 49 controls, 11 preclinical AD subjects, 21 patients with mild cognitive impairment (MCI) due to AD and 15 patients with mild dementia due to AD, were analyzed. CSF ratio of phosphorylated tau protein over amyloid beta peptide 42 (p-tau/A{beta}42) was computed and used as a marker of progression along the AD continuum. Whole-brain, voxel-wise eigenvector centrality mapping (ECM) was computed from resting-state fMRI and regression against p-tau/A{beta}42 was performed. Surviving clusters were used as data-derived seeds in functional connectivity analyses and investigated in relation to memory performance scores (delayed free recall and memory alteration) via complementary regression models. To investigate disease-stage-specific effects, the whole-brain connectivity maps of each cluster were compared between progressive groups.\n\nResultsDecreasing centrality in the inferior parietal lobule (IPL) is significantly correlated with the p-tau/A{beta}42 ratio and associated to memory function impairment across the AD continuum. The thalamus, anterior cingulate (ACC), midcingulate (MCC) and posterior cingulate cortex (PCC) show the opposite effect. The MCC shows the highest increase in centrality as memory performance decays. In the asymptomatic preclinical group, MCC shows reduced functional connectivity (FC) with the left hippocampus and stronger FC with the precuneus (PCu). Additionally, IPL shows reduced FC with the cerebellum, compensated by stronger FC between cerebellum and PCC. In the MCI group, PCC shows reduced FC with PCu, compensated by stronger FC with the left pars orbitalis, insula and temporal pole, as well as by stronger FC of MCC with its anterior and ventral neighboring areas and the cerebellum. In the mild dementia group, extensive functional decoupling occurs across the entire autobiographical memory network and functional resilience ensues in posterior regions and the cerebellum.\n\nConclusionsFunctional decoupling in preclinical AD occurs predominantly in AD-vulnerable regions (e.g. hippocampus, cerebellar lobule VI / Crus I, visual cortex, frontal pole) and coupling between MCC and PCu, as well as between PCC and cerebellum, emerge as intrinsic mechanisms of functional compensation. At the MCI stage, the PCu can no longer compensate for hippocampal decoupling, but the compensatory role of the MCC and PCC ensue into the stage of dementia. These findings shed light on the neural mechanisms of functional compensation across the pathophysiological continuum of AD, highlighting the compensatory roles of several key brain areas.\n\nHighlights- Inferior parietal lobule centrality implicated in Alzheimers disease\n- Increasing centrality in cingulate and thalamus involved in functional compensation\n- Preclinical functional alterations of hippocampus compensated by precuneus\n- Cerebellar involvement in functional compensation\n\n\nAbbreviations