Stage dependent differential influence of metabolic and structural networks on memory across Alzheimer’s disease continuum

Background Large-scale neuronal network breakdown underlies memory impairment in Alzheimer’s disease (AD). However, the differential trajectories of the relationships between network organization and memory across pathology and cognitive stages in AD remain elusive. We determined whether and how the influences of individual-level structural and metabolic covariance network integrity on memory varied with amyloid pathology across clinical stages without assuming a constant relationship. Methods 708 participants from the Alzheimer’s Disease Neuroimaging Initiative were studied. Individual-level structural and metabolic covariance scores in higher-level cognitive and hippocampal networks were derived from magnetic resonance imaging and [18F]fluorodeoxyglucose positron emission tomography using seed-based partial least square analyses. The non-linear associations between network scores and memory across cognitive stages in each pathology group were examined using sparse varying coefficient modelling. Results We showed that the associations of memory with structural and metabolic networks in the hippocampal and default mode regions exhibited pathology-dependent differential trajectories across cognitive stages using sparse varying coefficient modelling. In amyloid pathology group, there was an early influence of hippocampal structural network deterioration on memory impairment in the preclinical stage, and a biphasic influence of the angular gyrus-seeded default mode network metabolism on memory in both preclinical and dementia stages. In non-amyloid pathology groups, in contrast, the trajectory of the hippocampus-memory association was opposite and weaker overall, while no metabolism covariance networks were related to memory. Key findings were replicated in a larger cohort of 1280 participants. Conclusions Our findings highlight potential windows of early intervention targeting network breakdown at the preclinical AD stage. ### Competing Interest Statement The authors have declared no competing interest. * A : amyloid-beta plaques AD : Alzheimer’s disease ADNI : Alzheimer’s Disease Neuroimaging Initiative ANG : angular gyrus ANOVA : analysis of variance Aβ : amyloid-beta CDR : clinical dementia rating CN : cognitively normal DLPFC : dorsolateral prefrontal cortex DMN : default mode network ECN : executive control network FC : functional connectivity FDG : [18F]Fluorodeoxyglucose FWE : family-wise error FWHM : Full-Width at Half-Maximum GM : grey matter GMV : grey matter volume HIP : hippocampus ICV : intracranial volume INS : insular LV : latent variable MCI : mild cognitive impairment MMSE : mini-mental state examination MNI : Montreal Neurological Institute mPFC : medial prefrontal cortex MPRAGE : magnetization-prepare rapid-acquisition gradient echo N : neurodegeneration PCC : posterior cingulate cortex PLS : partial least squares PPC : posterior parietal cortex SN : salience network SOB : sum of boxes SPGR : sagittal inversion-recovery spoiled gradient-recalled SUVR : standardized uptake value ratio SVC : sparse varying coefficient T : tau neurofibrillary tangles accumulation VBM : voxel-based morphometry