Potential drivers of age‐ and beta‐amyloid‐related neurodegeneration in early and late Alzheimer’s Disease regions in cognitively normal older adults

Abstract Background Aging, cerebrovascular disease, β‐amyloid (Aβ), and tau pathology are hypothesized to play a role in neurodegeneration, but their interplay is unclear. We investigate associations of these predictors with neurodegeneration, and potential mediating effects on age‐ and Aβ‐related neurodegeneration, in an early Alzheimer’s disease (AD) region (medial temporal lobe (MTL)), and other earlier/later AD neocortical regions in cognitively normal older adults and a low‐Aβ subgroup. Method 351 adults (41‐91 years) from the Swedish BioFINDER‐2 study were included (65.5±11.8 years; low‐Aβ: n=232, 63.1±11.9 years). Using the Automated Segmentation for Hippocampal Subfields package for T1‐ and T2‐weighted MRI, volumes (dentate gyrus, subiculum (SUB), cornu ammonis 1) and thickness (entorhinal cortex, Brodmann areas (BA) 35/36, and parahippocampal cortex (PHC)) were obtained. FreeSurfer parcellation was used to obtain thickness of neocortical regions involved earlier/later in AD. [18F]RO948‐ and [18F]flutemetamol‐PET standard uptake value ratios were calculated for local tau (partial‐volume corrected) and global Aβ. White matter lesion volumes (WML) were obtained to estimate cerebrovascular disease. Global Aβ‐PET and cerebrospinal fluid Aβ‐42/40 ratio determined Aβ status. Results In the whole group, negative (partial) correlations of age/local tau‐PET/WML with structure in most examined regions were observed (Table 1). In the MTL, these predictors were mostly associated with SUB/BA35/PHC. Global Aβ‐PET showed consistent negative associations with neocortical thickness. Low‐Aβ group associations were comparable. In the whole group, age‐structure associations were mediated serially via Aβ‐local tau and directly via tau‐PET in regions with early AD pathology (SUB/BA35, precuneus/posterior cingulate (PPC); Fig.1). In a later AD region (inferior parietal cortex (IP)), local tau‐PET mediated Aβ‐IP association. In low‐Aβ individuals, local tau‐PET mediated the age‐PPC association (Fig.2). Global WML mediated age‐structure associations in posterior MTL and parietal regions in the whole (Fig.1) and low‐Aβ group (Fig.2). Conclusion The role of both Aβ‐ and tau‐PET in mediating age‐structure associations in regions typically linked to either early Aβ or tau, could point to an earlier role of Aβ in the MTL and tau in PPC than expected. WML mediating age‐effects on neurodegeneration, in posterior MTL and parietal regions, indicates a potential vulnerability of the posterior‐medial network to cerebrovascular disease.