Summary Alzheimer’s disease (AD) has a higher prevalence in women than men and is more frequently inherited from mothers than fathers. Yet, while neuroimaging and biomarker studies link maternal family history to stronger AD-related alterations, epidemiological studies suggest that paternal history confers comparable or even greater risk. Here, we leverage the deeply profiled PREVENT-AD cohort to derive three intermediate phenotypes of AD susceptibility. Drawing on nearly 1,000 individual study visits, we quantify how these intermediate phenotypes vary as a function of maternal versus paternal AD lineage. We show that lineage-specific differentiation, including both maternal and paternal biases, is reflected in the brain structure and phenome of adult children of AD patients. Cognitive and cardiovascular risk markers, together with associated genetic variants, show the strongest differentiation along the parental-lineage spectrum of disease susceptibility relative to other correlates of AD burden. Our cross-generational analysis ultimately delineates multidimensional parent-of-origin effects in AD genealogy.
Chloé Savignac, Frédéric St-Onge, S. Villeneuve et al.· Cell Reports Medicine· 0 citations
In Alzheimer’s disease (AD), misfolded proteins emerge across the entire brain in structured, yet not rigid, spatiotemporal patterns. Yet, a systematic bias of single-cell genomics toward sampling mostly cortical tissue limits our understanding of the whole-brain transcriptomic vulnerability to AD. Here, we develop a machine learning method to extrapolate local AD neuropathology signatures to the whole brain. By analyzing gene expression profiles of over two million cortical cells from 427 humans spanning the AD-pathology spectrum, we derive transcriptomic estimators of AD neuropathology. After extensive validations on datasets with known ground truth, we apply this framework to three million cells from 108 brain regions in the Siletti whole human brain atlas and derive an anticipated brain map of transcriptomic signatures indexing AD neuropathology. This interrogation of regions spanning the cortical, subcortical, and brainstem structures uncovers transcriptomic signatures associated with hyperphosphorylated tau in the medulla oblongata, dorsal raphe nucleus, and the tuberal and mammillary regions of the hypothalamus. At the cellular level, assessments of these signatures across 31 cell populations identify VGLUT1/2 expressing neurons, astrocytes, and microglia as key neuropathology-resembling populations. Within the hippocampus, pathology signatures surface in the rostral cornu ammonis (CA) subfields, particularly in the CA1 pyramidal neurons and dentate granule cells. β-amyloid-like signatures localize to the neocortex with laminar selectivity — most prominently in upper layer somatostatin+ intratelencephalic neurons (L2-L3), but also in deep layer intratelencephalic and corticothalamic neurons (L5-L6). Neocortical astrocytes and microglia exhibiting disease associated signatures similarly demonstrate a unique laminar preference. Together, this study provides the first whole human brain map of AD pathology-associated transcriptomic signals, and exposes cell type, region, and cortex layer specific vulnerabilities.
