Population-specific transcriptional-state remodeling of cortical and hypothalamic neurons in Alzheimer's disease

Abstract

Selective neuronal vulnerability shapes Alzheimer's disease, but it is commonly inferred from changes in the relative representation of neuronal populations rather than from molecular changes within those populations. We mapped both dimensions across disease progression in amyloid, tau, and combined amyloid-tau mouse models, extended the analysis to cortex and hypothalamus in an independent tau model, and tested the resulting framework in human Alzheimer's disease. Populations with similar reductions in representation showed markedly different degrees of molecular remodeling, while substantial state changes also occurred in populations whose representation remained close to wild type. Disease altered excitability, synaptic, and regulatory programs and reshaped the distribution of cellular states within matched neuronal identities. A particularly recurrent excitatory state linked CAMKK2-AMPK signaling with microtubule regulation. It expanded in glutamatergic populations early in the combined amyloid-tau model, but its direction was not fixed: the same state reversed with age in dentate granule-like neurons and was reduced in corticothalamic neurons of an independent tau model. Remodeling extended beyond cortex to hypothalamic Hdc-positive tuberomammillary neurons, which showed focused excitability-associated changes despite representation close to wild type. In human Alzheimer's disease, remodeling was strongest in several deep-layer and RORB-positive excitatory populations independently associated with vulnerability. The CAMKK2-AMPK-associated state was predominantly reduced rather than increased. An independently defined human depletion-associated neuronal identity instead overlapped other synaptic and calcium-signaling components of the same broader remodeling architecture. Neuronal involvement in Alzheimer's disease is therefore expressed as structured, population-specific remodeling of molecular state, extending across cortical and hypothalamic identities and only partly reflected in relative representation.