Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however, few studies have investigated its role in neurodegenerative processes such as Alzheimer’s disease (AD). Here, we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in humans, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.

Historically, the creation of the parasympathetic division of the autonomic nervous system of the vertebrates is inextricably linked to the unification of the cranial and sacral autonomic outflows. There is an intriguing disproportion between the entrenchment of the notion of a ‘cranio-sacral’ pathway, which informs every textbook schematic of the autonomic nervous system since the early XX^th century, and the wobbliness of its two roots: an anatomical detail overinterpreted by Walter Holbrook Gaskell (the ‘gap’ between the lumbar and sacral outflows), on which John Newport Langley grafted a piece of physiology (a supposed antagonism of these two outflows on external genitals), repeatedly questioned since, to little avail. I retrace the birth of a flawed scientific concept (the cranio-sacral outflow) and the way in which it ossified instead of dissipated. Then, I suggest that the critique of the ‘cranio-sacral outflow’ invites, in turn, a radical deconstruction of the very notion of a ‘parasympathetic’ outflow, and a more realistic description of the autonomic nervous system.