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Alzheimer’s disease (AD), the leading cause of dementia, is a major cause of death and a significant economic burden. In 2016, ∼700,000 Americans aged 65 and over died of AD, and the total health and social care payments for AD in the United States alone exceeded $230 billion (1). Currently, there are no validated disease-modifying therapies that slow the progression of human AD. In PNAS, Ofengeim et al. (2) provide new insights connecting two key aspects of AD pathogenesis—inflammatory signaling and the consequences of this for deposition of β-amyloid. AD manifests pathologically with extracellular β-amyloid deposits and intraneuronal tau aggregates. β-Amyloid is a cleavage product derived from the amyloid precursor protein (APP). Mutations in APP and in processing enzymes that produce β-amyloid suggest that excessive β-amyloid is sufficient to cause AD (3). Likewise, tau mutations cause forms of frontotemporal dementia, arguing for a pathogenic role for tau in AD. At the same time, increases in inflammatory processes are also prominent in AD brains or in response to β-amyloid and manifest with increased levels of activated microglia (macrophage-like cells in the CNS) and the secretion of chemokines and cytokines (4). Many of the loci implicated in AD risk from genome-wide association studies include genes regulating inflammation (5). However, how systemic immunity, monocytes, and brain-resident microglia affect AD pathogenesis has been unclear. Among the cytokines that are elevated in AD, TNF-α has been strongly implicated in inflammation and pathogenesis (6). One possibility is that microglia phagocytose extracellular β-amyloid and degrade these toxic molecules in lysosomes. However, β-amyloid may impair this protective activity (7). Single-cell analyses have also revealed a distinct microglial cell type associated with neurodegenerative diseases including …

RIPK1 promotes inflammation and β-amyloid accumulation in Alzheimer’s disease