Our proposed model delineates how cognitive decline associated with aging and neurodegenerative diseases arises from the coordinated activation of specific immune receptors—PIRB/LILRB2 and C5aR2 in neurons, TLRs and CR3 in astrocytes, and TLRs and CR3 in microglia (Figure 4). Here, LILRB2 is linked to neurodegenerative disease.