A model for IVIg mechanisms of action in the 3xTg-AD mice. Our observations suggest that IVIg can act on cerebral and peripheral immunity, markers of AD neuropathology and cognitive functions. Systemic injections of IVIg modulate the peripheral immunity and activate phagocytes by decreasing CX3CR1+ expression. These peripheral immune cells can potentially migrate to the brain where they can restore the immune homeostasis of the CNS. Alternatively, IVIg might directly enter the brain, attenuate neuroinflammation and provide a favorable environment against neurodegenerative diseases. In the CNS, IVIg could also directly impact AD pathology by modulating the metabolism of Aβ (production, aggregation, degradation or clearance). Together, correction of immunologic imbalance and decreased AD pathology could provide a favorable outcome on recognition memory and anxiety. Furthermore, these effects of IVIg in the 3xTg-AD mice support a multi-target action in AD, although further study is needed to dissect the therapeutic value of potential pharmacologic substitutes. Dotted line, speculative links; solid line, results from IVIg treatment. ↓, reduction; ↑, increase. 3xTg-AD, triple-transgenic mouse model of Alzheimer’s disease; AD, Alzheimer’s disease; CD, cluster of differentiation; CNS, central nervous system; CX3CR1, C-X3-C chemokine receptor 1; IL, interleukin; IVIg, intravenous immunoglobulin; mo, months of age; NOR, novel object recognition; sAβ42/40, soluble Aβ42/40; YKL-40, chitinase 3-like protein 1 (CHI3L1).