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Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight

Nature Reviews Immunology (2018) | Download Citation


Alzheimer disease is more than a pure proteopathy. Chronic neuroinflammation stands out during the pathogenesis of the disease and in turn modulates disease progression. The central nervous system (CNS) is separated from the blood circulation by the blood–brain barrier. In Alzheimer disease, neuroinflammation heavily relies on innate immune responses that are primarily mediated by CNS-resident microglia. APOE (which encodes apolipoprotein E) is the strongest genetic risk factor for Alzheimer disease, and APOE was recently shown to affect the disease in part through its immunomodulatory function. This function of APOE is likely linked to triggering receptor expressed on myeloid cells 2 (TREM2), which is expressed by microglia in the CNS. Here, we review the rapidly growing literature on the role of disease-associated microglia, TREM2 and APOE in the pathogenesis of Alzheimer disease and present an integrated view of innate immune function in Alzheimer disease.

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This work was funded by US National Institutes of Health grants R01AG047644, R01NS090934 and R01NS034467 and support from the JPB Foundation, the Tau Consortium and the Cure Alzheimer Disease Fund to D.M.H.

Reviewer information

Nature Reviews Immunology thanks O. Butovsky and M. Heneka for their assistance with the peer review of this manuscript.

Author information


  1. Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA

    • Yang Shi
    •  & David M. Holtzman


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Y.S. wrote the draft of the manuscript. D.M.H. reviewed and edited the manuscript.

Competing interests

D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech and Proclara. D.M.H. consults for AbbVie and Eli Lilly.

Corresponding author

Correspondence to David M. Holtzman.



A small peptide that is a major component of amyloid deposits in the brain and cerebrovasculature. It is generated from cleavage of amyloid precursor protein (APP). Depending on the carboxy-terminal cleavage site, amyloid-β peptides of varying lengths (36–43 amino acids; denoted as Aβ36–Aβ43) can be generated, among which Aβ40 and Aβ42 are the most prevalent species.


A microtubule-binding protein synthesized primarily in neurons. Under normal conditions, tau is most abundantly located in axons and serves to stabilize microtubules. In Alzheimer disease, tau becomes hyperphosphorylated, dissociates from microtubules, translocates from axons to neuronal cell bodies and dendrites and self-aggregates to form neurofibrillary tangles.

Aβ42/Aβ40 ratio

Aβ42 is more fibrillogenic than Aβ40. The level of Aβ42 produced relative to Aβ40 determines the propensity of amyloid plaque formation.

Kainic acid

A potent neuroexcitatory amino acid that serves as an agonist for kainate-class ionotropic glutamate receptors. High doses of kainic acid induce neuronal death by overexcitation of neurons.

5XFAD mice

An amyloid-β-depositing mouse model that overexpresses mutant human amyloid precursor protein (APP) carrying the Swedish (K670N and M671L), Florida (I716V) and London (V717I) mutations linked to familial Alzheimer disease along with human presenilin 1 (PS1) carrying the M146L and L286V mutations. Both transgenes are controlled under the Thy1 promoter. These mice accumulate high levels of intraneuronal Aβ42 around 6 weeks of age, followed by plaque deposition around 2 months of age.

APPSwePSEN1dE9 mice

An amyloid-β-depositing mouse model that expresses a chimeric mouse–human APP transgene carrying the Swedish mutations (K670N and M671L) and a mutant PSEN1 transgene lacking exon 9 (dE9) under the prion promoter. These mice begin to develop amyloid-β pathology around 6 months of age.

Ionized calcium-binding adaptor molecule 1

(IBA1). A microglia marker protein in the central nervous system that binds calcium and actin. It is involved in RAC GTPase-dependent membrane ruffling and phagocytosis during microglial cell activation.

3xTg-AD mice

A mouse model that harbours three mutant human genes (APPK670N,M671L, PSEN1M146V and MAPTP301L) and sequentially develops amyloid-β pathology and tau pathology starting at 6 months of age.

htau mice

A mouse model that expresses all six human tau isoforms, including 3R and 4R tau, under the endogenous human MAPT promoter and expresses no murine tau. These mice start to develop tau pathology around 9 months of age.

rTg4510 mice

A tauopathy mouse model overexpressing the 0N4R human tau isoform carrying the P301L mutation linked to familial frontotemporal dementia. Tau transgene expression is largely restricted to the forebrain by the Camk2a promoter and is regulatable by doxycycline. These mice develop tau pathology around 3–4 months of age and show substantial neuronal loss by 6 months of age.

P301S mice

A tauopathy mouse model overexpressing the 1N4R human tau isoform carrying the P301S mutation found in patients with frontotemporal dementia. These mice begin to accumulate tau pathology at 4–5 months of age and develop severe brain atrophy at 9 months of age.

APOE-targeted replacement mice

(APOE-TR mice). These mice express human apolipoprotein E (APOE) in place of the murine APOE under the endogenous murine Apoe promoter. Therefore, the expression level and pattern of human APOE are maintained in a physiological form.

APPPS1-21 mice

An amyloid-β-depositing mouse model that harbours mutant human transgenes of APP (K670N and M671L) and PSEN1 (L166P), which are both under the control of the Thy1 promoter. These mice begin to develop amyloid plaques in the neocortex at approximately 6 weeks of age, followed by deposits in the hippocampus at 3–4 months of age.

Superoxide dismutase 1 mice

(SOD1 mice). A mouse model for amyotrophic lateral sclerosis (ALS) that overexpresses human SOD1 carrying the G93A mutation. These mice recapitulate phenotypes in human patients with ALS, showing motor neuron loss in the spinal cord and paralysis in one or more limbs.

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