Sex differences are highly relevant to the study of Alzheimer’s disease where any difference between how the disease manifests in women vs. men could offer clues about the targets at which to aim treatments. Decades of research indicate that having the ApoE4 gene allele, the strongest genetic risk for late-onset Alzheimer’s, hits women harder across the lifespan than men.

Complexity was added to this assumption when a paper published in 2017 in the journal JAMA NEUROLOGY identified specific ages where sex differences in the risk for Alzheimer’s disease are more pronounced for carriers of ApoE4. The analysis raised questions about whether preventative efforts aimed at ApoE4 carriers need to start earlier in women than in men. The study also identified the need to understand what happens in the brains of men and women to account for this greater risk.

The paper from the laboratories of Dr. Pike and Dr. Finch used mouse models of Alzheimer’s disease to investigate a possible mechanism by which microglia may contribute to the increased risk of Alzheimer’s associated with the ApoE4 genotype and female sex.

It has been known for quite some time that microglia associate, or co-localize, with amyloid plaques. Alois Alzheimer himself (1864-1915), the German neuropathologist and psychiatrist credited with identifying the first published cases of Alzheimer’s disease, observed that microglia associate with plaques. The role of microglia in Alzheimer’s disease still is not completely defined. This is in part due to the complexity of microglia that are thought to protect against amyloid accumulation in early phases of the disease but might exacerbate pathology in advanced stages. The research described in this paper identified specific microglial interactions with amyloid plaques that have important protective functions in early stages of the disease when women who are also ApoE4 carriers might be the most vulnerable.

A link to the paper published in Acta Neuropathologica Communications is available on Open Access at the following link:

https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0729-z

Caleb E. Finch, Ph.D., and Christian Pike, Ph.D., University of Southern California