Apolipoprotein E Proteinopathy Is a Major Dementia-Associated Pathologic Biomarker in Individuals with or without the APOE Epsilon 4 Allele

The amygdala is vulnerable to multiple or mixed mis-aggregated proteins associated with neurodegenerative conditions that can manifest clinically with amnestic dementia; the amygdala region is often affected even at earliest disease stages. With the original intent of identifying novel dementiaassociated proteins, the detergent-insoluble proteome was characterized from the amygdalae of 40 participants from the University of Kentucky Alzheimer's Disease Center autopsy cohort. These individuals encompassed a spectrum of clinical conditions (cognitively normal to severe amnestic dementia). Polypeptides from the detergent-insoluble fraction were interrogated using liquid chromatography-electrospray ionization-tandem mass spectrometry. As anticipated, portions of peptides previously associated with neurologic diseases were enriched from subjects with dementia. Among all detected peptides, Apolipoprotein E (ApoE) stood out: even more than the expected Tau, APP/AD, and alpha-Synuclein peptides, ApoE peptides were strongly enriched in dementia cases, including from individuals lacking the APOE epsilon 4 genotype. The amount of ApoE protein detected in detergent-insoluble fractions was robustly associated with levels of complement proteins C3 and C4. Immunohistochemical staining of APOE epsilon 3/epsilon 3 subjects' amygdalae confirmed ApoE co-localization with C4 in amyloid plaques. Thus, analyses of human amygdala proteomics indicate that rather than being only an upstream genetic risk factor, ApoE is an aberrantly aggregated protein in its own right, and show that the ApoE protein may play active disease-driving mechanistic roles in persons lacking the APOE epsilon 4 allele. (Am J Pathol 2022, 192: 564-578; https://doi.org/10.1016/ j.ajpath.2021.11.013)

Automated summary

The proteomic analysis of human amygdala indicates that ApoE is not only a genetic risk factor but also an aberrantly aggregated protein, suggesting that ApoE may play an active disease-driving mechanistic role in individuals lacking the APOE epsilon 4 allele.