APOE*ε4 links exosomes to cognitive decline

Carriers of the APOE*ε4 allele have impaired exosome production in the brain that could underlie cognitive decline, according to a new study. The findings present opportunities for novel therapeutic approaches to neurodegenerative disease.

The endosomal–exosomal–lysosomal pathway is involved in neurodegeneration, and several studies have indicated that Alzheimer disease (AD) and the APOE*ε4 allele are associated with endosomal and lysosomal changes. In the new study, Efrat Levy, Paul Mathews and colleagues built on these previous findings and focused on the role of exosomes, the other component of the pathway.

“We sought to determine whether APOE*ε4 alters the exosomal pathway and whether there might be pathological linkage between the previously reported endosomal alterations and exosomal pathway changes,” explains Levy.

Using post-mortem tissue from people aged 46–98 years, the researchers compared brain exosome levels in heterozygous or homozygous APOE*ε4 carriers with those in people homozygous for APOE*ε3. The APOE*ε4 allele was associated with lower levels of exosomes than the APOE*ε3 allele. The same was seen in mice that expressed humanized APOE alleles. In the mice, exosome levels did not differ with genotype at 6 months of age, but did at 12 months, indicating an age-dependent effect of APOE*ε4.

Regulators of intracellular exosome formation were downregulated in mice that carried APOE*ε4, demonstrating that impairment of exosome biogenesis caused the lower exosome levels. In addition, extracellular vesicle membranes in APOE*ε4 carriers contained higher levels of cholesterol and ceramide than those in non-carriers.

The results fit with previous findings of endosomal changes in the same mice aged 18 months. “We propose that compromised exosome production in APOE*ε4-expressing individuals contributes to pathogenic alterations in endosomal compartments,” says Mathews.

Together, the findings suggest that impairments in exosome production cause endosomal and lysosomal deficits that interfere with protein processing in neurons.

“the findings suggest that impairments in exosome production cause endosomal and lysosomal deficits”

“Our study provides a novel mechanism to explain the cognitive decline that occurs independently of AD pathology in APOE*ε4 carriers,” says Levy. “We identify a direction for therapeutic strategies to restore the integrity of the endosomal and exosomal pathways, minimizing the neurodegenerative consequences of diseases such as AD.”