Clumps of APOE protein present in the brains of people with Alzheimer’s disease.

Alzheimer’s disease is a neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. A defining pathological feature of Alzheimer’s disease is the presence of misfolded proteins – specifically amyloid-beta and tau – that form clumps (called aggregates) in the brain. A recent study identified aberrant clumps of misfolded apolipoprotein E (APOE) protein in the brains of people who had Alzheimer’s disease.

Proteins are long chains of peptides. As proteins form, the chains fold into distinctive shapes and structures that dictate their function and activity. Protein folding is an error-prone process and can often result in misfolding. Misfolded proteins tend to clump together and are believed to be the primary cause of a wide range of diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Creutzfeldt-Jakob disease (“mad cow” disease), cystic fibrosis, and many other disorders. The brains of people who die with dementia-related disorders often exhibit the presence of many types of misfolded proteins.

APOE is a protein involved in lipid transport. A variant in the APOE gene, called apolipoprotein E4 (APOE4), is the major genetic risk factor for Alzheimer’s disease. Having one APOE4 allele increases a person’s Alzheimer’s disease risk as much as threefold; carrying two APOE4 alleles increases risk as much as 15-fold.

The investigators studied the brains of 40 people, collected during autopsies upon the participants' deaths. The participants' cognitive status ranged from normal to severe dementia. The investigators used mass spectrometry to characterize the complement of proteins in the amygdala, a region of the brain that is particularly susceptible to accumulating misfolded proteins.

They found that the brains of participants with dementia showed the presence of proteins commonly linked with neurological disorders, including tau, amyloid-beta, alpha-synuclein, and APOE. Of these, APOE was the most abundant, even among participants that did not carry any APOE4 alleles.

These findings suggest that the human amygdala accumulates copious misfolded proteins associated with Alzheimer’s disease and other neurodegenerative disease. The most notable of these is APOE, suggesting that in addition to contributing to genetic risk, the protein may play an active mechanistic role in driving disease progression in people with Alzheimer’s disease.

Interestingly, robust evidence suggests that APOE4 carriers have impaired brain transport of certain forms of omega-3 fatty acids, contributing to their risk of developing Alzheimer’s disease. Learn more in this peer-reviewed article by Dr. Rhonda Patrick.

• View full publication.