Using new disease models to investigate a common risk factor for Alzheimer's

While the complex genetics underlying Alzheimer’s disease (AD) susceptibility and resilience remain largely unknown, one clear gene affecting risk has emerged: apolipoprotein E (APOE). 

Humans have three slightly different versions (known as alleles) of APOE. The most common, ε3, appears to be neutral for AD, but ε2 provides some protection against AD while ε4 substantially increases AD risk. People who have two copies of APOE^ε4, estimated to be 2-3% of the population, are at greatest risk, but those with one copy of APOE^ε3 and one copy of APOE^ε4 are also more likely to develop AD over time.

Research into the molecular mechanisms that make people with APOE^ε3/ε4 and APOE^ε4/ε4 at higher AD risk, as well as any subtle differences between them, will provide needed insight into AD progression and possible therapeutic targets. A number of factors make human studies very difficult—e.g., long time frames, small patient populations, tissue inaccessibility—so model organism studies are also vital. Unfortunately, research using mice carrying humanized APOE alleles was highly restricted for many years. Now MODEL-AD, a research center based at The Jackson Laboratory (JAX), Indiana University and University of Pittsburgh, is working to develop and make accessible mouse models useful for AD research, including humanized APOE^ε3 and APOE^ε4 mouse strains.

In “The APOE^ε3/ε4 Genotype Drives Distinct Gene Signatures in the Cortex of Young Mice,” researchers led by JAX Professor Gareth Howell, Ph.D.Applies genetics and genomics approaches to study age-related neurodegeneration associated with Alzheimer’s disease, dementia and glaucoma.Gareth Howell , Ph.D. and Kate Foley, Ph.D., a former Tufts graduate student in the Howell lab, provide initial characterization of APOE^ε3/ε4 mice, the most common higher risk combination in humans. The findings show that even relatively young APOE^ε3/ε4 mice do indeed differ from their APOE^ε3/ε3 and APOE^ε4/ε4 counterparts at the molecular level.

“Much of the previous work studying the biology of APOE isoforms has been performed in mice homozygous for each risk genotype, such as APOE^ε3/ε3 and APOE^ε4/ε4 ,” says Howell. “However, in humans, the most common risk genotypes are heterozygous, such as APOE^ε3/ε4 . Using new mice developed by MODEL-AD, Dr. Foley was able to create littermate controls carrying both homozygous and heterozygous APOE genotypes.”

The research investigated the mice at two and four months old, with and without voluntary exercise, which is thought to lessen AD risk. Cholesterol levels, which are higher in human APOE^ε4 carriers, were not affected by the APOE genotype at this young age, but gene expression differed between the APOE^ε3/ε4 heterozygous mice and the homozygous APOE^ε4/ε4 mice at both time points. Of note, genes unique to the APOE^ε3/ε4 mice were enriched for “extracellular matrix” and “blood coagulation” functions at four months, indicating a possible early disruption of normal brain blood vessel integrity and function, a pathology seen worsened with age in humans. The APOE genotype did not affect how the mice responded to exercise, but ongoing aging studies will continue to track the possible interactions between the two variables to see if there are any notable protective effects over time.

“Dr. Foley’s work highlights the importance of considering heterozygous APOE genotypes when investigating the mechanisms of how APOE alleles modify risk for AD and related dementias,” says Howell.