Article In Brief
A woman with a rare variant of APOE and familial Alzheimer's disease (AD) had delayed development of AD by nearly 30 years. Independent researchers said the report is changing the thinking and focus of research about the biology of APOE in AD.
Delaying the onset of neurodegeneration is a major goal of Alzheimer's disease (AD) research. A new case report, published November 4 in Nature Medicine, indicates that one key to this long-sought effect may lie at one end of the APOE gene, where a rare mutation appears to have delayed the onset of clinical symptoms by almost three decades in a Colombian woman with a dominant form of early-onset AD.
“The very fact that this mutation led this individual to have onset delayed by almost 30 years is really important in itself, even before we understand the underlying biology of the mutation, because it says that even in the context of an extremely severe genetic form of Alzheimer's disease, you can modify the disease,” said Alison Goate, DPhil, professor of neuroscience and director of the Center on Alzheimer's Disease at the Icahn School of Medicine at Mount Sinai in New York, who was not involved in the study.
Understanding that underlying biology will likely now take center stage in many labs, according to several researchers, who were not involved in the Nature Medicine study.
“This groundbreaking finding is likely to open a new field in APOE biology and its impact on risk of Alzheimer's disease,” said Randall Bateman, MD, FAAN, Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine in St. Louis.
Study Design, Findings
The woman was a member of the 6,000-member Colombian kindred, who, like almost 1,200 of her relatives, carried an autosomal dominant mutation in presenilin 1, which greatly accelerates amyloid formation and leads to the first symptoms of AD between the ages of 42 and 46.
In the new study, an international team of researchers reported that this woman remained cognitively largely unimpaired into her seventies (her exact age was not reported to protect her confidentiality).
The team was led by Yakeel Quiroz, PhD, of Massachusetts General Hospital, Joseph Arboleda, MD, of the Massachusetts Eye and Ear Infirmary, Francisco Lopera, MD, of the Universidad de Antioquia, Medellin, Colombia, and Eric Reiman, MD, executive director of the Banner Alzheimer's Institute in Phoenix, AZ.
The team performed whole exome and whole genome sequencing, which revealed the woman carried two copies of the APOE-e3 allele and was homozygous for a previously described rare mutation on the allele called the Christchurch mutation. To date, she is the only member of the Colombian kindred known to carry two copies of the mutation, and the Alzheimer's literature contains only one other report of an individual homozygous for it, according to Dr. Reiman.
A bioinformatic analysis of her genome, based on the AD literature, indicated that the Christchurch mutation was the most likely factor explaining her delayed disease onset. Of 117 other kindred members tested, 6 percent carried one copy of the mutation, including four members who carried presenilin 1 mutations, all of whom developed mild cognitive impairment at a mean age of 45.
“Homozygosity of the Christchurch mutation appears to be necessary for protection,” Dr. Reiman told Neurology Today.
Imaging indicated that the individual had a very high burden of amyloid plaques, but remarkably limited tau tangles and neurodegeneration.
“This means that her resistance to Alzheimer's disease could not simply be explained by the magnitude of amyloid plaque deposition,” Dr. Reiman said. “Instead, it suggests that APOE may exert effects that are not just a ‘poor man's anti-amyloid treatment,’” but rather are operating downstream from amyloid production.
In vitro, the team found that the mutation reduced the aggregation of amyloid compared to the unmutated e3 allele.
The woman also had hyperlipoproteinemia, a condition seen in a proportion of people carrying two copies of the protective APOE e2 allele. “It turns out that everyone with one or two copies of the Christchurch mutation develops it as well, and that suggests it has something in common with the e2 allele.”
The team also noted that the mutation was in a region of the protein responsible for binding both lipids and heparan sulfate proteoglycans (HSPGs), protein-sugar complexes with multiple roles in cell signaling that have been linked to tau aggregation and propagation.
When they compared the HSPG-binding ability of the Christchurch apolipoprotein to that of other APOE alleles, they found that e4 had the highest affinity, followed by e3, then e2, then the Christchurch e3 mutant. Finally, the team raised an antibody to the mutant receptor region, and showed that, when added to the wild-type e3 protein, it strongly reduced HSPG binding, suggesting that the mutation likely exerts its effect through altering binding at this site.
There is still much work to be done to understand how the mutation protects against the high amyloid burden seen in this individual.
Dr. Reiman stressed, “but it may be that a treatment that interferes with binding of apolipoprotein at the HSPG receptor would be of some interest.”
He cautioned that this is still a single case report, with all the caveats that come with that. “The main value of a case report is to generate hypotheses that can be tested in a range of labs and models. Nonetheless, it is remarkable how much one can potentially learn from one research volunteer.”
“It is sometimes asked, ‘What is the relevance for the general population of studying the rare autosomal dominant forms of Alzheimer's disease, such as presenilin 1?’” Dr. Reiman said.
“What is remarkable about this finding is its implication of the major population-wide genetic risk factor for developing Alzheimer's disease in older age, namely APOE.”
“One of the most prominent findings in this study is that this mutation is not acting by preventing amyloid deposition,” commented Dr. Goate. “That definitely suggests it is acting downstream of aggregation, to prevent tau accumulation and neurodegeneration. Understanding the biology behind this variant and how it might impact risk is incredibly important in thinking about how we can mimic this mutation in therapeutic design—that is probably one of the most important things that can come out of this.”
“Although the genetic combination of an autosomal dominant Alzheimer's disease mutation with a homozygous mutation in APOE is incredibly rare, the impact on delaying the onset of Alzheimer's disease is profound,” said Dr. Bateman. “It is amazing what the Colombian team has accomplished with this finding, and it does increase the potential for APOE to be a therapeutic target.”
“We should be careful about overstating the results from a single individual,” cautioned John Hardy, PhD, chair of molecular biology of neurological disease at UCL Queen Square Institute of Neurology in London. “But that said, what is really welcome about this is that it focuses us back on APOE, which is the most important locus in the genome for modifying risk of Alzheimer's disease risk. It is an understudied area of biology, and so this finding is really welcome from that perspective.”
“This study is in some ways a vision of what would happen to someone who was successfully treated for tauopathy without addressing amyloid beta accumulation,” noted Marc Diamond, MD, professor of neurology and director of the Center for Alzheimer's and Neurodegenerative Diseases at University of Texas Southwestern Medical Center in Dallas.
“There is much more work to be done from the standpoint of biochemistry and cell biology to really understand what are the effects of the mutation in APOE that was described here. But the work is important, and it definitely changes how I am thinking about APOE in Alzheimer's disease. I hope it will inspire a lot more basic research.”