Sometimes, a single outlier of a patient case might lead to the emergence of new research and the elucidation of disease-related facts.
Researchers frequently draw links between the issues and solutions when they find such a case, which can result in even more compelling and convincing theories regarding the root of the problem and the best course of action.
A multinational team led by Harvard Medical School investigators from Massachusetts General Hospital and Massachusetts Eye & Ear has accomplished this. Their combined research has identified a novel genetic variation that offers protection against Alzheimer’s.
Their research, published on May 11 in Nature Medicine, describes an instance of a patient with a hereditary propensity to acquire Alzheimer’s at a young age. The patient had a high risk of early onset, yet he didn’t develop any cognitive impairment until he was in his late 60s.
The genetic mutation from another person in the same family, whose case was published in 2019, appears in a different gene from the recently discovered variant. The novel variation, however, indicates a common disease pathway.
The findings also hint at an area of the brain that may be an effective therapeutic target in the future.
The ‘Paisa’ Mutation
The case that piqued the interest of the researchers included a family member of the world’s most well-known kindred with a genetic variant known as the ‘Paisa’ mutation.
Those who carry this variant experience mild cognitive impairment at an average age of 44, dementia at an average age of 49, and succumb to dementia-related problems in their 60s.
The neurosurgeon who discovered this family and has been monitoring them for the past 30 years is Francisco Lopera, director of the Neuroscience Group of Antioquia in Medellin, Colombia, and a co-first author of the paper.
The same research team looked at a woman from the same family earlier who was cognitively normal into her 70s. They reported her case in 2019.
The researchers in the latest publication cited a case of a male Paisa mutation carrier who was cognitively normal until age 67. He developed moderate dementia at age 72 and passed away at age 74, which is decades later than the average Paisa mutation carrier.
According to Yakeel Quiroz, a senior co-author of the study, such unusual cases show how people with Alzheimer’s and their extended families can help enhance their understanding of the condition and pave the way for new research. She further stated that the knowledge they are gaining from this second example might help them establish new ideas about the sequence of events that may truly cause Alzheimer’s dementia and may direct them as to where in the brain they need to search to slow and stop disease progression.
Clinical evaluations by researchers at the University of Antioquia in Colombia, genetic and molecular studies at Mass Eye and Ear, Children’s Hospital Los Angeles, neuroimaging and biomarker studies at Mass General, and neuropathological studies by researchers at the University Medical Center Hamburg-Eppendorf in Germany were all part of the work.
What the researchers found in the Biomarker Study
The male patient was participating in the Mass General Colombia-Boston Biomarker Study (COLBOS), which invites 6,000 members of an extended family with the Paisa mutation to Boston for state-of-the-art neuroimaging, biomarker, and genetic testing.
Previously, the same study described a case where a female patient had two copies of the rare Christchurch genetic mutation, which affects the protein APOE3. This protein has a strong connection with Alzheimer’s. According to the researchers, the APOE Christchurch genetic mutation was absent in the male patient.
To find more variants that might have been shielding him against Alzheimer’s, the scientists carried out genetic and molecular tests at Mass Eye and Ear in partnership with Xiaowu Gai and associates from Children’s Hospital Los Angeles.
The newest and rarest variant Reelin gene—never reported before—was the most promising contender. They gave it the name Reelin-COLBOS.
The researchers further confirmed the protective impact of the Reelin-COLBOS variant in mouse models and neuropathological examinations in experiments directed by co-senior author Diego Sepulveda-Falla, a lead investigator at the Institute of Neuropathology, University Medical Center Hamburg-Eppendorf.
According to Sepulveda-Falla, in the postmortem analysis, both the protected cases—the APOE Christchurch and the Reelin-COLBOS case—displayed different protection patterns, one universal and the other highly localized.
He further added that these remarkable cases indicate that there are many different ways that Alzheimer’s protection might manifest itself and that possibly a treatment can be effective even if it only focuses on certain crucial brain regions, like the entorhinal cortex.
They are making us rethink our preconceived notions about neurodegeneration and cognitive decline. We are living in exciting times, and perhaps so is the field of Alzheimer’s research.
How might the Reelin Gene act protective against Alzheimer’s?
According to the researchers, Reelin is a “cousin” of the more well-known APOE protein. Reelin and APOE fight with one another to bind to related cellular receptors, basically vying for the same seat.
Reelin reduces the activation of tau, a protein known to produce pathological tangles in the brains of people with Alzheimer’s. The opposite happens when APOE attaches to the receptor.
Reelin is a protein that is essential for controlling the growth and operation of brain cells. Earlier studies have connected Reelin mutations to conditions like bipolar disorder, schizophrenia, epilepsy, and autism.
Mutations linked to the disease usually reduce protein function; however, in the case of Reelin-COLBOS, the protective variant promotes protein function.
What should we understand?
According to the co-author Arboleda-Velasquez, the first case revealed a variant that affected APOE, while the second demonstrated a mutation that impacted Reelin. It indicates that this signaling pathway, which regulates the phosphorylation of tau, among other effects, may be crucial to understanding why these patients were protected. This observation is significant for guiding therapy because it indicates that additional Reelin could potentially have favorable effects.
The most recent patient experienced neuroimaging tests at Massachusetts General Hospital at 73. These scans showed that although the patient had a significant load of amyloid-beta plaques and displayed tau tangles in several brain regions, the entorhinal cortex had notably sparse pathology.
Memory and learning depend heavily on the entorhinal cortex, and its degradation is known to cause dementia and cognitive decline. The mice studies in this paper further revealed that the Reelin-COLBOS variation protected against tau pathology.
Precisely knowing which part of the brain should be the target for delivery will become more crucial as researchers work to develop gene therapies that deliver treatments that alter or change gene expression.
Many Alzheimer’s treatments, including newly authorized medications by the FDA and others ongoing in clinical studies, attempt to prevent amyloid plaque development.
New Treatment Options
Because the two individuals with almost intact cognitive function had brains with incredibly high amounts of amyloid but were nonetheless protected, the study’s findings offer new therapy options.
The researchers cautioned that they could not completely rule out the possibility that other variables, such as extra gene mutations, contributed to the patient’s resistance to Alzheimer’s symptoms.
However, their experimental data from preclinical investigations suggest that the Reelin-COLBOS variation is involved.
Additionally, they are investigating possible therapeutic approaches that would focus on this defense mechanism.
With the knowledge gained from each unique instance, Arboleda-Velasquez, Quiroz, Lopera, and Sepulveda-Falla intend to continue their search for further protected patients within these Colombian families.
- Lopera, F., Marino, C., Chandrahas, A.S. et al. Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man. Nat Med (2023). https://doi.org/10.1038/s41591-023-02318-3.
- Arboleda-Velasquez, J.F., Lopera, F., O’Hare, M. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med 25, 1680–1683 (2019). https://doi.org/10.1038/s41591-019-0611-3.
- Haley, B. Newly Identified Genetic Variant Protects Against Alzheimer’s. Harvard Medical School. https://hms.harvard.edu/news/newly-identified-genetic-variant-protects-against-alzheimers. Published Online: 15th May 2023. Accessed: 17th May 2023.
- Sobey, R. Alzheimer’s groundbreaking research: Boston scientists discover genetic variant that protects against Alzheimer’s disease symptoms. Boston Herald. https://www.bostonherald.com/2023/05/15/alzheimers-groundbreaking-research-boston-scientists-discover-genetic-variant-that-protects-against-alzheimers-disease-symptoms/. Published Online: 15th May 2023. Accessed: 17th May 2023.