The most exciting thing is that the new Alzheimer’s case has revealed to us both the cause of Alzheimer’s and the cure for it.
“The genetic variant we have identified points to a pathway that can produce extreme resilience and protection against Alzheimer’s disease symptoms,” according to the authors of the new study.
A single patient’s journey can ignite new avenues of research and shed light on the mysteries of disease. When a novel case emerges, investigators have the opportunity to establish connections that foster powerful insights into the causes and treatments involved.
In a recent publication featured in Nature Medicine, an international team, led by researchers from two prominent Mass General Brigham hospitals—Massachusetts General Hospital (MGH) and Mass Eye and Ear—documents a groundbreaking case of a patient who possessed a genetic predisposition for early-onset Alzheimer’s disease but maintained cognitive function until their late 60s.
Through a collaborative effort encompassing clinical assessments conducted by investigators at the University of Antioquia in Colombia, genetic and molecular studies performed at Mass Eye and Ear and Children’s Hospital Los Angeles, neuroimaging and biomarker investigations carried out at MGH, and neuropathological examinations executed by researchers at the University Medical Center Hamburg-Eppendorf in Germany, the team identified a novel genetic variant that confers protection against Alzheimer’s disease.
Notably, this variant occurs in a distinct gene from the one previously reported within the same family in 2019, yet it illuminates a shared disease pathway.
Furthermore, the team’s findings provide valuable insights into a specific brain region that may serve as an optimal target for future therapeutic interventions.
“The genetic variant we have identified points to a pathway that can produce extreme resilience and protection against Alzheimer’s disease symptoms,” remarks co-senior author Joseph F. Arboleda-Velasquez. “These are the kinds of insights we cannot gain without patients. They are showing us what’s important when it comes to protection and challenging many of the field’s assumptions about Alzheimer’s disease and its progression.”
The particular case that drew the attention of investigators revolved around a family member belonging to the world’s largest-known kinship group with a genetic variation known as the “Paisa” mutation (Presenilin-1 E280A). Typically, individuals carrying this variant experience the onset of mild cognitive impairment around the age of 44, followed by dementia at 49, and succumb to dementia-related complications in their 60s. Dr. Francisco Lopera, the director of the Neuroscience Group of Antioquia in Medellín, Colombia, and co-first author of the Nature Medicine paper, discovered this family and has been diligently monitoring them for the past three decades.
In a previous study, the investigative team focused on a woman from this family who remained unaffected until her 70s, and her case was documented in 2019. Now, in their latest Nature Medicine publication, the researchers present the findings of a male carrier of the Paisa mutation who maintained cognitive functioning until the age of 67. Subsequently, he experienced mild dementia at 72 and passed away at 74—a considerable time span compared to the typical progression observed in most individuals with the Paisa mutation.
“What we have done with the study of these two protected cases is to read mother nature,” adds co-senior author Yakeel T. Quiroz. “The most exciting thing is that nature has revealed to us both the cause of Alzheimer’s and the cure for it. Mother nature did an exceptional experiment with these two subjects: it endowed them both with a gene that causes Alzheimer’s and at the same time with another gene that protected them from the symptoms of the disease for more than two decades. Therefore, the solution is to imitate nature by developing therapies that mimic the mechanism of protection of these genetic variants in subjects at risk of suffering from the disease.”
The male participant was enrolled in the COLBOS biomarker study (Mass General Colombia-Boston), which focuses on a large extended family of 6,000 individuals with the Paisa mutation. This research initiative involves advanced neuroimaging, biomarker assessments, and genetic examinations conducted in Boston. In a previous case identified within the same study, a female patient was found to carry two copies of a rare Christchurch genetic variant that affects APOE3—a protein strongly associated with Alzheimer’s disease. However, the presence of the APOE Christchurch genetic variant was ruled out in the male patient.
To explore potential protective factors against Alzheimer’s disease, the research team, in collaboration with Xiaowu Gai, Ph.D., and colleagues from Children’s Hospital Los Angeles, conducted genetic and molecular analyses at Mass Eye and Ear. Their investigation led them to discover a new and rare variant in the Reelin gene, which had never been reported before. This variant was named Reelin-COLBOS. Subsequent studies, overseen by co-senior author Diego Sepulveda-Falla, MD, a principal investigator at the Institute of Neuropathology at the University Medical Center Hamburg-Eppendorf, confirmed the protective role of the Reelin-COLBOS variant through mouse models and neuropathological examinations.
“Each of the protected cases, the APOE Christchurch and the Reelin-COLBOS case, shows a distinctive protective pattern in the postmortem analyses, one global and the other very localized,” points out Sepulveda-Falla. “These outstanding cases are teaching us that Alzheimer’s protection can take different shapes, and that perhaps a therapy can be successful just by targeting key brain structures such as the entorhinal cortex.”
The researchers liken Reelin to APOE, a more widely recognized protein. Both Reelin and APOE compete for binding to similar cellular receptors, contending for the same position. When Reelin occupies the receptor, it reduces the phosphorylation of tau, a protein that forms harmful tangles in Alzheimer’s disease. Conversely, when APOE binds to the receptor, it has the opposite effect.
Reelin plays a crucial role in regulating the development and functioning of brain cells. Previous studies have associated Reelin mutations with conditions such as autism, schizophrenia, epilepsy, and bipolar disorder. However, disease-linked mutations in Reelin reduce the protein’s functionality, while the protective variant identified in Reelin-COLBOS enhances its function.
“When we saw that one of our top candidates for the variant sat in Reelin, it was a bit shocking,” adds Arboleda-Velasquez. “The fact that the first case showed us a variant affecting APOE and the second case affects Reelin tells us that this signaling pathway that controls the phosphorylation of tau, among other effects, may be key to understanding why these patients were protected. This is critical to guide therapies because it clearly tells us that more Reelin could potentially have beneficial effects.”
The latest case, aged 73, underwent neuroimaging examinations at Massachusetts General Hospital. The results of these scans demonstrated a high amyloid-beta plaque burden and the presence of tau tangles in certain brain regions. However, it was notably observed that the patient had minimal tau pathology in the entorhinal cortex. The entorhinal cortex is a vital area involved in memory and learning, and its deterioration is associated with cognitive impairment and dementia. Notably, studies conducted on a mouse model exhibited that the Reelin-COLBOS variant offered protection against tau pathology.
“This case indicates that the entorhinal region may represent a tiny target that’s critical for protection against dementia,” adds Quiroz.
As researchers explore gene therapies with the potential to modify or control gene expression for future treatments, it becomes crucial to determine the specific brain region for targeted delivery.
Current treatments for Alzheimer’s disease, including drugs recently approved by the U.S. Food and Drug Administration, as well as drugs undergoing clinical trials, primarily aim to reduce the accumulation of amyloid plaques. However, the results of this study suggest promising new possibilities for treatment. Interestingly, the two patients who exhibited protection against Alzheimer’s had remarkably high levels of amyloid in their brains, yet remained safeguarded from the disease.
The researchers acknowledge that while they cannot completely exclude the possibility of other factors or gene variants influencing the patient’s resistance to Alzheimer’s disease symptoms, the experimental evidence obtained from preclinical studies strongly points to the Reelin-COLBOS variant.
Moving forward, Arboleda-Velasquez, Quiroz, Lopera, and Sepulveda-Falla intend to pursue further investigations to identify additional individuals within Colombian families who exhibit this protective trait. By studying each extraordinary case, they aim to gain valuable insights. Additionally, they are actively conducting research to explore treatment options that target this protective pathway.
“It is a huge privilege to have these genetic cases to work on,” comments Arboleda-Velasquez. “We are honored to be a part of the team that has made this discovery.”
Source: 10.1038/s41591-023-02318-3
Image Credit: Nathan Laine/Bloomberg via Getty Images