Rare variant of the reelin gene discovered

Gene variant could be another key to understanding Alzheimer’s

A single patient can sometimes provide groundbreaking new answers to understanding a disease. If other cases of the same type are then identified, researchers may be able to establish links between these cases and generate new hypotheses regarding causes and treatments.

This is what happened in the case of a special gene variant that scientists found in the brain of a deceased Alzheimer’s patient from Colombia: In a recent paper in Nature Medicine, an international research team led by scientists from two hospitals – Massachusetts General Hospital (MGH) and Mass Eye and Ear – report on a remarkable case. It involves a patient with a genetic predisposition to developing early Alzheimer’s disease, but who remained cognitively unimpaired until his late sixties. He developed mild dementia at the age of 72 and died at the age of 74 – decades later than is usually the case for most people with the Paisa mutation.

Through clinical investigations led by scientists at the University of Antioquia in Colombia, Department of Genetic and Molecular Studies conducted at Mass Eye and Ear and Children’s Hospital Los Angeles, and neuroimaging and biomarker studies conducted by researchers at the University Medical Center Hamburg-Eppendorf, the team was able to identify a new genetic variant that appears to offer protection against Alzheimer’s disease.

Common early-onset Alzheimer’s disease in certain areas of Colombia

In the sometimes isolated mountain villages of northwestern Colombia, Alzheimer’s disease occurs at an early stage of life – a phenomenon that is not observed in such a concentrated way anywhere else in the world. In these communities at the foot of the Andes, many people carry a particular gene mutation called “Paisa” (Presenilin-1 E280A). These people are all descended from Basque immigrants who came to the country over 250 years ago and brought the mutation with them. If both parents have the mutation, their child will also be affected. If only one parent is a carrier of the mutation, there is a 50 percent chance that the child will inherit it.

Although Alzheimer’s usually only appears at an advanced age, those people who are carriers of the so-called Paisa mutation already manifest symptoms of the disease at the average age of 44. As a rule, they die from the effects of dementia at around the age of 60.

All this knowledge is thanks to Francisco Lopero. The renowned neurologist, himself from the Paisa region, has been working intensively on the subject for 30 years. As early as 2019, he reported on a woman who was a carrier of the mutation but showed no signs of dementia until she was 70 years old. A remarkably exceptional case.

The variant now discovered is in a different gene from the case reported in 2019, but comes from the same family and suggests a common disease process. In addition, the findings point to a specific region of the brain that could be a target for treatments in the future.

Resistance and protection against symptoms of Alzheimer’s disease

“The genetic variant we identified points to a pathway that may lead to extreme resistance and protection from the symptoms of Alzheimer’s disease,” said co-lead author Joseph F. Arboleda-Velasquez, MD, PhD, an associate scientist at Mass Eye and Ear.

“Exceptional cases like this illustrate how individuals and extended families with Alzheimer’s disease can help improve our understanding of the disease and open new avenues for understanding the disease,” said co-senior author Yakeel T. Quiroz, PhD, a clinical neuropsychologist and neuroimaging researcher and director of the Familial Dementia Neuroimaging Laboratory in the Departments of Psychiatry and Neurology at Massachusetts General Hospital. “The insights we gain from this second case may help us identify where in the brain to look to delay and stop the progression of the disease, and may help us form new hypotheses about the sequence of mechanisms that may actually lead to Alzheimer’s dementia.”

Interdisciplinary collaboration enables identification of key puzzle pieces

The male patient had been enrolled in the Mass General Colombia-Boston (COLBOS) biomarker study, which includes members of an extended family group of about 6,000 people with the known Paisa mutation for advanced neuroimaging, biomarker and genetic testing in Boston.

The same study had previously discovered a case in which a patient carried two copies of a rare gene variant called Christchurch that affects the APOE3 protein – a protein strongly linked to Alzheimer’s disease. However, the researchers were able to rule out the presence of the APOE Christchurch gene variant in the male patient.

Working with Xiaowu Gai, Ph.D., at Mass Eye and Ear and with colleagues at Children’s Hospital Los Angeles, genetic and molecular analyses were conducted to identify other variants that could have protected the patient from Alzheimer’s disease. The most promising candidate was a new and rare variant of the reelin gene that had never been reported before.

The team called it Reelin-COLBOS. In studies led by co-senior author Diego Sepulveda-Falla, MD, a senior researcher at the Institute of Neuropathology at the University Medical Center Hamburg-Eppendorf, the team further confirmed the protective role of the Reelin-COLBOS variant through studies in mouse models and neuropathological studies.

APOE-Christchurch and Reelin-COLBOS show characteristic protective patterns

“Each of the protected cases, the APOE-Christchurch and the Reelin-COLBOS cases, show a characteristic pattern of protection in the post-mortem analyses, one global and the other very localised,” Sepulveda-Falla said. “These outstanding cases show us that protection against Alzheimer’s can take different forms, and that it may be possible for therapy to be successful simply by targeting important brain structures such as the entorhinal cortex. These new findings force us to rethink our previous concepts about neurodegeneration and cognitive decline. These are exciting times for us and hopefully for Alzheimer’s research.”

The researchers refer to Reelin as a “cousin” of the better-known APOE. Both Reelin and APOE compete to bind to similar cellular receptors, effectively vying for the same space. When Reelin is bound to the receptor, it reduces the phosphorylation of tau, a protein known to form pathological clumps in brains of Alzheimer’s patients. In contrast, when APOE binds to the receptor, it has the opposite effect.

Reelin is a protein that plays a central role in regulating the development and function of brain cells. In fact, in previous studies, mutations in Reelin have been associated with diseases such as autism, schizophrenia, epilepsy and bipolar disorder. But the disease-associated mutations differ in that they impair the protein’s function, whereas in the case of Reelin-COLBOS as a protective variant, it actually appears to increase the protein’s function.

“When we saw that Reelin was one of our top candidates for the variant, it was a bit shocking,” explains Arboleda-Velasquez. “The fact that the first case showed us a variant affecting APOE and the second case affects Reelin shows us that this signalling pathway, which among other effects controls the phosphorylation of tau, could be the key to understanding why these patients were protected.”

At age 73, the youngest patient underwent imaging scans at Massachusetts General Hospital. These scans showed that while the patient had a high burden of amyloid beta plaques and tau tangles in some areas of his brain, his entorhinal cortex showed remarkably limited tau pathology.

The entorhinal cortex plays a crucial role in memory processes and learning, and its degeneration is known to lead to cognitive impairment and dementia. Studies in a mouse model also showed that the Reelin-COLBOS variant protected against tau pathology. “This case indicates that the entorhinal region may be a tiny target that is critical for protection against dementia,” said co-senior author Quiroz.

Study points to new potential treatment strategies

Many treatment strategies for Alzheimer’s disease, including those drugs recently approved by the US Food and Drug Administration (FDA) and other drugs currently in clinical trials, aim to reduce the formation of amyloid plaques. The results of the study again point to potential new treatments, as the two protected patients had extremely high levels of amyloid in their brains, yet were protected.

“These exciting results demonstrate the power of academic collaboration, where a retinal disease genetics expert working with a local neuroimaging authority can work with leading neurologists and neuropathologists around the world to advance scientific discoveries,” summarised Joan W. Miller, MD, chair of ophthalmology at Mass Eye and Ear, Mass General Hospital and Brigham and Women’s Hospital, and David Glendenning Cogan, professor and chair of ophthalmology at Harvard Medical School, summarise: “Alzheimer’s disease remains a devastating disease with an immense global burden, and this work opens the door for further investigation into how this resilience pathway might lead to an effective therapeutic strategy.”

The researchers note that they cannot completely rule out the possibility that other factors, including additional gene variants, may have contributed to the patient’s resilience to the symptoms of Alzheimer’s disease. However, their experimental evidence in preclinical studies strongly points to the Reelin-COLBOS variant.