One amino acid swap due to a rare variant in a Colombian person could potentially steer the course of therapeutic strategies for diseases with neurodegeneration and dementia, such as Alzheimer’s disease.

Among the approximately 1200 patients studied who carry a specific mutation (PSEN1E280A) for autosomal dominant Alzheimer’s disease (ADAD), new evidence shows that one patient with an additional mutation delayed clinical onset by several decades. According to the COLBOS study (which stands for “Colombia-Boston biomarker study of ADAD”), carriers of the PSEN1E280A mutation typically experience mild cognitive impairment (MCI) by the median age of 44 and dementia by the median age of 49, but this male maintained full cognitive function until the age of 67. The patient carried a rare gain-of-function variant in RELN (H3447R, also known as RELN-COLBOS due to its association with the Colombia-Boston biomarker study).

The research article, “Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man,” was published in Nature Medicine.

The first cognitive assessment of the male carrier of the PSEN1-E280A mutation at age 67 revealed limited verbal learning skills and language difficulties in the context of functional independence. The patient was diagnosed with MCI, characterized by a decline in short-term memory and verbal fluency, at age 70. At age 72, his language had deteriorated further, progressing to mild dementia. At age 73, he required assistance with basic and instrumental activities of daily living and met criteria for moderate dementia. He died at the age of 74 from aspiration pneumonia. His relatives agreed to a brain donation for neuropathological study.

This is only the second known instance of such remarkable resistance to ADAD. The COLBOS group previously reported a female with the PSEN1E280A mutation and two copies of the APOE3 Christchurch (APOECh) (R136S) gene variant who showed no signs of cognitive impairment nearly 30 years after the typical onset of the disease. The researchers were able to identify shared characteristics by comparing this male case to the previously reported female case with the APOECh variant. Both of these patients had increased amyloid plaque burdens but a limited entorhinal tau tangle burden, and they remained cognitively intact for decades past the expected age of clinical onset.

Mice with a knock-in of the RELN-COLBOS gain-of-function variant do not have the pronounced structural and phenotypic brain abnormalities of RELN loss-of-function mutants, such as defects in cortex lamination, abnormal neuronal migration, and a swollen cerebellum. These mice also show strikingly lower levels of Tau phosphorylation, which may point to a role for RELN signaling in dementia resistance.

Co-senior author Joseph F. Arboleda-Velasquez, MD, PhD, associate scientist at Mass Eye and Ear, which is part of the Mass General Brigham system, told GEN that this research shows a critical pathway that, if targeted with therapeutics, could offer profound clinical benefits to patients. 

Yet, the researchers state that because the comparative neuropathology was conducted in a relatively small number of cases, the results should not be considered definitive and are only helpful to generate hypotheses.

For example, the sister of the male identified in the COLBOS study, who also carried the RELN-COLBOS mutation in addition to the PSEN1-E280A mutation, had severe dementia when she was first evaluated at age 64 and progressed to end-stage dementia at age 72. According to the family, she had hypothyroidism, hypertension, depression, and cognitive decline at age 58 and developed dementia at age 61. Although less protected than her brother, her MCI began 14 years ago and her dementia occurred 12 years later than expected for this population.

Arboleda-Velasquez added that the next thing that needs to be done is to characterize a few other protected subjects that they have identified and develop new therapies inspired by the ones that they have already discovered.