Pathological phosphorylation (yellow) of Tau proteins (red-orange) by kinases (violet) leads to disintegration of microtubules in an axon and aggregation of tau proteins.
In 2019, an international team that included researchers from two Mass General Brigham hospitals – Mass Eye and Ear and Massachusetts General Hospital (MGH) – reported on the case of a patient who did not develop cognitive decline until she was in her 70s, despite belonging to a family with a genetic mutation called Paisa that significantly increases the risk of developing early-onset Alzheimer’s disease.
In addition to having the genetic variant that causes an autosomal dominant form of Alzheimer’s, the woman had two copies of a rare variant of the APOE3 gene, called Christchurch (APOE3Ch). Now, the team of researchers has revealed that an additional 27 members of this family of more than a thousand members originating in Colombia who carry a single copy of the variant also experienced a delayed onset of the disease.
The study has been published in The New England Journal of Medicine and represents the first evidence that having one copy of the Christchurch variant may confer some level of protection against autosomal dominant Alzheimer’s, albeit less pronounced compared to having two copies. The findings have important implications for drug development, suggesting the potential effects of targeting this genetic pathway.
Cognitive decline was delayed in carriers of the variant
The research team evaluated 1,077 descendants of the Colombian family and identified 27 members of it who carried both the Paisa mutation and a copy of the Christchurch variant. On average, these family members began showing signs of cognitive decline at age 52, compared to a matched group of family members who did not have the variant, who began showing signs at age 47. Family members also showed signs of dementia four years later than those who did not carry the variant.
Two of these individuals underwent functional brain imaging. The scans showed lower levels of tau and preserved metabolic activity in areas typically involved in Alzheimer’s, even in the presence of amyloid plaques, proteins considered a hallmark of the disease. The team also analyzed autopsy samples from four deceased individuals that showed less pathology in the blood vessels, a characteristic that appears important for the protective effects of APOE3 Christchurch.
The authors note that their study was limited to a relatively small number of people who carried both the Paisa and Christchurch variants, and to a single extended family. They write that additional studies involving larger, ethnically diverse Alzheimer’s disease samples could shed more light on the protective effect of the Christchurch variant and help determine whether the findings from the family in Colombia could translate into discoveries relevant to the treatment of sporadic forms of Alzheimer’s.
“The most interesting thing is that if we are able to imitate the effect of this variant using drugs, it would open the door to treatments that can confer protection against the development of Alzheimer’s.”
The team is currently trying to improve their understanding of brain resilience among the remaining family members who carry a copy of the Christchurch variant, using structural and functional MRI scans and cognitive assessments, as well as analysis of blood samples. to evaluate their protein profiles and biomarkers.
“The main limitation of the study is that the number of subjects with PSEN1 and who carry this variant is very low (only 27 subjects in the largest cohort of PSEN1 mutations in the world, with 1,000 subjects, which is outrageous), so More studies are necessary in other populations, both in carriers of mutations in PSEN1 (also different from paisa), and in carriers of other mutations in other genes (PSEN2, APP or APOE e4) and in sporadic Alzheimer’s populations, trying to find out whether this protective effect is maintained and its magnitude,” said Eloy Rodríguez, a neurologist at the Marqués de Valdecilla-IDIVAL University Hospital and professor at the University of Cantabria, in statements to SMC Spain.
“The most interesting thing – and the main door it leaves open – is that, if we are able to imitate the effect of this variant using drugs, it would open the door to treatments that can confer protection against the development of Alzheimer’s disease,” adds the expert, who has not participated in the investigation.
Jordi Pérez-Tur, senior scientist of the CSIC at the Institute of Biomedicine of València (CSIC-CIBERNED) has highlighted in statements to the same medium that “as a whole, we are faced with findings with a very important aspect and that could not be seen so clearly recently: there are ways to slow the progression of Alzheimer’s disease.”
“Deciphering the mechanisms that make a person moderately resistant to the progression of Alzheimer’s disease may mean identifying new mechanisms that lead to effective therapies. In fact, the fact that a single genetic variant has this capacity may mean that slowing down the disease, while not easy, may be achievable,” he concludes.
