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TITLE: Could a rare gene delay Alzheimer’s? APOE3 Christchurch inspires hope for future therapies

URL: psypost.org/could-a-rare-gene-…

Researchers have uncovered promising insights into Alzheimer’s disease through a study focusing on a Colombian family with a high genetic risk for early-onset Alzheimer’s. A rare genetic variant known as APOE3 Christchurch (APOE3Ch), found in members of this family, appears to delay the onset of cognitive decline. While a previous case study showed that carrying two copies of this variant resulted in remarkable resilience to the disease, the new study suggests that even one copy of the variant provides some protection. These findings, published in The New England Journal of Medicine, offer new directions for understanding and potentially treating Alzheimer’s disease.

“As a clinician, I am highly encouraged by our findings, as they suggest the potential for delaying cognitive decline and dementia in older individuals. Now we must leverage this new knowledge to develop effective treatments for dementia prevention,” said co-first author Yakeel T. Quiroz, a clinical neuropsychologist and neuroimaging researcher and director of the Familial Dementia Neuroimaging Lab in the Departments of Psychiatry and Neurology at Massachusetts General Hospital.

“As a neuroscientist, I’m thrilled by our findings because they underscore the complex relationship between APOE and a deterministic mutation for Alzheimer’s disease, potentially paving the way for innovative treatment approaches for Alzheimer’s disease, including targeting APOE-related pathways.”

The study stemmed from a compelling medical mystery identified in 2019. Researchers reported a unique case of a woman who remained cognitively healthy until her late 70s, despite having a genetic predisposition to Alzheimer’s due to the Paisa mutation in the PSEN1 gene. This mutation nearly guarantees early-onset Alzheimer’s, typically manifesting in the mid-40s.

The woman’s resilience was linked to her carrying two copies of the APOE3 Christchurch variant. Inspired by this exceptional case, researchers aimed to investigate whether carrying just one copy of the APOE3Ch variant could also confer protection against Alzheimer’s in her extended family, which includes approximately 6,000 relatives and 1,200 carriers of the Paisa mutation.

The researchers conducted an analysis involving 1,077 members of the Colombian family with the PSEN1 mutation. Among them, they identified 27 individuals who carried one copy of the APOE3Ch variant. These participants underwent rigorous cognitive testing, neuroimaging, and, in some cases, postmortem brain analysis.

Using tools like the Functional Assessment Staging (FAST) system and the Mini-Mental State Examination (MMSE), the researchers assessed the participants’ cognitive status over time. To minimize bias, the study was conducted with a matched sample design, ensuring comparisons were controlled for variables like sex, education, and other genetic factors.

Individuals with one copy of the APOE3Ch variant experienced a delay of several years in the onset of mild cognitive impairment and dementia compared to those without the variant. Specifically, the median age at the onset of mild cognitive impairment was 52 years for carriers of the APOE3Ch variant, compared to 47 years for non-carriers.

Similarly, the median age for developing dementia was 54 years for carriers, while it was 50 years for non-carriers. While these delays were not as dramatic as those observed in the earlier case of a woman with two APOE3Ch copies, they nonetheless highlight the potential protective effects of the variant.

Further insights were gained through neuroimaging and pathological studies. Brain scans revealed that APOE3Ch carriers had a relatively limited accumulation of tau, a protein closely associated with Alzheimer’s pathology, despite a high burden of amyloid plaques. The reduced tau accumulation appeared to contribute to less neurodegeneration and better-preserved brain function. Postmortem analyses further supported these findings, showing that APOE3Ch carriers had less damage to cerebral blood vessels and a reduced presence of tau in critical brain regions.

Despite these promising findings, the researchers acknowledge several limitations. The study’s sample size for individuals with the APOE3Ch variant was relatively small, and all participants came from the same extended family, limiting the generalizability of the results. Additionally, the study focused on a rare form of Alzheimer’s caused by a specific genetic mutation, which may not fully translate to the more common, sporadic forms of the disease. Future research with larger, more diverse populations will be necessary to confirm these results and explore their broader implications.

Building on this work, the research team plans to further investigate the resilience seen in APOE3Ch carriers. This involves advanced brain imaging, cognitive testing, and biomarker analysis to identify the specific molecular and physiological factors at play.

“As a next step, we are currently focused on improving our understanding of the brain resilience among the remaining family members who carry one copy of the Christchurch variant. This involves conducting structural and functional MRI scans and cognitive evaluations, as well as analyzing blood samples to assess their protein and biomarker profiles,” said Quiroz. “The unwavering commitment to research shown by our Colombian patients with autosomal dominant Alzheimer’s and their families has been indispensable in making this study possible and allowing us to continue to work toward interventions for this devastating disease.”

The study, “APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease,” was authored by Yakeel T. Quiroz, David Aguillon, Daniel C. Aguirre-Acevedo, Daniel Vasquez, Yesica Zuluaga, Ana Y. Baena, Lucia Madrigal, Liliana Hincapié, Justin S. Sanchez, Stephanie Langella, Rafael Posada-Duque, Jessica L. Littau, Nelson D. Villalba-Moreno, Clara Vila-Castelar, Liliana Ramirez Gomez, Gloria Garcia, Elizabeth Kaplan, Sofia Rassi Vargas, J. Alejandro Ossa, Pablo Valderrama-Carmona, Paula Perez-Corredor, Susanne Krasemann, Markus Glatzel, Kenneth S. Kosik, Keith Johnson, Reisa A. Sperling, Eric M. Reiman, Diego Sepulveda-Falla, Francisco Lopera, and Joseph F. Arboleda-Velasquez.

URL: psypost.org/could-a-rare-gene-…

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