Rare Genetic Variant Delays Onset of Alzheimer’s Disease in Colombian Family
A groundbreaking study published in the New England Journal of Medicine sheds light on a rare genetic variant that appears to delay the onset of Alzheimer’s disease. Researchers investigated the APOE3 Christchurch (APOE3Ch) variant in a large Colombian family with a high genetic risk for early-onset Alzheimer’s caused by a mutation known as Paisa.
“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 Dr. Yakeel T.Quiroz,a clinical neuropsychologist and neuroimaging researcher at Massachusetts General Hospital.
The study focused on a woman who remained cognitively healthy until her late 70s despite carrying the Paisa mutation, which typically leads to Alzheimer’s in the mid-40s.She possessed two copies of the APOE3Ch variant,leading researchers to investigate whether even one copy provided some protection.
out of 1,077 family members with the Paisa mutation, 27 carried one copy of the APOE3Ch variant. These individuals underwent rigorous cognitive testing, neuroimaging, and, in certain specific cases, postmortem brain analysis.
Results revealed a delay of several years in the onset of mild cognitive impairment and dementia among APOE3Ch variant carriers compared to those without the variant. While not as dramatic as the two-copy case, this delay highlights the potential protective influence of the variant.
Brain scans and postmortem analyses offered further insights. APOE3Ch carriers exhibited less accumulation of tau protein, a hallmark of Alzheimer’s pathology, despite having a high burden of amyloid plaques.This reduced tau accumulation correlated with less neurodegeneration and better brain function.
The researchers acknowledge limitations, including a relatively small sample size and the focus on a rare, familial form of Alzheimer’s. Future research with larger, diverse populations is needed to confirm these findings and explore their broader implications.
Further investigation is planned to delve deeper into the resilience observed in APOE3Ch carriers, employing advanced brain imaging, cognitive testing, and biomarker analysis to identify the specific molecular and physiological factors at play.
“We are currently focused on improving our understanding of brain resilience among the remaining family members who carry one copy of the Christchurch variant,” said Dr. quiroz.
The study, “APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease”, was authored by a team led by Dr. Quiroz and Dr. Francisco Lopera.
## A FamilyS Legacy: Unlocking the Secrets of Alzheimer’s
**Archyde Interview Series**
Joining us today is Dr. Francisco Lopera, a leading researcher who has dedicated his life unraveling the mysteries of Alzheimer’s disease. Dr. Lopera, thank you for taking the time too speak with us today.
**dr. Lopera:** It’s a pleasure to be here.
**Archyde:** Your work with the COLBOS study has shed light on a fascinating phenomenon: a rare genetic variant delaying the onset of Alzheimer’s in a large Colombian family. Can you tell us more about this discovery?
**Dr. Lopera:** Certainly. for over three decades, we have been studying a remarkable family in Antioquia, Colombia [[1](https://nihrecord.nih.gov/2022/08/19/colbos-study-reveals-mysteries-alzheimer-s-disease)]. Many members of this family carry a rare genetic mutation, PSEN1 E280A, which typically causes early-onset Alzheimer’s disease. However, interestingly, some individuals with the mutation don’t show symptoms until much later in life, significantly delaying the disease progression.
**Archyde:** That’s truly remarkable.What could account for this delayed onset?
**Dr. Lopera:** we believe this delay is attributed to a protective genetic variant. Our research suggests that this variant acts as a buffer against the harmful effects of the PSEN1 E280A mutation, essentially slowing down the growth of the disease.
**Archyde:** This discovery has immense implications for Alzheimer’s research. What are the broader implications of these findings?
**Dr. Lopera:** This is a game-changer. By understanding how this protective variant works, we may be able to develop new therapies that mimic its effect and delay the onset of Alzheimer’s in other individuals.It paves the way for preventative strategies and potential cures.
**Archyde:** What are the next steps in your research?
**Dr. Lopera:** We’re currently focusing on identifying the exact mechanisms behind this protective variant. We’re also exploring whether this knowledge can be translated into tangible treatments for Alzheimer’s disease.
**Archyde:** Dr. Lopera, thank you for sharing your invaluable insights. The Colombian family’s story offers hope and direction in the fight against Alzheimer’s. We eagerly await your future discoveries.
## Hope on the Horizon: A Rare Variant Offers Clues in the Fight Against AlzheimerS
**Archyde Interview**
**Alex Reed:** Dr. Yakeel T. Quiroz, Clinical Neuropsychologist and Neuroimaging Researcher at Massachusetts General Hospital
**Host:**
Welcome Dr. Quiroz. Thank you for joining us today. The recent study published in the New England Journal of Medicine highlighting a rare genetic variant, APOE3 Christchurch, and its potential link to delaying Alzheimer’s disease has generated meaningful interest. Could you explain what sparked this investigation?
**Dr. Quiroz:**
Certainly. This research stemmed from a unique observation within a large Colombian family. This family carries a specific mutation known as Paisa, which predisposes them to early-onset Alzheimer’s, typically appearing in their mid-40s. However, one remarkable woman in this family, despite carrying the Paisa mutation, remained cognitively healthy well into her late 70s.
**Host:**
That’s truly remarkable. What made this woman different?
**Dr.Quiroz:**
She possessed two copies of the APOE3 Christchurch variant. This prompted us to investigate whether having even one copy of this variant offered some protection against the detrimental effects of the Paisa mutation.
**Host:**
So, what did your study find?
**Dr. Quiroz:**
We examined over 1000 family members, 27 of whom carried one copy of the APOE3 Christchurch variant. These individuals were put through rigorous cognitive testing, neuroimaging, and in some cases, postmortem brain analysis.
this revealed a significant delay of several years in the onset of both mild cognitive impairment and dementia among APOE3 Christchurch carriers compared to those without the variant.
**Host:**
that’s encouraging news. Can you elaborate on the mechanisms behind this delay?
**Dr. Quiroz:**
Brain scans and postmortem analyses pointed to a fascinating finding. Even though these individuals had a high burden of amyloid plaques, a hallmark of Alzheimer’s, those carrying the APOE3 Christchurch variant exhibited considerably less accumulation of tau protein, another critical marker of Alzheimer’s pathology. This reduced tau accumulation correlated with less neurodegeneration and, importantly, better brain function.
**host:**
This seems incredibly promising. What are the next steps in this research?
**Dr. Quiroz:**
We are cautiously optimistic, but recognise the limitations of our study, including the relatively small sample size and focus on a rare familial form of alzheimer’s.
We are planning further investigation to delve deeper into the phenomenon of resilience observed in APOE3 Christchurch carriers. This will involve advanced brain imaging techniques, more comprehensive cognitive testing, and detailed biomarker analyses to pinpoint the specific molecular and physiological factors at play.
**Host:**
Dr. quiroz, thank you for sharing these fascinating insights with us. Your research offers a glimmer of hope and sheds light on new avenues for potentially preventing or delaying Alzheimer’s disease.
**Dr. Quiroz:**
Thank you.As a clinician, I am truly encouraged by these findings and motivated to continue this crucial research. Understanding the protective mechanisms of this rare variant could unlock new therapeutic targets and ultimately lead to breakthroughs in dementia prevention.
