Your Daily digest for NIH Director's Blog

[Article Digests for Psychology & Social Work]

NIH Director's Blog

 

(https://directorsblog.nih.gov/2024/07/18/study-of-protective-gene-variant-provides-insight-into-delaying-onset-of-alzheimers-dementia/) Study of Protective Gene Variant Provides Insight into Delaying Onset of Alzheimer’s Dementia
Jul 18th 2024, 09:00

Credit: Donny Bliss/NIH

(https://www.nia.nih.gov/health/alzheimers-and-dementia/alzheimers-disease-fact-sheet#:~:text=Estimates%20vary%2C%20but%20experts%20suggest,of%20dementia%20among%20older%20adults.) Alzheimer’s disease is currently the seventh leading cause of death in the U.S. While your likelihood of developing Alzheimer’s-related cognitive impairment increases with age, risk for this disease and age of its onset depend on many factors, including the genes you carry. An intriguing new study suggests that having just one copy of a protective gene variant may be enough to delay cognitive impairment from this devastating disease in individuals who are otherwise genetically predisposed to developing early-onset Alzheimer’s dementia.

The findings, from a study supported in part by NIH and reported in (http://doi.org/10.1056/NEJMoa2308583) The New England Journal of Medicine, offer important insights into the genetic factors and underlying pathways involved in Alzheimer’s dementia.1 While much more study is needed, the findings have potential implications for treatments that could one day work like this gene variant does to delay or perhaps even prevent Alzheimer’s dementia.

This research comes from an international team including (https://mapp.mgh.harvard.edu/yakeel-quiroz/) Yakeel Quiroz, Massachusetts General Hospital, Boston; (https://eye.hms.harvard.edu/josepharboleda) Joseph Arboleda-Velasquez, Mass Eye and Ear, Boston; and Francisco Lopera, University of Antioquia, Colombia. For the last 40 years, Lopera has been studying a Colombian family of about 6,000 blood relatives, 1,200 of whom carry a mutation known as Paisa (or Presenilin-1 E280A) that predisposes them to developing early-onset Alzheimer’s dementia. Those who carry a single copy of this gene variant typically show signs of cognitive decline in their early 40s, progressing to dementia by age 50. They frequently die from dementia-related complications in their 60s.

In 2019, the researchers reported on an extraordinary individual who was an exception to this prognosis.2 Even though she carried the Paisa mutation, she didn’t develop any notable cognitive decline until her late 70s—30 years later than expected. The researchers traced her protection against dementia to two copies of a rare variant of the APOE gene dubbed Christchurch. Further study of her brain after death also found lower levels of inflammation and (https://directorsblog.nih.gov/2016/05/24/alzheimers-disease-tau-protein-predicts-early-memory-loss/) tau protein, which forms damaging (https://www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/what-happens-brain-alzheimers-disease#:~:text=In%20Alzheimer's%20disease%2C%20however%2C%20abnormal,the%20synaptic%20communication%20between%20neurons.) tangles inside neurons in the Alzheimer’s brain.

Christchurch is a rare variant, and it’s far more common for people to carry one copy of the protective variant versus two. Would a single copy of the Christchurch variant offer some protection against Alzheimer’s dementia, too? To find out in the new study, the researchers analyzed data from 27 members of this family carrying a single copy of the Christchurch variant among 1,077 carriers of the Paisa mutation.

The researchers compared Christchurch carriers to those without the protective variant and found the variant did delay the age of onset of Alzheimer’s-related cognitive decline and dementia. The median age at the onset of mild cognitive impairment was 52 in family members with the Christchurch variant, compared to approximately age 47 in a matched group without the variant. Similarly, the median age at the onset of dementia was 54, compared to the median age of 50 in noncarriers.

To learn more, the researchers imaged the brains of two of the individuals who had one copy of Christchurch. The brain scans showed lower levels of tau and more normal metabolic activity in brain areas that are known to play a role in Alzheimer’s. Interestingly, their brains still showed accumulations of amyloid proteins, which form plaques that are another hallmark of Alzheimer’s. The team also analyzed autopsy samples from four deceased individuals with one copy of the Christchurch variant and found that blood vessels in their brains appeared healthier, which may help to explain the protective effects of Christchurch. The findings suggest a significant role for blood vessel health in protecting the brain from cognitive decline, as well as a role for disease of the brain blood vessels in contributing to cognitive decline and dementia.

The researchers note this study is limited to a relatively small number of people with both the Paisa and Christchurch variants in one group of related individuals. Further studies involving larger and more diverse samples are needed to learn more about this protective gene variant and its effects on the brain in the general population. The hope is these findings may one day yield new approaches to delaying the onset of Alzheimer’s or slowing its progression in millions more people around the world at risk of developing this devastating disease.

References:

[1] Quiroz YT, et al. (https://pubmed.ncbi.nlm.nih.gov/38899694/) APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease. The New England Journal of Medicine. DOI: 10.1056/NEJMoa2308583 (2024).

[2] Arboleda-Velasquez JF, et al. (https://pubmed.ncbi.nlm.nih.gov/31686034/) Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nature Medicine. DOI: 10.1038/s41591-019-0611-3 (2019).

NIH Support: National Institute on Aging, National Institute of Neurological Disorders and Stroke

Forwarded by:
Michael Reeder LCPC
Baltimore, MD

This information is taken from free public RSS feeds published by each organization for the purpose of public distribution. Readers are linked back to the article content on each organization's website. This email is an unaffiliated unofficial redistribution of this freely provided content from the publishers. 

 

(#) unsubscribe from this feed
-------------- next part --------------
An HTML attachment was scrubbed...
URL: <http://lists.clinicians-exchange.org/pipermail/article-digests-clinicians-exchange.org/attachments/20240719/b36d375d/attachment.htm>