A Rare Genetic Trait Can Delay Early-Onset Alzheimer’s: Study

Early-Onset Alzheimer's

Some individuals have a genetic tendency to develop Alzheimer’s before they reach the age of 65. Researchers at Mass General Brigham have identified a genetic variation that may protect those whose other gene variant predisposes them to early-onset Alzheimer’s. This discovery could lead to new treatment targets for early-onset disease.

Although Alzheimer’s typically occurs after 65, it can manifest as early as the 30s. Early-onset Alzheimer’s is the term used to describe Alzheimer’s disease that develops before the age of 65.

According to researchers, genetic factors, including three rare gene variants: amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), are responsible for most of the early-onset Alzheimer’s cases [1].

Recently, Mass General Brigham researchers found a genetic variation that appears to help shield individuals genetically prone to early-onset Alzheimer’s, which may lead to the discovery of novel treatment targets. The New England Journal of Medicine published the findings [2].

Two Specific Genetic Variations

Researchers investigated two specific genetic mutations in this study.

The first is the Paisa mutation (Presenilin-1 E280A), which occurs in an extensive Colombian family. According to earlier studies, those who carry this mutation have a higher chance of getting Alzheimer’s disease, with symptoms potentially appearing as early as their 40s [3].

The second genetic variant the team investigated was the APOE3 gene, known as Christchurch (APOE3Ch) [4]. The APOE gene carries the instructions required to produce the apolipoprotein E protein. Various APOE gene variants influence the onset of Alzheimer’s.

Researchers from Mass General Brigham presented a study in 2019 that included a person who had two copies of the Christchurch variant and a very high genetic risk for Alzheimer’s but who did not experience cognitive impairment until she was in her late 70s [5].

The Christchurch mutation may help protect the brain from clumps created by high levels of tau protein, which are thought to be a characteristic of the disease, according to a different study published in January 2024 [6].

The Findings: One Copy of the Gene Variant Delays Early-Onset Alzheimer’s.

Researchers examined genetic data from 1,077 members of the Paisa-mutant Colombian family. They found that 27 family members had one copy of the Christchurch variant and one copy of the Paisa mutation. On average, these family members did not display evidence of cognitive impairment before age 52, whereas those who did not inherit the Christchurch variant developed symptoms at age 47.

Researchers also found that family members with at least one copy of the Christchurch variant developed dementia four years later than those who did not inherit the variant.

The findings were encouraging for the researchers since they indicate the possibility of postponing cognitive decline and dementia in older people.

Yakeel T. Quiroz, PhD, a clinical neuropsychologist and neuroimaging researcher at Massachusetts General Hospital and the study’s first co-author, stated they must use this new knowledge to build effective dementia prevention treatments. He was excited about the results as a neuroscientist because they highlight the intricate connection between APOE and a deterministic mutation that causes Alzheimer’s disease, possibly opening the door for novel therapeutic strategies that target APOE-related pathways [7].

What’s Next?

As a next step, the researchers are concentrating on deepening their knowledge of brain resilience in the surviving family members who have one copy of the Christchurch variant. It includes performing structural and functional MRI scans, cognitive evaluations, and analyzing blood samples to determine protein and biomarker profiles.

Quiroz added that the continuous commitment to research demonstrated by their Colombian patients with autosomal dominant Alzheimer’s and their families was critical in enabling this study and allowing them to continue working toward treatments for this devastating disease.

Alzheimer’s Research Association is a non-profit organization dedicated to helping caregivers of Alzheimer’s disease and dementia. We provide the latest information and news about the illness and helpful tips to help caregivers cope with their daily caregiving challenges. We realize the most important thing that a caregiver needs is financial assistance. Therefore, we provide grants to caregivers to ease their financial burden. Caregivers can apply for grants here: Alzheimer’s Grant Application.

You can also help caregivers in their endeavor by donating as much as possible: Donation To Alzheimer’s Research Associations.

References

  1. Dai, M.H., Zheng, H., Zeng, L.D. and Zhang, Y., 2018. The genes associated with early-onset Alzheimer’s disease. Oncotarget, 9(19), p.15132.
  2. Quiroz, Y.T., Aguillon, D., Aguirre-Acevedo, D.C., Vasquez, D., Zuluaga, Y., Baena, A.Y., Madrigal, L., Hincapié, L., Sanchez, J.S., Langella, S. and Posada-Duque, R., 2024. APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease. New England Journal of Medicine, 390(23), pp.2156-2164.
  3. Fuller, J.T., Cronin-Golomb, A., Gatchel, J.R., Norton, D.J., Guzmán-Vélez, E., Jacobs, H.I., Hanseeuw, B., Pardilla-Delgado, E., Artola, A., Baena, A. and Bocanegra, Y., 2019. Biological and cognitive markers of presenilin1 E280A autosomal dominant Alzheimer’s disease: A comprehensive review of the Colombian kindred. The journal of prevention of Alzheimer’s disease, 6, pp.112-120.
  4. Xiao, B., Kuruvilla, J. and Tan, E.K., 2024. Resilience conferred by APOE-R136S: a defense bestowed by nature to combat Alzheimer’s disease. Signal Transduction and Targeted Therapy, 9(1), p.52.
  5. Arboleda-Velasquez, J.F., Lopera, F., O’Hare, M., Delgado-Tirado, S., Marino, C., Chmielewska, N., Saez-Torres, K.L., Amarnani, D., Schultz, A.P., Sperling, R.A. and Leyton-Cifuentes, D., 2019. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nature medicine, 25(11), pp.1680-1683.
  6. Chen, Y., Song, S., Parhizkar, S., Lord, J., Zhu, Y., Strickland, M.R., Wang, C., Park, J., Tabor, G.T., Jiang, H. and Li, K., 2024. APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell, 187(2), pp.428-445.
  7. A genetic trait may help delay early onset Alzheimer’s. Medical News Today. https://www.medicalnewstoday.com/articles/could-a-genetic-trait-delay-alzheimers. Published Online: 25th June. 2024. Accessed: 12th July, 2024.
  8. Alltucker, K. Could a genetic trait delay Alzheimer’s?. USA Today. https://www.usatoday.com/story/news/health/2024/06/19/alzheimers-gene-discovery-delays-disease-study/74125939007/. Published Online: 20th June, 2024. Accessed: 12th July, 2024.

Maternal or Paternal Alzheimer’s History: Which is More Important?

Maternal or Paternal Alzheimer’s

Scientists agree that genetics plays a significant role in the development of Alzheimer’s. Recently, researchers at Mass General Brigham have found that whether a person inherits Alzheimer’s risk from their mother or father affects the likelihood of biological changes in the brain that cause the condition.

Although experts may not know the specific etiology of Alzheimer’s disease, they do know that a variety of factors, including genetics, have a role.

According to earlier research, having genes from both parents may raise an individual’s chance of Alzheimer’s. According to a March 2024 study, there are 17 genetic variations linked to Alzheimer’s disease, with the APOE4 gene being one of the major genetic risk factors for the illness [1].

Previous research indicates that approximately 25% of all Alzheimer’s cases are familial, implying that someone in the family experienced the disorder [2].

Recently, researchers at Mass General Brigham have revealed that a person’s inherited Alzheimer’s genetic risk may also be determined by whether it comes from their biological mother or father. The journal JAMA Neurology published this research [3].

Researchers Focused on Toxic Protein Accumulation in Brain

Researchers examined data from over 4,400 individuals aged 65 to 85 from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study, which aimed at Alzheimer’s prevention [4].

Researchers inquired the participants if and when their biological parents experienced memory loss symptoms, as well as if they were formally diagnosed with Alzheimer’s. Participants also underwent PET scans to gauge the levels of a protein called beta-amyloid in their brains.

Hyun-Sik Yang, MD, an associate neurologist at Brigham and Women’s Hospital, assistant professor of neurology at Harvard Medical School, and corresponding author of this study, stated that amyloid-beta buildup, which happens at a preclinical (pre-symptomatic) stage, is believed to be the initial step of Alzheimer’s disease. All research participants exhibited normal cognitive function, but some showed considerable amyloid accumulation.

He added that the preclinical stage of Alzheimer’s provides a rare opportunity for preventive measures before it is too late. Therefore, they concentrated on amyloid-beta instead of other subsequent processes or symptoms [5].

Maternal or Paternal History of Alzheimer’s May Increase the Risk?

The research team concluded that brain beta-amyloid levels were higher in those whose mothers had a history of memory problems at any age and whose fathers had a history of early-onset memory impairment before the age of 65. Paternal history of late-onset dementia was not associated with an increased risk.

According to Yang, their research revealed that maternal and paternal history of memory loss or dementia may have different impacts on the offspring’s risk of Alzheimer’s. Furthermore, the study emphasized the need to collect family history for both parents and their onset age.

According to Yang, researchers anticipate that genes from both the mother and the father will have an equal impact on the offspring in most complex medical illnesses. However, in this instance, they found a notable asymmetry that raises the possibility that a mother’s genetic makeup may have a higher influence on the likelihood of developing Alzheimer’s disease.

The researchers conjectured that mitochondrial inheritance might be involved in Alzheimer’s since previous research has shown this pattern of maternal inheritance in mitochondrial disorders [6].

Previous research has already linked mitochondrial dysfunction to dementia symptoms [7], so this could shed more light on the relationship. Mitochondria are known as the powerhouses of the cells.

Other reasons include genomic imprinting, which is the chemical change of DNA on the mother’s or father’s side and may affect the offspring’s risk of developing Alzheimer’s disease.

Limitations of the Study

However, the disparity in life expectancies between men and women might have impacted the study’s findings. Yang observed that one of the study’s limitations is that some participants’ parents died while they were young before they might exhibit indications of cognitive impairment.

According to him, the fathers of the study participants aged 65 years or older may not have lived long enough to develop dementia, which may have influenced their results.

Furthermore, social factors like education and financial availability might have also affected whether or not someone was officially diagnosed with cognitive impairment and when they acknowledged it.

It is also worth noting that most participants were non-Hispanic whites. The effect might not be the same in other races and ethnicities.

What’s Next?

The researchers aim to expand the study to include other groups and investigate how parental history influences cognitive decline and amyloid accumulation over time, as well as why maternal DNA plays a role.

Co-author Reisa Sperling, MD, principal investigator of the A4 Study and Mass General Brigham neurologist, stated that the results could be soon employed in clinical translation.

Alzheimer’s Research Association is a non-profit organization dedicated to helping caregivers of Alzheimer’s disease and dementia. We provide the latest information and news about the illness and helpful tips to help caregivers cope with their daily caregiving challenges. We realize the most important thing that a caregiver needs is financial assistance. Therefore, we provide grants to caregivers to ease their financial burden. Caregivers can apply for grants here: Alzheimer’s Grant Application.

You can also help caregivers in their endeavor by donating as much as possible: Donation To Alzheimer’s Research Associations.

References

  1. Fortea, J., Pegueroles, J., Alcolea, D., Belbin, O., Dols-Icardo, O., Vaqué-Alcázar, L., Videla, L., Gispert, J.D., Suárez-Calvet, M., Johnson, S.C. and Sperling, R., 2024. APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease. Nature medicine, pp.1-8.
  2. Bird, T.D., 2018. Alzheimer disease overview. GeneReviews®[Internet].
  3. Seto, M., Hohman, T.J., Mormino, E.C., Papp, K.V., Amariglio, R.E., Rentz, D.M., Johnson, K.A., Schultz, A.P., Sperling, R.A., Buckley, R.F. and Yang, H.S., 2024. Parental History of Memory Impairment and β-Amyloid in Cognitively Unimpaired Older Adults. JAMA neurology.
  4. Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Open-Label Extension Study. International Alzheimer’s and Related Dementias Research Portfolio (IADRP). https://iadrp.nia.nih.gov/project/anti-amyloid-treatment-asymptomatic-alzheimers-disease-a4-open-label-extension-study-2. Funding Year: 2022. Accessed: 11th July, 2024.
  5. Maternal history of Alzheimer’s may be the most important to genetic risk. Medical News Today. https://www.medicalnewstoday.com/articles/maternal-alzheimers-may-be-most-important-genetic-risk. Published Online: 21st June. 2024. Accessed: 11th July, 2024.
  6. Chinnery, P.F., 2021. Primary mitochondrial disorders overview. GeneReviews®[Internet].
  7. Briston, T. and Hicks, A.R., 2018. Mitochondrial dysfunction and neurodegenerative proteinopathies: mechanisms and prospects for therapeutic intervention. Biochemical Society Transactions, 46(4), pp.829-842.
  8. Maternal inheritance of Alzheimer’s disease tied to increased risk of developing disease. Science Daily. https://www.sciencedaily.com/releases/2024/06/240617173717.htm. Published Online: 17th June, 2024. Accessed: 11th July, 2024.

Alzheimer’s Study: Sleep Apnea During REM Stage Linked to Memory Decline

Sleep Apnea During REM Stage

Researchers from the University of California, Irvine, discovered that sleep apnea severity during the REM stage of sleep negatively impacts verbal memory. According to the researchers, the adverse effect is particularly severe among older persons at risk for Alzheimer’s.

Obstructive sleep apnea (OSA) is a disorder in which an individual has breathing pauses or interruptions during sleep. Researchers estimate that approximately 936 million people worldwide suffer from this condition [1].

Previous research has connected OSA to an increased risk for various neurological disorders, including cognitive decline, dementia [2], Parkinson’s disease [3], and Alzheimer’s disease [4].

Researchers at the University of California have now discovered that verbal memory is adversely affected by the severity of sleep apnea during the rapid eye movement (REM) stage of sleep, particularly in older persons who are at a higher risk of developing Alzheimer’s. The journal Alzheimer’s Research & Therapy recently published this research [5].

What is Verbal Memory?

Verbal memory was the primary focus of this study. According to Bryce A. Mander, PhD, associate professor in the Department of Psychiatry and Human Behavior at the University of California and co-corresponding author of this study, verbal memory refers to the capability to remember words in the appropriate context.

Examples of verbal memory include remembering someone’s name, the names of streets at an intersection connected to a memory, and how words are paired together.

He further stated that verbal memory is very vulnerable to Alzheimer’s and is one of the initial types of memory to be affected by the condition’s biomarkers. Its susceptibility to deterioration with age and Alzheimer’s led researchers to study this type of memory.

Effect of sleep apnea during REM sleep on verbal memory

The recent study included 81 individuals with an average age of roughly 62, and 70% of them had a parental history of Alzheimer’s. The group had 62% female participants. Every study participant underwent verbal memory tests and polysomnography, a diagnostic procedure for sleep disorders.

At the end of the study, researchers discovered that REM sleep apnea episodes have a detrimental effect on a person’s verbal memory, particularly in those participants who have a family history of Alzheimer’s or a genetic susceptibility to the condition.

The researchers initially hypothesized that events in non-rapid eye movement (NREM) sleep would be more predictive since some specific brain waves occur only during NREM sleep support memory.

However, they believe these REM findings make sense because REM sleep may aid memory and has a higher metabolic requirement than NREM sleep, and in some memory-related brain areas, even higher than when awake.

Mander noted that if you deprive your brain of oxygen during high metabolic demand, you may be more prone to sustaining brain damage. The team is looking into this possibility for their upcoming studies.

Possibility of sleep apnea-related Alzheimer’s treatment

These findings highlight the potential impact of sleep apnea occurrences during REM sleep. They are frequently rejected clinically in favor of global sleep apnea metrics, which have historically been poor at predicting cognitive and health effects.

These findings support the notion that studying the brain state in which sleep apnea occurs will provide a better understanding of the cognitive implications of sleep apnea.

Additionally, the researchers believe that this may emphasize how crucial it is to concentrate on how sleep apnea severity is measured when examining the health and neurodegenerative impacts of Alzheimer’s, as well as how sleep apnea treatment may be tailored to reduce the cognitive effects of the disease.

Mander further stated that although OSA is a known risk factor for Alzheimer’s, it is unclear which features of the condition are significant for the cognitive impairment linked to the illness’s risk. Finding these particular connections is essential to comprehend the reasons why sleep apnea is associated with a higher risk of dementia and to develop treatment plans that specifically address the processes underlying this correlation.

Mander said that their research demonstrated the complex connection between memory loss, sleep apnea, and the risk of Alzheimer’s disease. Identifying and responding to REM-specific events is critical for establishing proactive, tailored approaches to assessment and therapy based on individual sleep patterns.

References

  1. Sleep Apnea Statistics and Facts You Should Know. National Council on Aging. https://www.ncoa.org/adviser/sleep/sleep-apnea-statistics/. Published Online: 8th May, 2024. Accessed: 1st July, 2024.
  2. Guay‐Gagnon, M., Vat, S., Forget, M.F., Tremblay‐Gravel, M., Ducharme, S., Nguyen, Q.D. and Desmarais, P., 2022. Sleep apnea and the risk of dementia: A systematic review and meta‐analysis. Journal of sleep research, 31(5), p.e13589.
  3. Yu, Q., Hu, X., Zheng, T., Liu, L., Kuang, G., Liu, H., Wang, X., Li, J., Huang, J., Wang, T. and Lin, Z., 2023. Obstructive sleep apnea in Parkinson’s disease: A prevalent, clinically relevant and treatable feature. Parkinsonism & Related Disorders, p.105790.
  4. Tsai, M.S., Li, H.Y., Huang, C.G., Wang, R.Y., Chuang, L.P., Chen, N.H., Liu, C.H., Yang, Y.H., Liu, C.Y., Hsu, C.M. and Cheng, W.N., 2020. Risk of Alzheimer’s disease in obstructive sleep apnea patients with or without treatment: real‐world evidence. The Laryngoscope, 130(9), pp.2292-2298.
  5. Lui, K.K., Dave, A., Sprecher, K.E., Chappel-Farley, M.G., Riedner, B.A., Heston, M.B., Taylor, C.E., Carlsson, C.M., Okonkwo, O.C., Asthana, S. and Johnson, S.C., 2024. Older adults at greater risk for Alzheimer’s disease show stronger associations between sleep apnea severity in REM sleep and verbal memory. Alzheimer’s Research & Therapy, 16(1), p.102.
  6. Obstructive sleep apnea during REM stage linked to memory decline. Medical News Today. https://www.medicalnewstoday.com/articles/sleep-apnea-severity-rem-sleep-memory-decline. Published Online: 21st May, 2024. Accessed: 1st July, 2024.
  7. Study links sleep apnea severity during REM stage to verbal memory decline. ScienceDaily. https://www.sciencedaily.com/releases/2024/05/240514183457.htm. Published Online: 14th May, 2024. Accessed: 1st July, 2024.