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.
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References
- 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.
- Bird, T.D., 2018. Alzheimer disease overview. GeneReviews®[Internet].
- 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.
- 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.
- 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.
- Chinnery, P.F., 2021. Primary mitochondrial disorders overview. GeneReviews®[Internet].
- 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.
- 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.
