Maternal history of Alzheimer’s may be the most important to genetic risk

ISLAMABAD, June 22 (Online): Researchers agree that genetics play a crucial role in the development of Alzheimer’s disease.
Previous research shows that about 25% of all Alzheimer’s disease cases are familial.
Researchers from Mass General Brigham say that a person’s inherited Alzheimer’s genetic risk may also be dependent upon whether they receive it from their biological mother or father.
Although researchers still do not know the exact cause of Alzheimer’s disease, they do know there are quite a few factors involved, including genetics.

Past studies suggest that inherited genes from both parents can increase a person’s risk of developing Alzheimer’s disease. One top genetic risk factor for Alzheimer’s is the APOE4 geneTrusted Source, and a study published in March 2024 identified 17 genetic variantsTrusted Source associated with this condition.

Previous research shows that about 25%Trusted Source of all Alzheimer’s disease cases are familial, meaning someone in the family had the condition.

Now, researchers from Mass General Brigham say that a person’s inherited Alzheimer’s genetic risk may also be dependent upon whether they receive it from their biological mother or father.

Toxic protein accumulation in the brain the focal point of the study
For this study, researchers analyzed data from about 4,400 participants between the ages of 65 and 85 of the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4)Trusted Source study aimed at Alzheimer’s disease prevention.

Participants were asked if their biological parents had memory loss symptoms and when, as well as if they had received any formal diagnoses of Alzheimer’s.

Study participants also received PET scans to measure the amounts of a protein called beta-amyloidTrusted Source in their brains.

“Amyloid-beta accumulation is thought to be the earliest disease process of Alzheimer’s disease that occurs at a preclinical (pre-symptomatic) stage,” Hyun-Sik Yang, MD, associate neurologist at Brigham and Women’s Hospital, assistant professor of neurology at Harvard Medical School, and corresponding author of this study told Medical News Today.

“Our study participants all had normal cognition, but some had substantial amyloid accumulation. The preclinical stage of Alzheimer’s disease represents a unique window for preventive intervention before it is too late. Thus, we focused on amyloid-beta rather than other later processes or symptoms,” he told us.

Maternal history of Alzheimer’s may have greater risk impact
At the study’s conclusion, Yang and his team found that participants with a maternal history of memory issues at all ages and a paternal history of early-onset memory impairment before the age of 65 were linked to higher beta-amyloid levels in the brain.

“Maternal history of any age at onset and paternal history of early onset dementia were associated with increased risk, while paternal history of late-onset dementia was not,” Yang told MNT. However, he added:

“Our study suggests that maternal and paternal history of dementia/memory loss might carry different weight in their impact on the offspring’s Alzheimer’s disease risk. Also, our study highlights the importance of collecting family history for both parents and their age at onset.”

“In the usual complex diseases in medicine, we expect genes from the father and the mother to have the same effect on the offspring,” he continued.

“However, in this case, we observed a striking asymmetry suggesting that genetic information from the mother might have a stronger impact on the risk of Alzheimer’s disease,“ said Yang.

“This maternal inheritance pattern has been observed in mitochondrial disordersTrusted Source, so we speculate whether mitochondrial inheritance may play a role in Alzheimer’s disease,“ the researcher continued.

Dysfunction of the mitochondria — the so-called cellular powerhouses — has previously been associated with symptoms of dementia, so this could provide further insight about this link.

“Other explanations include genomic imprinting — chemical modification of DNA on the mother’s or father’s side — that may impact the offspring’s risk of having Alzheimer’s disease,” Yang told us.

Different life expectancies for males versus females may have influenced the study results, though, according to the author: “[I]n our study participants — who are 65+ years old — parent generation, many fathers (males) might not have lived long enough to get dementia. This might have affected our result, too.”

‘Broad clinical implications’ in determining Alzheimer’s risk risk
After reviewing this study, Karen D. Sullivan, PhD, ABPP, a board-certified neuropsychologist, owner of I CARE FOR YOUR BRAIN, and Reid Healthcare Transformation Fellow at FirstHealth of the Carolinas in Pinehurst, NC, not involved in this research, told MNT this research is an important contribution to understanding the heritability of Alzheimer’s disease.

“Using an impressive sample size of 4,000, they showed that late-onset paternal history does not raise (the) risk for Alzheimer’s disease but early-stage paternal history and maternal history at any age were associated with elevated risk of amyloid plaque burden,” Sullivan said.

“These results show a preferential maternal inheritance of Alzheimer’s disease starting even before diagnosable memory loss. This finding has broad clinical implications for risk stratification and who we need to be targeting for early identification, pre-clinical studies with advanced neuroimaging,” she noted.

“We have known for some time that the cure for Alzheimer’s disease is going to be many years, if not decades before the clinical symptoms of memory loss, word-finding difficulty, and apathy begin,” Sullivan continued.

“These data point us in an evidence-based direction about who we should be looking the most closely at. Sex chromosomes are an exciting new specialty research in Alzheimer’s disease and we need to track this cohort longitudinally to see their clinical trajectory,” she further explained.

‘Need for more nuanced approaches in Alzheimer’s prevention’
MNT also spoke with Jasdeep S. Hundal, PsyD, ABPP-CN, associate professor of psychiatry and neurology at the Hackensack Meridian Health School of Medicine and director of The Center for Memory & Healthy Aging at Hackensack Meridian Jersey Shore University Medical Center in New Jersey, about this study. Hundal was also not involved in this research.

He commented that this study underscores the intricate role genetics can play in Alzheimer’s disease, particularly highlighting how maternal inheritance significantly impacts amyloid accumulation, a key biomarkerTrusted Source for Alzheimer’s disease.

“This is intriguing because it reinforces the importance of family history in assessing Alzheimer’s risk, but also points to the need for more nuanced approaches in prevention and early detection strategies. The fact that maternal history has a different impact compared to paternal history could lead to more personalized and effective interventions. Additionally, the study’s emphasis on expanding research to include more diverse populations is crucial for a comprehensive understanding of the disease.”

– Jsdeep S. Hundal, PsyD, ABPP-CN

Hundal said there are several reasons why researchers need to continue to investigate how genetics and family history impact a person’s risk of developing Alzheimer’s disease, including identifying higher-risk individuals earlier in life, creating personalized care plans, and discovering new drugs and other therapeutic interventions

“Continued research into the genetic and familial aspects of Alzheimer’s disease is vital for advancing early detection, personalized treatment, and prevention strategies, ultimately improving patient outcomes and reducing the societal burden of the disease,” he added.