Medscape Medical News
Megan Brooks
June 27, 2024
Alzheimer’s disease (AD) is highly heritable, and previous research suggests a preferential maternal inheritance of AD. New data confirm this hypothesis but also highlight the importance of considering family history in both parents.
In a large cohort of cognitively normal older adults, a family history of memory impairment in the mother at any age and in the father before age 65 (early-onset) was associated with increased brain amyloid beta (Aβ), an AD biomarker.
This “intriguing finding suggests maternal and paternal family history of dementia/memory loss might carry different weights, but we do not fully understand the reason,” study investigator Hyun-Sik Yang, MD, assistant professor of neurology at Harvard Medical School and associate neurologist at Brigham and Women’s Hospital, Boston, told Medscape Medical News.
The findings, said Yang, “highlight the importance of obtaining family history for both parents, as well as asking the parental age at onset if patients report a family history of dementia. The details of the family history might matter.”
“The paternal history of late-onset dementia should not be discounted entirely, though, especially if it was autopsy confirmed,” Yang added.
The study was published online on June 17 in JAMA Neurology.
Prevention, Treatment Implications?
Previous research has shown that a family history of AD, particularly in the mother, can increase the risk of developing the disease twofold to 15-fold, depending on the number of affected relatives.
Yet, prior studies investigating family history and AD biomarkers had a limited sample size and lacked statistical power to fully determine the extent to which maternal vs paternal history affects AD pathology in the preclinical stage.
To investigate further, Yang and colleagues analyzed cross-sectional data from 4413 cognitively normal older adults (mean age, 71 years; 59% women) screened with PET to assess their cortical Aβ burden as part of the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study.
They observed elevated mean Aβ levels in individuals with a history of memory impairment in both parents (mean standardized uptake value ratio [SUVR], 1.12) and in those with only a maternal history (mean SUVR, 1.10) compared with those with only a paternal history or no family history (mean SUVR, 1.08 for both) of memory loss.
Paternal history of early-onset — but not late-onset — memory impairment was also associated with elevated Aβ-PET (mean SUVR, 1.19) compared with no paternal history of memory loss (mean SUVR, 1.09).
Maternal history of memory loss was associated with elevated Aβ in both early-onset and late-onset groups. This suggests “preferential maternal inheritance of AD starting from the preclinical stage, a finding which has broad clinical and scientific implications,” the investigators noted.
Understanding Mechanisms
In an accompanying editorial, Dena Dubal, MD, PhD, of the University of California, San Francisco, and Holly Elser, MD, PhD, of the University of Pennsylvania, Philadelphia, noted that “maternal transmission of AD may be rooted in biological origins related to passing on the maternal X chromosome, mitochondria, and specific genomic imprinting (or silencing of genes) to offspring.”
“Deeply understanding the maternal transmission of Alzheimer’s disease risk matters as it may unravel mechanisms at the intersection of female-specific biology, risk, and resilience in health and disease,” they wrote.
“Unraveling and then targeting female-specific biology might help both men and women decrease AD risk or even treat the disease,” Dubal and Elser concluded.
The study was funded by the National Institutes of Health (NIH). The A4 Study is funded by NIH grants, Eli Lilly and Company, and several philanthropic organizations. Yang has received personal fees from Genentech, Inc. Dubal has consulted for Unity Biotechnology and S.V. Health and holds a patent for Methods for Improving Cognition.
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