Mothers aren't the only ones at risk for inherited Alzheimer's disease

Alzheimer's disease AD is highly heritable, and previous studies have suggested that AD is preferentially inherited maternally. New data support this hypothesis but also highlight the importance of considering both parents' family histories.

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), a biomarker for AD.

This “intriguing finding suggests that maternal and paternal family histories of dementia/memory loss may have different effects, although the reasons for this are not fully understood,” said Dr. Yang Hyun-sik, an assistant professor of neurology at Harvard Medical School and an associate neurologist at Brigham and Women's Hospital in Boston. Medscape Medical News.

Yang said the findings “highlight the importance of determining the family history of parents and, if patients report a family history of dementia, asking about their parents' age of onset. Details of the family history may be important.”

“However, the father's history of having late-onset dementia should not be completely ignored, especially if it was confirmed by autopsy,” Yang added.

The study was published online June 17. JAMA Neurology.

What are the implications for prevention and treatment?

Previous studies have shown that a person's risk of developing the disease may increase by anywhere from two to fifteen times, depending on the number of affected relatives, especially if there is a maternal family history of AD.

However, previous studies investigating family history and AD biomarkers had limited sample sizes and lacked statistical power to fully determine the extent to which maternal and paternal medical history influences AD pathology at the preclinical stage.

To investigate further, Yang and his colleagues analyzed cross-sectional data from 4,413 cognitively normal older adults (mean age 71 years, 59% women) whose cortical Aβ burden was assessed by PET scans as part of the Anti-Amyloid Treatment for Asymptomatic Alzheimer's Disease (A4) Study.

Elevated mean Aβ levels were observed in individuals with a parental history of memory impairment (mean standardized intake ratio [SUVR]The risk of memory loss was higher in those with only a maternal history (mean SUVR, 1.12) and those with only a maternal history (mean SUVR, 1.10) compared with those with only a paternal history or no family history (mean SUVR, both 1.08).

Early-onset (but not late-onset) paternal history of memory impairment was also associated with elevated Aβ-PET (mean SUVR, 1.19) compared with no history of paternal memory impairment (mean SUVR, 1.09).

A history of maternal memory loss was associated with elevated Aβ in both early- and late-onset cohorts, “suggesting preferential maternal inheritance of AD from a preclinical stage onwards, a finding with broad clinical and scientific implications,” the researchers noted.

Understanding the mechanism

In an accompanying editorial, Dena Duvall, 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 Alzheimer's disease may have biological origins related to the transmission of maternal X chromosomes, mitochondria, and specific genomic imprinting (or gene silencing) to offspring.”

“A deeper understanding of mother-to-child transmission of Alzheimer's disease risk is important because it may elucidate mechanisms at the intersection of female-specific biology, risk, and health and disease resilience,” the researchers wrote.

“Understanding and targeting female-specific biology may help both men and women reduce their risk of Alzheimer's disease and even treat the disease,” Duvall and Elser concluded.

This work was funded by the National Institutes of Health (NIH). The A4 study is funded by grants from the NIH, Eli Lilly and Company, and several philanthropic foundations. Yang has received personal fees from Genentech.. Duval is He serves as a consultant to Unity Biotechnology and SV Health and holds a patent on methods for enhancing cognitive performance.