Summary: A new study finds that inheriting Alzheimer’s risk from your mother, regardless of her age at onset, is linked to increased amyloid levels in the brain. This protein is a hallmark of Alzheimer’s disease.
The findings suggest maternal history of memory impairment, even without a formal diagnosis, could be a crucial factor in identifying individuals at risk of Alzheimer’s.
Key Facts:
- Maternal history of memory impairment, regardless of age at onset, is associated with higher amyloid levels in the brain.
- Paternal history of early-onset memory impairment is also linked to higher amyloid levels.
- The study involved over 4,400 cognitively unimpaired adults aged 65-85.
Source: Mass General
A new study by investigators from Mass General Brigham suggests that whether a person inherits risk of Alzheimer’s disease from their mother or father influences risk of biological changes in the brain that lead to disease.
By evaluating 4,400 cognitively unimpaired adults ages 65-85, the team found those with a history of Alzheimer’s disease (AD) on either their mother’s side or both parents’ sides had increased amyloid in their brains.
Their results are published in JAMA Neurology.
“Our study found if participants had a family history on their mother’s side, a higher amyloid level was observed,” said senior corresponding author Hyun-Sik Yang, MD, a neurologist at Mass General Brigham and behavioral neurologist in the Division of Cognitive and Behavioral Neurology at Brigham and Women’s Hospital. He is also a physician investigator of Neurology for the Mass General Research Institute.
Yang collaborated with other researchers from Mass General Brigham, as well as investigators from Vanderbilt and Stanford University. He said previous smaller studies have investigated the role family history plays in Alzheimer’s disease.
Some of those studies suggested maternal history represented a higher risk of developing Alzheimer’s, but the group wanted to revisit the question with cognitively normal participants and access to a larger clinical trial data set.
The team examined the family history of older adults from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study, a randomized clinical trial aimed at AD prevention. Participants were asked about memory loss symptom onset of their parents. Researchers also asked if their parents were ever formally diagnosed or if there was autopsy confirmation of Alzheimer’s disease.
“Some people decide not to pursue a formal diagnosis and attribute memory loss to age, so we focused on a memory loss and dementia phenotype,” Yang said.
Researchers then compared those answers and measured amyloid in participants. They found maternal history of memory impairment at all ages and paternal history of early-onset memory impairment was associated with higher amyloid levels in the asymptomatic study participants.
Researchers observed that having only a paternal history of late-onset memory impairment was not associated with higher amyloid levels.
“If your father had early onset symptoms, that is associated with elevated levels in the offspring,” said Mabel Seto, PhD, first author and a postdoctoral research fellow in the Department of Neurology at the Brigham.
“However, it doesn’t matter when your mother started developing symptoms — if she did at all, it’s associated with elevated amyloid.”
Seto works on other projects related to sex differences in neurology. She said the results of the study are fascinating because Alzheimer’s tends to be more prevalent in women. “It’s really interesting from a genetic perspective to see one sex contributing something the other sex isn’t,” Seto said. She also noted the findings were not affected by whether study participants were biologically male or female.
Yang noted one limitation of the study is some participants’ parents died young, before they could potentially develop symptoms of cognitive impairment. He said social factors like access to resources and education may have also played a role in when someone acknowledged cognitive impairment and if they were ever formally diagnosed.
“It’s also important to note a majority of these participants are non-Hispanic white,” Seto added. “We might not see the same effect in other races and ethnicities.”
Seto said the next steps are to expand the study to look at other groups and examine how parental history affects cognitive decline and amyloid accumulation over time and why DNA from the mother plays a role.
Reisa Sperling, MD, a co-author on the paper, principal investigator of the A4 Study and a neurologist at Mass General Brigham, said the findings could be used soon in clinical translation.
“This work indicates that maternal inheritance of Alzheimer’s disease may be an important factor in identifying asymptomatic individuals for ongoing and future prevention trials,” Sperling said.
Authorship: In addition to Seto, Yang and Sperling, Mass General Brigham authors include Kathryn V. Papp, Rebecca E. Amariglio, Dorene M. Rentz, Keith A. Johnson, Aaron P. Schultz, and Rachel F. Buckley. Additional authors include Timothy J. Hohman and Elizabeth C. Mormino.
Disclosures: Yang has received personal fees from Genentech, Inc., outside the submitted work. Hohman serves on the Scientific Advisory Board for Vivid Genomics, outside the submitted work. Eli Lilly and Co. funded the A4 Study but had no direct influence in the submitted work.
Funding: This work was funded by the United States National Institutes of Health (K23AG062750, R01AG063689 U19AG010483, and DP2AG082342). The A4 Study is funded by NIH grants, Eli Lilly and Co, and several philanthropic organizations.
About this Alzheimer’s disease and genetics research news
Author: Alex Pantano
Source: Mass General
Contact: Alex Pantano – Mass General
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Parental history of memory impairment is associated with β-amyloid in cognitively unimpaired elderly” by Hyun-Sik Yang et al. JAMA Neurology
Abstract
Parental history of memory impairment is associated with β-amyloid in cognitively unimpaired elderly
Importance
Studies have suggested that maternal history of late-onset Alzheimer disease, but not paternal, predisposes individuals to higher brain β-amyloid (Aβ) burden, reduced brain metabolism, and lower gray matter volumes.
Objective
To characterize maternal vs paternal history of memory impairment in terms of brain Aβ-positron emission tomography (Aβ-PET) and baseline cognition among a large sample of cognitively unimpaired older adults.
Design, Setting, and Participants
This cross-sectional study leveraged data from 4413 individuals who were screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, a randomized clinical trial conducted across 67 sites in the US, Australia, Canada, and Japan aimed at Alzheimer disease prevention. Data were collected between April 2014 and December 2017 and analyzed from December 2022 to June 2023. Participants were cognitively unimpaired adults (Clinical Dementia Rating = 0 and/or Mini-Mental State Examination score ≥25) between the ages of 65 and 85 years who underwent PET imaging to assess cortical Aβ levels for trial eligibility. A total of 4492 participants were screened, and 79 missing data were excluded.
Main Outcomes and Measures
Demographic characteristics (eg, age, sex, education), apolipoprotein E genotyping, participant-reported parental history of memory impairment and parental age at symptom onset were collected as variables. Parental history was assessed in terms of continuous neocortical 18F-florbetapir Aβ-PET and the Preclinical Alzheimer Cognitive Composite.
Results
Of 4413 individuals (mean [SD] age, 71.27 [4.66] years, 2617 women [59.3%]), mean Aβ-PET was elevated in individuals with history of memory impairment in both parents (n = 455; mean [SD] standardized uptake value ratio [SUVR] = 1.12 [0.19]; Wilcoxon P = 1.1 × 10−5) and in those with only maternal history (n = 1772; mean [SD] SUVR = 1.10 [0.19]; Wilcoxon P = 2.70 × 10−5) compared with those with only paternal history (n = 632; mean [SD] SUVR = 1.08 [0.18]; Wilcoxon P = 1.1 × 10−5) or no family history (n = 1554; mean [SD] SUVR = 1.08 [0.19]; Wilcoxon P = 1.1 × 10−5).
Paternal history of early-onset memory impairment (age <65 years) but not late-onset (age ≥65 years) was associated with elevated participant Aβ-PET (mean [SD] SUVR = 1.19 [0.21]; P = 3.00 × 10−6) in comparison with no paternal history (mean [SD] SUVR = 1.09 [0.19]) whereas maternal history was associated with elevated Aβ in both early-onset and late-onset groups. There was no association with cognition.
Conclusions and Relevance
In this study, maternal history (at any age) and paternal history of early-onset memory impairment were associated with Aβ burden among asymptomatic older individuals. Sex-specific parental history may help inform clinicians on likelihood of Aβ burden in offspring and help identify high-risk individuals at the earliest stages of disease for prevention.
