Parental History of Memory Impairment and β-Amyloid in Cognitively Unimpaired Older Adults

Question  Is parental history of memory impairment associated with brain β-amyloid burden among cognitively unimpaired individuals?

Findings  In this cross-sectional study of 4413 individuals screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, individuals with a maternal history of memory impairment had elevated neocortical β-amyloid cross-sectionally compared with individuals with only paternal history or no parental history. Examining parental age at symptom onset, only paternal history of early-onset memory impairment (age <65 years) was associated with β-amyloid, whereas maternal onset at any age was associated with β-amyloid.

Meaning  In this study, maternal history of memory impairment at any age at onset was associated with β-amyloid burden among asymptomatic older individuals, whereas only paternal history of early-onset memory impairment was associated with offspring β-amyloid levels.

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.