Genetic risk score for Alzheimer's disease predicts brain volume differences in mid and late life in UK biobank participants.

Introduction: We estimated the ages when associations between Alzheimer's disease (AD) genes and brain volumes begin among middle-aged and older adults.

Methods: Among 45,616 dementia-free participants aged 45-80, linear regressions tested whether genetic risk score for AD (AD-GRS) had age-dependent associations with 38 regional brain magnetic resonance imaging volumes. Models were adjusted for sex, assessment center, genetic ancestry, and intracranial volume.

Results: AD-GRS modified the estimated effect of age (per decade) on the amygdala (-0.41 mm [-0.42, -0.40]); hippocampus (-0.45 mm [-0.45, -0.44]), nucleus accumbens (-0.55 mm [-0.56, -0.54]), thalamus (-0.38 mm [-0.39, -0.37]), and medial orbitofrontal cortex (-0.23 mm [-0.24, -0.22]). Trends began by age 45 for the nucleus accumbens and thalamus, 48 for the hippocampus, 51 for the amygdala, and 53 for the medial orbitofrontal cortex. An AD-GRS excluding apolipoprotein E (APOE) was additionally associated with entorhinal and middle temporal cortices.

Discussion: APOE and other genes that increase AD risk predict lower hippocampal and other brain volumes by middle age.