Date Published: September 12, 2017
Publisher: BioMed Central
Author(s): Jessica Z. K. Caldwell, Jody-Lynn Berg, Jeffrey L. Cummings, Sarah J. Banks.
Alzheimer’s disease (AD) impacts men and women differently, but the effect of sex on predementia stages is unclear. The objective of this study was to examine whether sex moderates the impact of florbetapir positron emission tomography (PET) amyloid positivity (A+) on verbal learning and memory performance and hippocampal volume (HV) in normal cognition (NC) and early mild cognitive impairment (eMCI).
Seven hundred forty-two participants with NC and participants with eMCI from the Alzheimer’s Disease Neuroimaging Initiative (second cohort [ADNI2] and Grand Opportunity Cohort [ADNI-GO]) were included. All had baseline florbetapir PET measured, and 526 had screening visit HV measured. Regression moderation models were used to examine whether A+ effects on Rey Auditory Verbal Learning Test learning and delayed recall and right and left HV (adjusted for total intracranial volume) were moderated by diagnosis and sex. Age, cognition at screening, education, and apolipoprotein E ε4 carrier status were controlled.
Women with A+, but not those with florbetapir PET amyloid negative (A-),eMCI showed poorer learning. For women with NC, there was no relationship of A+ with learning. In contrast, A+ men trended toward poorer learning regardless of diagnosis. A similar trend was found for verbal delayed recall: Women with A+, but not A-, eMCI trended toward reduced delayed recall; no effects were observed for women with NC or for men. Hippocampal analyses indicated that women with A+, but not those with A−, eMCI, trended toward smaller right HV; no significant A+ effects were observed for women with NC. Men showed similar, though nonsignificant, patterns of smaller right HV in A+ eMCI, but not in men with A− eMCI or NC. No interactive effects of sex were noted for left HV.
Women with NC showed verbal learning and memory scores robust to A+, and women with A+ eMCI lost this advantage. In contrast, A+ impacted men’s scores less significantly or not at all, and comparably across those with NC and eMCI. Sex marginally moderated the relationship of A+ and diagnosis with right HV, such that women with NC showed no A+ effect and women with A+ eMCI lost that advantage in neural integrity; the pattern in men was less clear. These findings show that women with A+ eMCI (i.e., prodromal AD) have differential neural and cognitive decline, which has implications for considering sex in early detection of AD and development of therapeutics.
Florbetapir positron emission tomography (PET) amyloid positivity (A+) is a biomarker for fibrillar amyloid associated with a high likelihood of progression to Alzheimer’s disease (AD) dementia . β-Amyloid (Aβ) accumulation has been linked to brain atrophy [1–3] and cognitive decline in AD [1–7]. However, findings have been mixed regarding whether and how A+ relates to cognitive dysfunction or hippocampal volume (HV) across the spectrum of normal cognition (NC), early mild cognitive impairment (eMCI), and AD [4, 8–13].
In the present study, we examined the moderating effects of sex on the impact of diagnosis and A+ on verbal learning and memory and HV. The main finding was that sex moderated the effects of A+ and diagnosis on verbal learning. In addition, we showed that sex marginally moderated the effects of A+ and diagnosis on verbal delayed recall and that sex marginally moderated the effects of A+ and diagnosis on right HV. In contrast, no sex moderation effects were observed for left HV.
The present study shows that sex moderates the relationship of A+ and diagnosis with verbal learning performance and marginally moderates the effect of A+ and diagnosis on verbal delayed recall and right hemisphere HV. Whereas women with NC show learning and memory scores that are robust to A+ effects, women with prodromal AD lose this advantage; in contrast, A+ impacts men’s learning and memory scores in a less significant way or not at all and comparably across NC and eMCI. For right HV, the marginal sex moderation effect showed that women with NC had no effect of A+ on HV. Women with prodromal AD, but not those with SNAP, lost that advantage in right HV neural integrity; effects among men remain unclear. Further study of sex effects in prodromal AD and AD dementia has the potential to lead to clinical developments that increase diagnostic accuracy at early stages, as well as to increase the accuracy of treatment group formation and outcome assessment when developing novel therapeutics.