Age, Sex, and APOE ε4 Effects on Memory, Brain Structure, and β-Amyloid Across the Adult Life Span

Abstract

Importance: Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals who remain free of dementia. Ideally, the full adult age spectrum should be included to assess brain imaging findings associated with typical aging.

Objective: To compare age, sex, and APOE ε4 effects on memory, brain structure (adjusted hippocampal volume [HVa]), and amyloid positron emission tomography (PET) in cognitively normal individuals aged 30 to 95 years old.

Design, setting, and participants: Cross-sectional observational study (March 2006 to October 2014) at an academic medical center. We studied 1246 cognitively normal individuals, including 1209 participants aged 50 to 95 years old enrolled in a population-based study of cognitive aging and 37 self-selected volunteers aged 30 to 49 years old.

Main outcomes and measures: Memory, HVa, and amyloid PET.

Results: Overall, memory worsened from age 30 years through the 90s. The HVa worsened gradually from age 30 years to the mid-60s and more steeply beyond that age. The median amyloid PET was low until age 70 years and increased thereafter. Memory was worse in men than in women overall (P < .001) and more specifically beyond age 40 years. The HVa was lower in men than in women overall (P < .001) and more specifically beyond age 60 years. There was no sex difference in amyloid PET at any age. Within each sex, memory performance and HVa were not different by APOE ε4 status at any age. From age 70 years onward, APOE ε4 carriers had significantly greater median amyloid PET than noncarriers. However, the ages at which 10% of the population were amyloid PET positive were 57 years for APOE ε4 carriers and 64 years for noncarriers.

Conclusions and relevance: Male sex is associated with worse memory and HVa among cognitively normal individuals, while APOE ε4 is not. In contrast, APOE ε4 is associated with greater amyloid PET (from age 70 years onward), while sex is not. Worsening memory and HVa occur at earlier ages than abnormal amyloid PET. Therefore, neuropathological processes other than β-amyloidosis must underlie declines in brain structure and memory function in middle age. Our findings are consistent with a model of late-onset Alzheimer disease in which β-amyloidosis arises in later life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits.

Figure 1

Memory, Adjusted Hippocampal Volume (HVa), and Amyloid Positron Emisison Tomography (PET) in Modality-Specific Units by Age, With Participants Categorized Into 4 Groups by Sex and APOE ε4 Genotype (Carriers vs Noncarriers). Solid lines represent estimated median regression lines, while dotted lines represent 95% bootstrap CIs. Knots were placed at ages 50, 75, and 80 years.

Figure 2

Estimated Median Regression Lines in Scaled Units vs Age for All 4 Demographic Groups, With Separate Panels for Memory, Adjusted Hippocampal Volume (HVa), and Amyloid Positron Emission Tomography (PET). Knots were placed at ages 50, 75, and 80 years. Blue lines represent relationships in men, and orange represent relationships in women. Solid lines represent APOE ε4 carriers, and dashed lines APOE ε4 noncarriers.

Figure 3

Plots of Groupwise Differences in Scaled Units for Memory, Adjusted Hippocampal Volume (HVa), and Amyloid Positron Emission Tomography (PET). Comparisons are shown for differences among APOE ε4 carriers vss noncarriers within sex and for male vs female within APOE ε4 genotype. The solid line in each plot represents the estimated difference in medians, while the dotted lines represent 95% bootstrap CIs for this difference. A horizontal line at 0 (ie, no difference) is shown for reference. Plots in which significant groupwise differences were found are outlined in red. This red outlining illustrates a pattern showing differences in memory and HVa were due to sex not APOE ε4, while differences in amyloid PET were due to APOE ε4 and not sex.

Figure 4

Probability of Amyloid Positron Emission Tomography (PET) Positivity vs Age by APOE ε4 Genotype. The data are estimated from a logistic model. Amyloid PET positivity was defined as a SUVR of 1.4 or greater. The estimated age at which 10% (the dashed horizontal line) of the population is positive is 57 years (95% CI, 53–59 years) for APOE ε4 carriers and 64 years (95% CI, 62–66 years) for APOE ε4 noncarriers.