Long-term associations between amyloid positron emission tomography, sex, apolipoprotein E and incident dementia and mortality among individuals without dementia: hazard ratios and absolute risk

Abstract

Dementia and mortality rates rise inexorably with age and consequently interact. However, because of the major logistical difficulties in accounting for both outcomes in a defined population, very little work has examined how risk factors and biomarkers for incident dementia are influenced by competing mortality. The objective of this study was to examine long-term associations between amyloid PET, APOE ɛ4, sex, education and cardiovascular/metabolic conditions, and hazard and absolute risk of dementia and mortality in individuals without dementia at enrolment. Participants were enrolled in the Mayo Clinic Study of Aging, a population-based study of cognitive ageing in Olmsted County, MN, USA. All were without dementia and were age 55-92 years at enrolment and were followed longitudinally. Predictor variables were amyloid PET, APOE ɛ4 status, sex, education, cardiovascular/metabolic conditions and age. The main outcomes were incident dementia and mortality. Multivariable, multi-state models were used to estimate mortality and incident dementia rates and absolute risk of dementia and mortality by predictor variable group. Of the 4984 participants in the study, 4336 (87%) were cognitively unimpaired and 648 (13%) had mild cognitive impairment at enrolment. The median age at enrolment was 75 years; 2463 (49%) were women. The median follow-up time was 9.4 years (7.5 years after PET). High versus normal amyloid (hazard ratio 2.11, 95% confidence interval 1.43-2.79), APOE ɛ4 (women: hazard ratio 2.24, 95% confidence interval 1.80-2.77; men: hazard ratio 1.37, 95% confidence interval 1.09-1.71), older age and two additional cardiovascular/metabolic conditions (hazard ratio 1.37, 95% confidence interval 1.22-1.53) were associated with the increased hazard of dementia (all P < 0.001). Among APOE ɛ4 carriers with elevated amyloid, remaining lifetime risk of dementia at age 65 years was greater in women [74% (95% confidence interval 65-84%) high and 58% (95% confidence interval 52-65%) moderate amyloid], than men [62% (95% confidence interval 52-73%) high and 44% (95% confidence interval 35-53%) moderate amyloid]. Overall, the hazard and absolute risk of dementia varied considerably by predictor group. The absolute risk of dementia associated with predictors characteristic of Alzheimer's disease was greater in women than men while at the same time the combination of APOE ɛ4 non-carrier with normal amyloid was more protective in women than men. This set of findings may be attributed in part to different biological effects and in part to lower mortality rates in women.

Keywords: APOE; amyloid PET; dementia; mortality; sex.

Graphical abstract

Figure 1

Multi-state transition model and numbers of mortality and incident dementia events per 100 person-years by sex and age group. (A) Multi-state transition model. The three states in this model are denoted by boxes: alive without dementia, alive with dementia and deceased. The three possible transition paths are denoted by arrows: progression from without dementia to dementia, from without dementia to death and from dementia to death. (B–D) Estimated event rates for each transition type by continuous-age separately for men and women; (B) incident dementia events per 100 person-years by sex and age, (C) death events without dementia per 100 person-years by sex and age and (D) death events with dementia per 100 person-years by sex and age. In the tables below the plots in (B–D), we show actual event counts by age bin. In (B-D), males are denoted by a solid blue line and females by a dashed red line. Estimates are based on the person-years analysis using Poisson models.

Figure 2

HRs for state-to-state transitions associated with different subgroups. Three state-to-state transitions are illustrated: progression from without dementia to dementia, from without dementia to death and from dementia to death. We summarize the association between predictor variables and incidence rates in our multi-state model in the form of HRs where the reference group is the overall study population average for the amyloid, sex and APOE variables. This presentation allows for direct comparison of the rate in a predictor variable subgroup compared to the population average and allows visual comparisons of all possible pairwise comparisons since each HR estimate in the figure shares a common anchor point. The HRs for education and CMC are shown for a specified contrast. + and − symbols in the top panel represent APOE ɛ4 status: + refers to carrier, −refers to non-carrier. HRs estimates are from the multi-state intensity model.

Figure 3

Absolute predictions by age associated with different predictor variable subgroups. The two rows illustrate different risk predictor variable subgroups, amyloid PET level by APOE ɛ4 group among (A) men and (B) women. Other predictor variable effects were weighted to the frequencies observed in the overall study population. Amyloid PET level is indicated by colour (green = normal, gold = moderate, blue = high) while line type indicates APOE e4 group (solid = carrier, dashed = non-carrier). The columns are arranged by the three possible states in the multi-state model illustrated in Fig. 1A: alive without dementia, alive with dementia or deceased. The columns are also arranged from left to right to reflect group-level change over time in a cohort beginning at age 65 years: progression from the alive without dementia category into the alive with dementia or the deceased category. The y-axis scale of the middle column (i.e. predicted proportion of original cohort alive with dementia) is limited to a smaller range compared to the other columns to better show the alive with dementia curves. Estimates are based on predicted state curves obtained from the multi-state intensity model.

Figure 4

Remaining lifetime risk of dementia by sex, APOE genotype, and amyloid group for a person without dementia at starting ages 65, 75 or 85 years. The remaining lifetime risk for all 12 combinations of amyloid group, sex and APOE ɛ4 comes from the competing risks model and is averaged over all the combinations of education and CMC. The standard deviation for the remaining lifetime risk was computed using a grouped jackknife with 20 groups. Estimates are based on remaining lifetime risk estimates obtained from the multi-state intensity model.