Association of Alzheimer Disease With Life Expectancy in People With Down Syndrome

Abstract

Importance: People with Down syndrome have a high risk of developing Alzheimer disease dementia. However, penetrance and age at onset are considered variable, and the association of this disease with life expectancy remains unclear because of underreporting in death certificates.

Objective: To assess whether the variability in symptom onset of Alzheimer disease in Down syndrome is similar to autosomal dominant Alzheimer disease and to assess its association with mortality.

Design, setting, and participants: This study combines a meta-analysis with the assessment of mortality data from US death certificates (n = 77 347 case records with a International Classification of Diseases code for Down syndrome between 1968 to 2019; 37 900 [49%] female) and from a longitudinal cohort study (n = 889 individuals; 46% female; 3.2 [2.1] years of follow-up) from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI).

Main outcomes and measures: A meta-analysis was conducted to investigate the age at onset, age at death, and duration of Alzheimer disease dementia in Down syndrome. PubMed/Medline, Embase, Web of Science, and CINAHL were searched for research reports, and OpenGray was used for gray literature. Studies with data about the age at onset or diagnosis, age at death, and disease duration were included. Pooled estimates with corresponding 95% CIs were calculated using random-effects meta-analysis. The variability in disease onset was compared with that of autosomal dominant Alzheimer disease. Based on these estimates, a hypothetical distribution of age at death was constructed, assuming fully penetrant Alzheimer disease. These results were compared with real-world mortality data.

Results: In this meta-analysis, the estimate of age at onset was 53.8 years (95% CI, 53.1-54.5 years; n = 2695); the estimate of age at death, 58.4 years (95% CI, 57.2-59.7 years; n = 324); and the estimate of disease duration, 4.6 years (95% CI, 3.7-5.5 years; n = 226). Coefficients of variation and 95% prediction intervals of age at onset were comparable with those reported in autosomal dominant Alzheimer disease. US mortality data revealed an increase in life expectancy in Down syndrome (median [IQR], 1 [0.3-16] years in 1968 to 57 [49-61] years in 2019), but with clear ceiling effects in the highest percentiles of age at death in the last decades (90th percentile: 1990, age 63 years; 2019, age 65 years). The mortality data matched the limits projected by a distribution assuming fully penetrant Alzheimer disease in up to 80% of deaths (corresponding to the highest percentiles). This contrasts with dementia mentioned in 30% of death certificates but is in agreement with the mortality data in DABNI (78.9%). Important racial disparities persisted in 2019, being more pronounced in the lower percentiles (10th percentile: Black individuals, 1 year; White individuals, 30 years) than in the higher percentiles (90th percentile: Black individuals, 64 years; White individuals, 66 years).

Conclusions and relevance: These findings suggest that the mortality data and the consistent age at onset were compatible with fully penetrant Alzheimer disease. Lifespan in persons with Down syndrome will not increase until disease-modifying treatments for Alzheimer disease are available.

Figure 1.. Forest Plot of Mean Age at Onset of Alzheimer Disease Dementia in Adults With Down Syndrome

Forest plot of mean age at onset of Alzheimer disease dementia (years) in adults with Down syndrome across 44 eligible studies from the systematic review (N = 2695 individuals). The points represent the mean, the arms indicate the 95% CIs, the light blue diamond indicates the overall pooled estimate (calculated with the DerSimonian-Laird method), and its width indicates the 95% CI. The dotted line indicates the pooled estimate of age at onset (53.8 years). The minimal sample size for a study to be eligible was 5 or more participants. Weights were calculated using random-effects analysis.

Figure 2.. Forest Plot of Mean Age at Death and Mean Duration of Alzheimer Disease Dementia in Adults With Down Syndrome

The forest plot shows (A) the mean age at death across 9 eligible studies (N = 324) and (B) the mean disease duration across 7 eligible studies from the systematic review (N = 226 individuals) for Alzheimer disease dementia in adults with Down syndrome. The points indicate the mean, the arms indicate the 95% CI, the light blue diamond represents the overall pooled estimate (calculated with the DerSimonian-Laird method), and its width represents the confidence interval. The dotted line indicates the pooled estimates for age at death (58.4 years) and duration (4.6 years). The minimal sample size for a study to be eligible was 5 or more participants. Weights were calculated using random-effects analysis.

Figure 3.. Variability in Age at Onset

Panel A shows the natural logarithm of coefficients of variation (LnCV, SD / mean × 100) of the 44 studies on age at onset of Alzheimer disease dementia in adults with Down syndrome (DSAD) included in the systematic review and the LnCV of 60 studies on symptom onset in autosomal dominant Alzheimer disease. Panel B shows the span of age at onset. The span of age at onset was calculated by computing the 95% prediction interval (PI) range of the same studies included in panel A, by subtracting the lower 95% PI to the upper 95% PI. A larger PI range indicates a wider interval (in years) in which 95% of individuals will develop symptoms. Dots indicate a single study, the size of the dot indicates the sample size, whiskers indicate the 25th and 75th percentiles, and the bold line in the boxes indicate the median. Panel C shows the 95% prediction intervals (PI) for the largest individual cohort studies. For DSAD, the data is from the study of Tsiouris et al. For ADAD, individual pathogenic variants are indicated in the Figure. ADAD indicates autosomal dominant Alzheimer disease. ^aOnset refers to the onset of dementia in DSAD and to the onset of progressive cognitive symptoms in ADAD, as determined by clinicians.

Figure 4.. Association of Alzheimer Disease With Life Expectancy in People With Down Syndrome

Panel A shows the hypothetical distribution of age at death in people with Down syndrome based on the data on age at onset and disease duration of Alzheimer disease dementia obtained in the systematic review and assuming full Alzheimer disease penetrance. Panel B shows the Centers for Disease Control and Prevention (CDC) mortality data of age at death in individuals with Down syndrome in the US between 1968 and 2019. The graph on the top right side of panel B is an overlay of the predicted percentiles based on the hypothetical distribution shown in panel A. CDC mortality data on age at death stratified by race (Panel C) and sex (Panel D). In panel C, orange lines indicate the 10th and 90th percentiles; gray lines indicate the 25th and 75th percentiles; and blue lines indicate the median. The shaded areas in panels C and D represent differences between each percentile according to race and sex.

Figure 5.. Reporting of Congenital Heart Defects and Dementia in Death Certificates

Panel A shows the US Centers for Disease Control and Prevention (CDC) mortality data by cause of death. Results are expressed as the percentage based on the total number of deaths recorded each year. Panel B shows the concordance between the CDC mortality data and the age at death from Alzheimer disease (AD) calculated from the hypothetical death distribution. The black dashed lines indicate the estimate, and the black dotted lines indicate the CI for the inflection point estimated using threshold regressions. Panel C shows the proportion of deaths with a diagnosis of dementia obtained from death certificates at the CDC, from the difference between the estimated and observed age at death (imputed), and from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort.