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

• Published in: JAMA network open 2022-05, Vol.5 (5), p.e2212910-e2212910
• Main Authors: Iulita, Maria Florencia, Garzón Chavez, Diana, Klitgaard Christensen, Maria, Valle Tamayo, Natalia, Plana-Ripoll, Oleguer, Rasmussen, Sonja A, Roqué Figuls, Marta, Alcolea, Daniel, Videla, Laura, Barroeta, Isabel, Benejam, Bessy, Altuna, Miren, Padilla, Concepción, Pegueroles, Jordi, Fernandez, Susana, Belbin, Olivia, Carmona-Iragui, María, Blesa, Rafael, Lleó, Alberto, Bejanin, Alexandre, Fortea, Juan
• Format: Article
• Language: English
• Subjects: Age; Alzheimer's disease; Dementia; Down syndrome; Life expectancy; Meta-analysis; Mortality; Neurology; Online Only; Original Investigation
• ISSN: 2574-3805; 2574-3805
• DOI: 10.1001/jamanetworkopen.2022.12910

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. 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. 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). 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. 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 percentil