The link between Alzheimer’s disease and Down syndrome
People with Down syndrome are genetically predisposed to developing Alzheimer´s disease. The strong association between Alzheimer disease and Down syndrome has a genetic basis through a gene-dose effect of the amyloid precursor protein (APP) gene located on chromosome 21, which is triplicated in this population. Consequently, neuropathologic changes associated with Alzheimer disease are universally seen in persons with Down syndrome by age 40, and biomarker changes follow a predictable course that is strikingly similar to that found in autosomal dominant Alzheimer disease. Because of these similarities, Down syndrome has been conceptualized as genetically determined Alzheimer disease, just like the autosomal dominant forms. However, the implications of this conceptualization on the predictability of symptom onset in Down syndrome and the limit Alzheimer disease imposes on life expectancy, have not been fully explored.
What have we done in this study?
We conducted a meta-analysis to investigate the age at onset, age at death, and duration of Alzheimer disease dementia in people with Down syndrome. We compared whether the variability in symptom onset of Alzheimer disease in Down syndrome was similar to 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 extracted from death certificates compiled by the US Centers for Disease Control and Prevention (CDC).
We found that the variability of age at symptom onset in Down syndrome was comparable to autosomal dominant Alzheimer disease. This finding is very important considering the emphasis typically given on the variability of age at onset in Down syndrome. We also found that mortality data (compiled from CDC records between 1968-2019) and the consistent age at onset were compatible with fully penetrant Alzheimer disease.
Relevance of the study
This study highlighted that Alzheimer disease should be recognized as a critical medical priority in people with Down syndrome. Increasing life expectancy and closing the gap with the general population will require effective prevention and management of Alzheimer disease. This knowledge has considerable implications for policy making and counselling to families.