Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study

Abstract

Background: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome.

Methods: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid β peptides 1-42 and 1-40 and their ratio (Aβ_1-42/1-40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with ¹⁸F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate.

Findings: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aβ_1-42/1-40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. ¹⁸F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life.

Interpretation: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments.

Funding: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.

Figure 1

Clinical and neuropsychological changes with age in adults with Down syndrome (A) Point prevalence of Alzheimer's disease dementia, prodromal Alzheimer's disease, and no clinical symptoms of Alzheimer's disease in individuals with Down syndrome. (B) Age-related changes in CAMCOG-DS scores in individuals with Down syndrome with mild or moderate intellectual disability (analysed separately), with bands representing 95% CIs. The vertical dashed line at 50·2 years represents the median age at the expected symptom onset (ie, prodromal Alzheimer's disease diagnosis). CAMCOG-DS=Cambridge Cognitive Examination for Older Adults with Down Syndrome.

Figure 2

Imaging signature of Alzheimer's disease in adults with Down syndrome for brain structure, glucose metabolism, and amyloid β deposition All panels compare individuals with Down syndrome with symptomatic Alzheimer's disease with those with no clinical evidence of dementia. The left panel represents loss of cortical thickness, the middle panel loss of brain glucose metabolism, and the right panel the increase in cerebral fibrillar amyloid β deposition.

Figure 3

Biomarker changes with age in adults with Down syndrome and control participants Shading represents 95% CIs. The vertical dashed lines at 50·2 years represent the age at the expected symptom onset (eg, median age of prodromal Alzheimer's disease diagnosis). Aβ_1–40=amyloid β peptide 1–40. Aβ_1–42=amyloid β peptide 1–42. CSF=cerebrospinal fluid. FDG=¹⁸F-fluorodeoxyglucose. NFL=neurofilament light chain. SUVR=standardised uptake value ratio.

Figure 4

Integrated model of the natural history of Alzheimer's disease in individuals with Down syndrome Comparison of structural, metabolic, and biochemical biomarker changes as a function of age by use of the standardised differences between participants with Down syndrome and controls fitted with a locally estimated scatterplot smoothing curve. Positive standardised differences represent higher biomarker values in participants with Down syndrome than in euploid controls, and negative values represent lower biomarker values. The vertical dashed line at 50·2 years represents the age at the expected symptom onset (median age of prodromal Alzheimer's disease diagnosis). Aβ_1–40=amyloid β peptide 1–40. Aβ_1–42=amyloid β peptide 1–42. CAMCOG-DS=Cambridge Cognitive Examination for Older Adults with Down Syndrome. CSF=cerebrospinal fluid. NFL=neurofilament light chain. p-tau=tau phosphorylated at threonine 181.