Summary

Background

     Important insights into the early pathogenesis of Alzheimer’s disease can be provided by studies of autosomal dominant Alzheimer’s disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer’s disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.

Methods

     In this cross-sectional study, we included participants (aged ≥۲۵ years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer’s disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25–۷۳ years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β۴۲ (Aβ۴۲) to Aβ۴۰ (Aβ۴۲/۴۰) was measured to evaluate its Spearman’s correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ۴ status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ۴۲/۴۰ was evaluated.

Findings

     ۱۹۲ individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer’s disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ۴۲/۴۰ were negatively correlated in carriers of autosomal dominant Alzheimer’s disease mutations (n=216; r=–۰·۵۶۵; p<0·۰۰۰۱) and in people with Down syndrome (n=32; r=–۰·۸۰۱; p<0·۰۰۰۱). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·۸۰ centiloids [SD 28·۳۳]) versus asymptomatic mutation carriers (24·۶۱ centiloids [30·۲۷]; p=0·۱۱) and between symptomatic people with Down syndrome (77·۲۵ centiloids [41·۷۶]) versus symptomatic mutation carriers (69·۱۵ centiloids [51·۱۰]; p=0·۳۴). APOE ɛ۴ status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset –۲۳·۰ vs –۱۷·۵; p=0·۰۰۰۲). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome.

Interpretation

     Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer’s disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome.

Funding

     The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.

Introduction

     Down syndrome, caused by full or partial triplication of chromosome 21, is one of the most common genetic disorders, with approximately one in 700 children born with Down syndrome in the USA each year.1 Due to this triplication, individuals with Down syndrome have an extra copy of the APP gene and overproduce amyloid β (Aβ). Consequently, almost all adults with Down syndrome develop amyloid plaques and tau neurofibrillary tangles, which are the hallmarks of Alzheimer’s disease.2 Given this fact and the substantial increase in life expectancy in people with Down syndrome, there is a growing population of adults with Down syndrome developing Alzheimer’s disease.1,3

     Previous studies have used cognition, fluid biomarker, and imaging measures to understand the presentation and progression of Alzheimer’s disease in individuals with Down syndrome.3–۶ The cognitive symptoms of Alzheimer’s disease develop at approximately 50–۵۵ yearsof-age in people with Down syndrome, with CSF markers changing years before the onset of these symptoms.3–۵ PET imaging studies have also identified amyloid accumulation in cortical and subcortical brain regions years before the presentation of clinical symptoms.6 However, questions remain regarding the nature of amyloid deposition in individuals with Down syndrome versus individuals with other forms of Alzheimer’s disease, particularly autosomal dominant Alzheimer’s disease.

Results

     ۱۹۲ individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer’s disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. Controls from the two studies were combined into a single group. For the autosomal dominant mutation types present in people included in our study, see appendix (pp 8–۹). Participant characteristics for each group are shown in the table. Groups did not differ by age or APOE ε۴-positivity status. There were fewer women in the Down syndrome group (44%) compared with the control (61%) and mutation carrier (53%) groups. Compared with carriers of autosomal dominant Alzheimer’s disease mutations, a smaller proportion of individuals with Down syndrome identified as non-White (p=0∙۰۳۱), although most people in our analysis identified as White. A higher proportion of mutation carriers (38%) than people with Down syndrome (15%) were categorised as symptomatic (p<0∙۰۰۰۱). Of the 101 symptomatic mutation carriers, 57 (56%) had very mild dementia (CDR 0∙۵), ۲۷ (۲۷%) had mild dementia (CDR 1), and 17 (17%) had moderate or severe dementia (CDR 2–۳). Of the 28 symptomatic participants with Down syndrome, 16 (57%) had mild cognitive impairment and 12 (43%) had dementia due to Alzheimer’s disease.