Comparison of amyloid accumulation between Down syndrome and autosomal‐dominant Alzheimer disease
Authors: Boerwinkle Anna H. , Gordon Brian A. , Wisch Julie K. , Flores Shaney , Henson Rachel L. , Butt Omar Hameed , Chen Charles D. , Benzinger Tammie L.S. , Fagan Anne M. , Handen Benjamin L , Christian Bradley T , Head Elizabeth , Mapstone Mark , Klunk William E , Rafii Michael S , O'Bryant Sid E. , Price Julie C , Schupf Nicole , Laymon Charles M , Krinsky‐McHale Sharon J , Lai Florence , Rosas H. Diana , Hartley Sigan L , Zaman Shahid , Lott Ira T , Silverman Wayne , Brickman Adam M. , Lee Joseph H. , Allegri Ricardo Francisco , Berman Sarah , Chhatwal Jasmeer P. , Chui Helena C , Cruchaga Carlos , Farlow Martin R. , Fox Nick C , Goate Alison , Day Gregory S , Graff‐Radford Neill R. , Jucker Mathias , Lee Jae‐Hong , Levin Johannes , Martins Ralph N , Mori Hiroshi , Perrin Richard J. , Salloway Stephen P. , Sanchez‐Valle Raquel , Schofield Peter R , Xiong Chengjie , Karch Celeste M. , Hassenstab Jason J. , McDade Eric , Bateman Randall J. , Ances Beau M ,   the Alzheimer's Biomarker Consortium‐Down Syndrome and the Dominantly Inherited Alzheimer Network
Published: December 2022

Background

Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development.

Method

We assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium‐Down Syndrome (ABC‐DS) and 265 mutation‐carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated‐years‐to‐symptom‐onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC‐DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40.

Result

The relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ ‐23 but was not elevated in DS until EYO ≥ ‐15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5).

Conclusion

These results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5‐10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.