Alzheimer’s polygenic risk score is associated with Dementia and memory phenotypes in Down syndrome
Priyanka Gorijala, Muhammad Muaaz Aslam, Lam‐Ha Dang, Victoria Fernandez, Yun Ju Sung, Kang‐Hsien Fan, Eleanor Feingold, M. Ilyas Kamboh, Joseph H. Lee, Carlos Cruchaga- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Down syndrome (DS) is a complex neurological disorder manifested by triplication of chromosome 21, which includes the amyloid precursor protein (APP) gene. Triplication of APP which is known for the buildup of Amyloid Beta plaques, a hallmark of Alzheimer’s disease (AD) pathology. Although researchers have studied genetic factors of AD risk in DS, the overall genetic contribution of AD in DS is still not clear. While the polygenic risk score (PRS) explains the overall genetic architecture and overlap between complex traits, no study has used PRS to understand the relative burden of AD risk variants in DS.
Methods
We constructed PRS using Bellenguez et al (2022) summary statistics for five different cohorts: DS (n = 282), sporadic early‐onset (sEOAD, n = 395), sporadic late‐onset (sLOAD, n = 2259), familiar early‐onset (fEOAD, n = 196), familial late‐onset (fLOAD, n = 1413). Unrelated European ancestry samples were selected for analysis (4,545 cases, 2,890 controls). To understand AD risk beyond APOE, PRS including and excluding APOE region was calculated using PRSiceV2.3. Chromosome 21 was excluded from the analysis. We tested the association of PRS with clinical status in each cohort and compared it between cohorts. We further tested association of neuropsychological batteries for cognition/memory, and cerebrospinal fluid (CSF) biomarkers with the AD PRS for DS individuals.
Results
The PRS of AD was associated with sEOAD, fLOAD and sLOAD, but not with fEOAD. DS status was significantly associated with the AD PRS including APOE (OR = 0.62, P = 1.86×10−3). Down Syndrome Mental Status Examination (DSMSE) memory score was associated with AD PRS regardless of APOE inclusion (P = 8.61×10−4 with APOE, and P = 4.94×10−2 without APOE). In addition, DSMSE total score (P = 4.53×10−3), Dementia Questionnaire for People with Learning Disabilities (DLD) cognitive score (P = 1.46×10−2), CSF Aβ40 (P = 1.28×10−2), and Aβ42 (P = 4.21×10−2) were associated with the AD PRS including APOE.
Conclusions
Our study suggests that even if DS individuals were depleted with AD risk variants, the overall genetic architecture for AD is still associated with cognitive and memory phenotypes, as well as AD biomarkers. This suggests that AD risk modulates APP metabolism/Aβ formation and tau protein binding, thus playing a role in the onset and progression of dementia in DS.