Associations of Alzheimer's disease risk variants with gene expression, amyloidosis, tauopathy, and neurodegeneration

Abstract

Background: Genome-wide association studies have identified more than 30 Alzheimer's disease (AD) risk genes, although the detailed mechanism through which all these genes are associated with AD pathogenesis remains unknown. We comprehensively evaluate the roles of the variants in top 30 non-APOE AD risk genes, based on whether these variants were associated with altered mRNA transcript levels, as well as brain amyloidosis, tauopathy, and neurodegeneration.

Methods: Human brain gene expression data were obtained from the UK Brain Expression Consortium (UKBEC), while other data used in our study were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We examined the association of AD risk allele carrier status with the levels of gene expression in blood and brain regions and tested the association with brain amyloidosis, tauopathy, and neurodegeneration at baseline, using a multivariable linear regression model. Next, we analyzed the longitudinal effects of these variants on the change rates of pathology using a mixed effect model.

Results: Altogether, 27 variants were detected to be associated with the altered expression of 21 nearby genes in blood and brain regions. Eleven variants (especially novel variants in ADAM10, IGHV1-68, and SLC24A4/RIN3) were associated with brain amyloidosis, 7 variants (especially in INPP5D, PTK2B) with brain tauopathy, and 8 variants (especially in ECHDC3, HS3ST1) with brain neurodegeneration. Variants in ADAMTS1, BZRAP1-AS1, CELF1, CD2AP, and SLC24A4/RIN3 participated in more than one cerebral pathological process.

Conclusions: Genetic variants might play functional roles and suggest potential mechanisms in AD pathogenesis, which opens doors to uncover novel targets for AD treatment.

Keywords: Alzheimer disease; Amyloid; Gene expression; Neurodegeneration; Risk variants; Tau.

Fig. 1

Association of the variants with gene expression in peripheral blood and brain regions. The significant associations between the variants and the levels of gene expression in blood were identified from the ADNI database, and the significant associations in specific brain regions were obtained from the Braineac dataset. FDR-adjusted P values with statistical significance are shown. Abbreviations: CRBL, cerebellar cortex; FCTX, frontal cortex; HIPP, hippocampus; MEDU, medulla; OCTX, occipital cortex; PUTM, putamen; SNIG, substantia nigra; TCTX, temporal cortex; THAL, thalamus; WHMT, intralobular white matter

Fig. 2

Association of the variants with brain amyloidosis, tauopathy, and neurodegeneration (FDG-PET levels or MRI hippocampal volumes) at baseline. We tested for significant associations of AD risk allele carrier status with brain amyloidosis, based on CSF Aβ₄₂ or amyloid-PET data; the associations with brain neurodegeneration, based on FDG-PET or MRI HVa data; and the associations with brain tauopathy, based on CSF pTau or tau-PET data. a The minor allele carriers of ABCA7 rs3752246, BZRAP1-AS1 rs2526378, FERMT2 rs17125944, SLC24A4/RIN3 rs10498633, and SLC24A4/RIN3 rs12590654 were significantly associated with decreased CSF Aβ₄₂ levels, and ADAM10 rs593742, IGHV1-68 rs79452530, and CELF1 rs3740688 associated with increased CSF Aβ₄₂ levels. b The minor allele carriers of ABCA7 rs3752246 were associated with increased amyloid-PET levels, and ADAMTS1 rs2830500, CLU rs11136000, and EPHA1 rs11771145 associated with decreased levels of amyloid-PET. c The minor allele carriers of BZRAP1-AS1 rs2526378 and HS3ST1 rs6448807 were associated with decreased FDG-PET levels. d The minor allele carriers of ECHDC3 rs11257242 were associated with increased MRI HVa levels. e The minor allele carriers of BIN1 rs744373 and BIN1 rs6733839 had lower CSF pTau levels, and CD2AP rs9381563 and INPP5D rs10933431 had higher CSF pTau levels. f The minor allele carriers of BIN1 rs744373 and BIN1 rs7561528 had higher tau-PET levels, and SLC24A4/RIN3 rs10498633 had lower tau-PET levels

Fig. 3

Longitudinal effects of the variants on the change rates of brain amyloidosis, tauopathy, and neurodegeneration. a The risk C allele carrier of FERMT2 rs17125944 was associated with decreased CSF Aβ₄₂ levels at baseline, although these changes over time were not obvious from the longitudinal analysis. b The longitudinal effect of PTK2B rs28834970 on the change rate of CSF pTau levels was significant. The minor allele carriers of PTK2B rs28834970 exhibited faster rise in CSF pTau levels. c Longitudinal effects of CELF1 rs3740688 and PICALM rs3851179 on the change rate of MRI HVa levels were significant. The minor allele carriers of CELF1 rs3740688 and PICALM rs3851179 exhibited slower decline in MRI HVa levels. d Longitudinal effects of ADAMTS1 rs2830500, CD2AP rs9381563, and CD33 rs3865444 on the change rate of FDG-PET levels were significant. The minor allele carriers of CD2AP rs9381563 exhibited faster decline in FDG-PET levels, and the minor allele carriers of ADAMTS1 rs2830500 and CD33 rs3865444 exhibited slower decline in FDG-PET levels. We analyzed the longitudinal effects of these variants on the change rates of pathology using a linear mixed effect model. The shaded regions refer to 95% confidence intervals

Fig. 4

Role of variants in top 30 non-APOE AD risk genes in AD pathogenesis. Although most AD-associated genetic variants described to date are located in intronic or noncoding regions, these variants still could affect the nearby gene expression and exert protective or disease-inducing effects in AD-related amyloidosis, tauopathy, or neurodegeneration. Based on our analysis of all currently available data in ADNI, 11 variants were associated with brain amyloidosis, 7 variants associated with brain tauopathy, and 8 variants associated with brain neurodegeneration. Among them, variants in ADAMTS1, BZRAP1-AS1, and CELF1 affect the mechanisms involved both in brain amyloidosis and neurodegeneration, CD2AP in brain tauopathy and neurodegeneration, and SLC24A4/RIN3 in brain amyloidosis and tauopathy, implying these genes might contribute to AD risk via either common or distinct mechanisms