Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer's Disease

Abstract

Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and prion diseases have a certain degree of clinical, pathological, and molecular overlapping. Previous studies revealed that many causative mutations in AD, PD, and FTD/ALS genes could be found in clinical familial and sporadic AD. To further elucidate the missing heritability in early-onset Alzheimer's disease (EOAD), we genetically characterized a Thai EOAD cohort by Next-Generation Sequencing (NGS) with a high depth of coverage, capturing variants in 50 previously recognized AD and other related disorders' genes. A novel mutation, APP p.V604M, and the known causative variant, PSEN1 p.E184G, were found in two of the familiar cases. Remarkably, among 61 missense variants were additionally discovered from 21 genes out of 50 genes, six potential mutations including MAPT P513A, LRRK2 p.R1628P, TREM2 p.L211P, and CSF1R (p.P54Q and pL536V) may be considered to be probably/possibly pathogenic and risk factors for other dementia leading to neuronal degeneration. All allele frequencies of the identified missense mutations were compared to 622 control individuals. Our study provides initial evidence that AD and other neurodegenerative diseases may represent shades of the same disease spectrum, and consideration should be given to offer exactly embracing genetic testing to patients diagnosed with EOAD. Our results need to be further confirmed with a larger cohort from this area.

Keywords: 50 genes; Alzheimer’s disease; EOAD; Thailand; next generation sequencing.

Figure 1

Schematic representation of the missense mutations in definite early-onset Alzheimer’s disease (EOAD) cases. Panel (a) shows the position of causative selected-mutations and coding risk variants relative to the respective gene and protein sequences. Panel (b) illustrates the position of each mutated amino acid residue relative to the 3D protein or domain structure. APP, Amyloid-beta precursor protein; Cu_bd, copper-binding domain; APP_E2, E2 domain of amyloid-beta precursor protein; KU, Kunitz-type serine protease inhibitor domain; β_APP, Beta-amyloid precursor protein; UTR, untranslated region; APP_N, N-terminal fragment of the β-amyloid precursor protein.

Figure 2

Visualization of neurodegenerative disorders of 23 genes in network modules. Each biological process was represented with the nodes which are connected with lines to indicate interactions. The orange nodes indicated beta-amyloid metabolic process genes, while regulation of protein tyrosine kinase activity and mitochondrial fission genes are presented as green/yellow and purple, respectively. The light-blue nodes revealed genes associated with axo-dendritic transport.

Figure 3

Distribution of neurodegenerative genes in the human genome where causative or probably causative variants were reported to cause early-onset dementia.