Absence of coding somatic single nucleotide variants within well-known candidate genes in late-onset sporadic Alzheimer's Disease based on the analysis of multi-omics data

INTRODUCTION Genome-wide association studies (GWAS) in late onset Alzheimer's disease (LOAD) provide lists of individual genetic determinants. However, GWAS are not good at capturing the synergistic effects among multiple genetic variants and lack good specificity. METHODS We applied tree-based machine learning algorithms (MLs) to discriminate LOAD (> 700 individuals) and age-matched unaffected subjects using single nucleotide variants (SNVs) from AD studies, obtaining specific genomic profiles with the prioritized SNVs. RESULTS The MLs prioritized a set of SNVs located in close proximity genes PVRL2, TOMM40, APOE and APOC1. The captured genomic profiles in this region showed a clear interaction between rs405509 and rs1160985. Additionally, rs405509 located in APOE promoter interacts with rs429358 among others, seemingly neutralizing their predisposing effect. Interactions are characterized by their association with specific comorbidities and the presence of eQTL and sQTLs. DISCUSSION Our approach efficiently discriminates LOAD from controls, capturing genomic profiles defined by interactions among SNVs in a hot-spot region.

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The Role of Microglia in Sporadic Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201248 ◽

2021 ◽

Vol 79 (3) ◽

pp. 961-968

Author(s):

Wolfgang J. Streit ◽

Habibeh Khoshbouei ◽

Ingo Bechmann

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Genetic Mutations ◽

Sporadic Alzheimer’S Disease ◽

Immune Effector ◽

Effector Cells ◽

Immune Effector Cells ◽

Amyloid Cascade

Microglia constitute the brain’s immune system and their involvement in Alzheimer’s disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer’s disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea.

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Association between the c. 2495 A>G ATP7B Polymorphism and Sporadic Alzheimer's Disease

International Journal of Alzheimer s Disease ◽

10.4061/2011/973692 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 7

Author(s):

Serena Bucossi ◽

Stefania Mariani ◽

Mariacarla Ventriglia ◽

Renato Polimanti ◽

Massimo Gennarelli ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Single Nucleotide Polymorphism ◽

Logistic Regression ◽

Atp7b Gene ◽

Regression Analyses ◽

Susceptibility Loci ◽

Nucleotide Polymorphism ◽

Sporadic Alzheimer’S Disease ◽

Single Nucleotide

Nonceruloplasmin-bound copper (“free”) is reported to be elevated in Alzheimer's disease (AD). In Wilson's disease (WD) Cu-ATPase 7B protein tightly controls free copper body levels. To explore whether the ATP7B gene harbours susceptibility loci for AD, we screened 180 AD chromosomes for sequence changes in exons 2, 5, 8, 10, 14, and 16, where most of the Mediterranean WD-causing mutations lie. No WD mutation, but sequence changes corresponding to c.1216 T>G Single-Nucleotide Polymorphism (SNP) and c.2495 A>G SNP were found. Thereafter, we genotyped 190 AD patients and 164 controls for these SNPs frequencies estimation. Logistic regression analyses revealed either a trend for the c.1216 SNP (P=.074) or a higher frequency for c.2495 SNP of the GG genotype in patients, increasing the probability of AD by 74% (P=.028). Presence of the GG genotype in ATP7B c.2495 could account for copper dysfunction in AD which has been shown to raise the probability of the disease.

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