There is increasing evidence that several mitochondrial abnormalities are present
in the brains of patients with Alzheimer's disease (AD). Decreased alpha-ketoglutarate
dehydrogenase complex (alpha KGDHc) activity was identified in some patients with
AD. The alpha KGDHc is a key enzyme in the Krebs cycle. This enzyme is very sensitive
to the harmful effect of reactive oxygen species, which gives them a critical role
in the Alzheimer and mitochondrial disease research area. Previously, several genetic
risk factors were described in association with AD. Our aim was to analyze the associations
of rare damaging variants in the genes encoding alpha KGDHc subunits and AD. The three
genes (OGDH, DLST, DLD) encoding alpha KGDHc subunits were sequenced from different
brain regions of 11 patients with histologically confirmed AD and the blood of further
35 AD patients. As a control group, we screened 134 persons with whole-exome sequencing.
In all subunits, a one-one rare variant was identified with unknown significance based
on American College of Medical Genetics and Genomics (ACMG) classification. Based
on the literature research and our experience, R263H mutation in the DLD gene seems
likely to be pathogenic. In the different cerebral areas, the alpha KGDHc mutational
profile was the same, indicating the presence of germline variants. We hypothesize
that the heterozygous missense R263H in the DLD gene may have a role in AD as a mild
genetic risk factor.
