Role of diffuse low-level heteroplasmy of mitochondria! DNA in Alzheimer's disease neurodegeneration

Alzheimer's disease (AD) is the most common form of dementia in the elderly. The vast majority of cases are not linked to a known genetic defect and the molecular mechanisms underlying AD pathogenesis are still elusive. Evidence suggests that mitochondrial dysfunction is a prominent feature of the disease, and that mitochondria' DNA (mtDNA) alterations may represent a possible starting point of the pathophysiological cascade. Although specific mtDNA alterations have been reported in AD patients both in brain and peripheral tissues, such as D-loop mutations, 4977-bp deletion and poly-C tract D310 cytosine insertion, a generalized subtle allelic shift has also been demonstrated. This shift is significant for a few nucleotide positions (nps), but it is also detectable for most nps, although at a lower level. As single allelic substitutions can unlikely be determinant, it is proposed that the combination of all of them could lead to a less efficient oxidative phosphorylation, thus influencing AD development and course.