To clarify the mechanism of disease of sporadic and inherited Alzheimer’s and Parkinson’s disease.

Inherited and sporadic Alzheimer’s and Parkinson’s Disease (APD) are clinically indistinguishable except for age of onset; both are associated with DNA mutations that result in abnormal beta-amyloid and alpha-synuclein accumulation, respectively. However, it is unknown how DNA mutations occur in non-dividing neurons. Recently, somatic at-risk DNA loci mutated in cancer and autoimmune diseases were found to be encoded by mutation-prone DNA. Therefore, a plausible explanation for APD is that (1) known inherited APD-associated loci are mutation-prone and (2) a constant environmental factor causes constant DNA damage and mutations independent of DNA duplication.

Inherited at-risk loci within APD genes were evaluated for the presence of mutation-prone DNA, in particular somatic hypermutation (SHM) hotspots. Environmental factors able to cause constant DNA damage independent of geographic location or time were investigated.

The main at-risk codons for beta-amyloid and alpha-synuclein were analyzed: twelve of sixteen (75%) beta-amyloid mutations associated with Alzheimer’s disease and four of five (80%) alpha-synuclein mutations associated with Parkinson’s disease arose in DNA sequences that are encoded by or adjacent to SHM hotspots. The rate of SHM-induced mutagenesis is accelerated by neuronal cytidine deaminase activity. The number of at-risk loci arising in SHM hotspots supports development of sporadic APD without obvious risk factors and more common prevalence of Alzheimer’s disease. Among environmental factors only oxidative stress from minimum ionizing particle (MIP) radiation has the energy spectrum, constant presence over time, and geographic distribution required to cause somatic DNA mutations at a predictable rate.

The combination of APD sequences containing mutation-prone SHM hotspots and MIP radiation-related oxidative stress as constant source of mutations explain that sporadic APD are common; persons with inherited APD have an earlier age of onset due to one or more pre-existing mutated at-risk loci.