To clarify the significance of Lewy body (LB)-related alpha-synucleinopathy in aging, we investigated the incidence of LBs in 1,241 consecutive autopsy cases (663 males and 578 females). LB pathology was identified histologically in sections stained with hematoxylin and eosin and with anti-ubiquitin and anti-alpha-synuclein antibodies. Cases without LBs were classified as LB stage 0 (987 cases). Cases with LBs were classified as follows: LB stage I = incidental LBs (149 cases); LB stage II = LB-related degeneration without attributable clinical symptoms (47 cases); LB stage III = Parkinson disease without dementia (10 cases); LB stage IV = dementia with Lewy bodies (DLB) transitional (limbic) form (25 cases); and LB stage V = DLB neocortical form (23 cases). The average age at death was greater for those cases with LBs. There were no gender differences in the LB pathology. G842A polymorphism in the paraoxonase I gene was associated with men in LB stage II or above and suggests a gender-specific risk factor. LB stage V had higher stages of neurofibrillary tangle and senile plaque involvement and also had a higher frequency of apolipoprotein E epsilon4. Our findings indicate that LBs are associated with cognitive decline, either independently or synergistically with neurofibrillary tangles and senile plaques.