We previously reported on enhanced susceptibility to death of lymphocytes from Alzheimer’s disease (AD) patients
when exposed to hydrogen peroxide (H2O2)-induced oxidative stress and an increased resistance to death in those of
patients with a history of skin cancer. This is consistent with our hypothesis proposing that the cellular machinery controlling
cell death is deregulated in opposite directions in Alzheimer’s disease (AD) and cancer, to explain the inverse association
observed in epidemiological studies. Here we investigated whether the observed increased susceptibility correlates
with the degree of dementia severity. Peripheral lymphocytes from 23 AD patients, classified using the Clinical Dementia
Rating (CDR) into severe dementia (CDR 3, n=10) and mild-to-moderate dementia (CDR 1- 2, n=13), and 15 healthy controls
(HC) (CDR 0), were exposed to H2O2 for 20 hours. Lymphocyte death was determined by flow cytometry and
propidium iodide staining. The greatest susceptibility to H2O2-induced death was observed for lymphocytes from severe
dementia patients, whereas those with mild-to-moderate dementia exhibited intermediate values, compared to healthy controls.
A significant increase in the apoptosis/necrosis ratio was found in AD patients. Poly (ADP-ribosyl) polymerase-1
(PARP-1) inhibition significantly protected from H2O2-induced death of lymphocytes, whereby a lower degree of protection
was observed in severe AD patients. Moreover, inhibition of PARP-1 abolished the differences in apoptosis/necrosis
ratios observed between the three groups of patients. These results support the notion that AD is a systemic disorder,
whereby enhanced susceptibility to H2O2-induced death in peripheral lymphocytes correlates with dementia severity and
enhanced death in AD patients is attributable to a PARP-dependent increase in the apoptosis/necrosis ratio.