Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon 4/4 genotype

Sleep disruption, nightly restlessness, sundowning, and other circadian dis turbances are frequently seen in Alzheimer's disease (AD) patients. Changes in the suprachiasmatic nucleus and pineal gland are thought to be the biol ogical basis for these behavioral disturbances. Melatonin is the main endoc rine message for circadian rhythmicity from the pineal. To determine whethe r melatonin production was affected in AD, melatonin levels were determined in the cerebrospinal fluid (CSF) of 85 patients with AD (mean age, 75 +/- 1.1 yr) and in 82 age-matched controls (mean age, 76 +/- 1.4 yr). Ventricul ar postmortem CSF was collected from clinically and neuropathologically wel l defined AD patients and from control subjects without primary neurologica l or psychiatric disease. In old control subjects (>80 yr of age), CSF mela tonin levels were half of those in control subjects of 41-80 yr of age [176 +/- 58 (n = 29) and 350 +/- 66 (n = 53) pg/mL, respectively; P = 0.016]. W e did not find a diurnal rhythm in CSF melatonin levels in control subjects . In AD patients the CSF melatonin levels were only one fifth (55 +/- 7 pg/ mL) of those in control subjects (273 +/- 47 pg/mL; P = 0.0001). There was no difference in the CSF melatonin levels between the presenile (42 +/- 11 pg/mL; n = 21) and the senile (59 +/- 8 pg/mL; n = 64; P = 0.35) AD patient s. The melatonin level in AD patients expressing apolipoprotein E-epsilon 3 /4 (71 +/- 11 pg/mL) was significantly higher than that in patients express ing apolipoprotein E-epsilon 4/4 (32 +/- 8 pg/ml; P = 0.02). In the AD pati ents no significant correlation was observed between age of onset or durati on of AD and CSF melatonin levels. In the present study, a dramatic decreas e in the CSF melatonin levels was found in old control subjects and even mo re so in AD patients. Whether supplementation of melatonin may indeed impro ve behavioral disturbances in AD patients should be investigated.