The amyloid beta-peptides A beta 40 and A beta 42 are highly amyloidogenic constituents of brain beta-amyloid plaques in Alzheimer's disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (A beta PP), including alpha- beta-, and gamma-secretases. Talsaclidine is a functionally selective muscarinic m1 agonist that stimulates non-amyloidogenic alpha-secretase processing in vitro. We compared cerebrospinal fluid (CSF) levels of A beta 40 and A beta 42 measured by ELISA before and at the end of 4 weeks of treatment with talsaclidine. The medication was administered in a double-blind, placebo-controlled, and randomized clinical study to 40 patients with AD. Talsaclidine (n = 34) decreased CSF levels of A beta 42 by a median of 19% (p < 0.001) as compared to baseline. The mean difference between CSF levels of A beta 42 before and after treatment with talsaclidine (n = 34) was -46 +/- 73 (SD) pg/ml as compared to 0 +/- 8 (SD) pg/ml with placebo (n = 6) (p < 0.05). CSF levels of A beta 40 increased during treatment with placebo (n = 6) while they remained stable during treatment with talsaclidine (n = 31) (1.118 +/- 1.710 ng/ml, and -0.170 +/- 0.967 ng/ml, respectively; p < 0.05). These data show that treatment with the m1 agonist talsaclidine reduced A beta peptides, and particularly A beta 42, in AD patients, suggesting it as a potential amyloid lowering therapy of AD.

The association between depression and apolipoprotein E (apoE) was investigated in 137 out-patients with Alzheimer’s disease. An ICD-10 diagnosis of depression was found in 21.1% of all patients. There was a good correlation between clinicians’ diagnoses and blinded rating by the Montgomery-Åsberg Depression Rating Scale (r = 0.70). In male patients, apoE 3/3 was detected in 34.1%, 3/4 in 38.6%, 4/4 in 13.6%, 2/4 in 6.8% and 2/3 in 6.8% of cases. In female patients, apoE 3/3 was detected in 35.5%, 3/4 in 45.2%, 4/4 in 12.8%, 2/4 in 3.2% and 2/3 in 3.2% of cases. When analyzing the variance of gene dosage effect, the frequency of the apoE Ε4 allele was significantly increased in depressed women but not in men. This effect remained stable in stepwise regression analysis when depression as the dependent variable was tested against the independent variables age, age of onset, duration of disease, cognitive status and years of school education.