Portelius, Erik, Zetterberg, Henrik, Dean, Robert A., Marcil, Alexandre, Bourgeois, Philippe, Nutu, Magdalena, Andreasson, Ulf, Siemers, Eric, Mawuenyega, Kwasi G., Sigurdson, Wendy C., May, Patrick C., Paul, Steven M., Holtzman, David M., Blennow, Kaj, Bateman, Randall J.

Amyloid-β (Aβ) producing enzymes are key targets for disease-modifying Alzheimer’s disease (AD) therapies since Aβ trafficking is at the core of AD pathogenesis. Development of such drugs might benefit from the identification of markers indicating in vivo drug effects in the central nervous system. We have previously shown that Aβ(1-15) is produced by concerted β-and […]

Dockens, Randy, Wang, Jun-Sheng, Castaneda, Lorna, Sverdlov, Oleksandr, Huang, Shu-Pang, Slemmon, Randy, Gu, Huidong, Wong, Oi, Li, Hewei, Berman, Robert M., Smith, Christina, Albright, Charles F., Tong, Gary

Background and Objectives: Avagacestat is an orally active γ-secretase inhibitor that selectively inhibits amyloid β (Aβ) synthesis in cell culture and animal models. The objective of the current study was to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple doses of avagacestat over 28 days in healthy young men and elderly men and women […]

Baker, Laura D., Bayer-Carter, Jennifer L., Skinner, Jeannine, Montine, Thomas J., Cholerton, Brenna A., Callaghan, Maureen, Leverenz, James B., Walter, Brooke K., Tsai, Elaine, Postupna, Nadia, Lampe, Johanna, Craft, Suzanne

We previously showed that amyloid-β 1-42 (Aβ(42)) levels in cerebrospinal fluid (CSF) were markedly altered in response to a 4-week dietary intervention in normal aging and mild cognitive impairment (MCI). Here, we re-examined the data to assess whether diet-induced effects on CSF Aβ(42) were modulated by high intensity physical activity (hi-PA). Normal older adults (n […]

Blennow, Kaj, Zetterberg, Henrik, Rinne, Juha O., Salloway, Stephen, Wei, Jenny, Black, Ronald, Grundman, Michael, Liu, Enchi

Background: Given the slow and variable clinical course of Alzheimer disease, very large and extended clinical trials are needed to identify a beneficial clinical effect of disease-modifying treatments. Therefore, biomarkers are essential to prove that an anti-β-amyloid (Aβ) drug candidate affects both Aβ metabolism and plaque load as well as downstream pathogenic mechanisms.; Objective: To […]

Galasko, Douglas R, Peskind, Elaine, Clark, Christopher M., Quinn, Joseph F., Ringman, John M., Jicha, Gregory A., Cotman, Carl, Cottrell, Barbara, Montine, Thomas J., Thomas, Ronald G., Aisen, Paul

Objective: To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers.; Design: Double-blind, placebo-controlled clinical trial.; Setting: Academic medical centers.; Participants: Subjects with mild to moderate Alzheimer disease.; Intervention: Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C […]

Endres, Kristina, Fahrenholz, Falk, Lotz, Johannes, Hiemke, Christoph, Teipel, Stefan, Lieb, Klaus, Tüscher, Oliver, Fellgiebel, Andreas

Objective: We investigated induction of α-secretase A disintegrin and metalloprotease 10 (ADAM10) by the synthetic retinoid acitretin (Neotigason; Actavis, München-Riem, Germany) in patients with mild to moderate Alzheimer disease (AD) via measurement of CSF content of α-secretase-derived amyloid precursor protein (APPs-α).; Methods: Twenty-one patients clinically diagnosed with mild to moderate AD received acitretin (30 mg […]

Siemers, Eric R., Friedrich, Stuart, Dean, Robert A., Gonzales, Celedon R., Farlow, Martin R., Paul, Steven M., Demattos, Ronald B.

Objectives: Active and passive immunization strategies have been suggested as possible options for the treatment of Alzheimer disease (AD). LY2062430 (solanezumab) is a humanized monoclonal antibody being studied as a putative disease-modifying treatment of AD.; Methods: Patients with mild to moderate AD were screened and selected for inclusion. Initial screening was performed for 54 subjects, […]

Hampel, Harald, Ewers, Michael, Bürger, Katharina, Annas, Peter, Mörtberg, Anette, Bogstedt, Anna, Frölich, Lutz, Schröder, Johannes, Schönknecht, Peter, Riepe, Matthias W., Kraft, Inga, Gasser, Thomas, Leyhe, Thomas, Möller, Hans-Jürgen, Kurz, Alexander, Basun, Hans

Objective: Lithium, a first-line drug for the treatment of bipolar depression, has recently been shown to regulate glycogen synthase kinase-3 (GSK-3), a kinase that is involved in the phosphorylation of the tau protein. Since hyperphosphorylation of tau is a core pathological feature in Alzheimer’s disease, lithium-induced inhibition of GSK-3 activity may have therapeutic effects in […]