Eric Siemers

Introduction: Effectiveness of Alzheimer's disease (AD) treatments is commonly evaluated with coprimary outcomes; cognition with function to ensure clinical meaningfulness of a cognitive effect.Methods: We reviewed the literature for functional outcomes in mild AD or mild cognitive impairment (MCI) patients (distinct from combined mild‐moderate/severe AD) treated with approved AD drugs. Cognitive and functional treatment differences in mild AD patients in solanezumab EXPEDITION/EXPEDITION2 studies were compared across time.Results: Seven publications provided MCI/mild AD functional outcomes, one of which reported a significant functional treatment effect. Secondary analyses of EXPEDITION studies suggested a smaller functional effect of solanezumab relative to cognition. An increasing effect of solanezumab over 18 months was shown for cognition and function.Discussion: Function as the sole measure to demonstrate clinical meaningfulness of cognitive effects in mild AD may have limitations. For disease‐modifying treatments, point differences on cognitive and functional scales should be qualified with duration of treatment.

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. Patients with mild to moderate AD were screened and selected for inclusion. Initial screening was performed for 54 subjects, and 29 of these underwent additional screening; after this second screening, a total of 19 subjects were included. Single doses of solanezumab using 0.5, 1.5, 4.0, and 10.0 mg/kg were administered. Safety assessments included gadolinium-enhanced magnetic resonance imaging of the brain and cerebrospinal fluid (CSF) analyses at baseline and 21 days after dosing. Plasma and CSF concentrations of solanezumab and amyloid β (Aβ) and cognitive evaluations were obtained. Administration of solanezumab was generally well tolerated except that mild self-limited symptoms consistent with infusion reactions occurred for 2 of 4 subjects given 10 mg/kg. No evidence of meningoencephalitis, microhemorrhage, or vasogenic edema was present based on magnetic resonance image and CSF analyses. A substantial dose-dependent increase in total (bound plus unbound) Aβ was demonstrated in plasma; CSF total Aβ also increased. No changes in cognitive scores occurred. A single dose of solanezumab was generally well tolerated, although infusion reactions similar to those seen with administration of other proteins may occur with higher doses. A dose-dependent change in plasma and CSF Aβ was observed, although changes in cognitive scores were not noted. Further studies of solanezumab for the treatment of AD are warranted.

Amyloid-beta (Abeta) peptides, and total and phosphorylated tau are potential biomarkers for use in the development of treatments for Alzheimer's disease. Abeta(1-41) forms extracellular amyloid plaques, while tau and phospho-tau form intracellular neurofibrillary tangles in the brains of Alzheimer's disease patients. Plasma and cerebrospinal fluid concentrations of Abeta decreased following the clinical administration of gamma-secretase inhibitors and increased following the clinical administration of an anti-Abeta antibody. Therapies targeting Abeta decreased tau and phospho-tau concentrations in the cerebrospinal fluid. These biochemical biomarkers appear to be useful to establish therapeutic dosing for Phase III trials. Pivotal registration trials that rely on clinical measures as primary end points can utilize biochemical biomarkers as secondary outcomes indirectly measuring Alzheimer's disease pathology.

LY450139 dihydrate, a γ-secretase inhibitor, was studied in a randomized, controlled trial of 70 patients with Alzheimer disease. Subjects were given 30 mg for 1 week followed by 40 mg for 5 weeks. Treatment was well tolerated. Aβ_1-40 in plasma decreased by 38.2%; in CSF, Aβ_1-40 decreased by 4.42 ± 9.55% (p = not significant). Higher drug doses may result in additional decreases in plasma Aβ concentrations and a measurable decrease in CSF Aβ.

Biomarkers are likely to be important in the study of Alzheimer disease (AD) for a variety of reasons. A clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in about 10% to 15% of cases, and biomarkers might improve the accuracy of diagnosis. Importantly for the development of putative disease-modifying drugs for Alzheimer disease, biomarkers might also serve as indirect measures of disease severity. When used in this way, sample sizes of clinical trials might be reduced, and a change in biomarker could be considered supporting evidence of disease modification. This review summarizes a meeting of the Alzheimer's Association's Research Roundtable, during which existing and emerging biomarkers for AD were evaluated. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or ligands binding to amyloid plaque are discussed. Additionally, biochemical biomarkers in blood or cerebrospinal fluid are assessed. Currently appropriate uses of biomarkers in the study of Alzheimer disease, and areas where additional work is needed, are discussed.