The annual rate of change in cognitive performance on each test was calculated using linear mixed models. Overall differences in baseline (year 1) and annual rates of change were compared across all groups, followed by pairwise group comparisons. Neuropathologic assessment At autopsy, the right hemibrain was coronally sliced and frozen, and the whole left hemibrain was fixed in 10% buffered formaldehyde for at least 2 weeks and subsequently sectioned in the coronal plane. Routine diagnostic sections were obtained from the middle frontal Inhibitors,research,lifescience,medical gyrus (MFG), the superior and middle temporal gyri (SMTG),

the inferior parietal (IP) lobule, the primary visual cortex, the anterior cingulate, the amygdala, the hippocampus

and entorhinal cortex, basal ganglia and basal forebrain, the thalamus, midbrain including the substantia nigra, pons, medulla, spinal cord, and cerebellum. Tissues were processed, embedded in paraffin, cut at 10 μm, and stained with Inhibitors,research,lifescience,medical hematoxilyn and eosin and with silver Hirano method (Yamamoto and Hirano 1986). Lewy body (LB) pathology was assessed in the brain stem and anterior cingulate cortex with alpha-synuclein immunohistochemistry (Synuclein 1 Transduction Laboratories, Palo Alto, CA, Inhibitors,research,lifescience,medical USA; dilution, 1:500). Silver stained Inhibitors,research,lifescience,medical sections were used in the standard assessment of AD pathology according to CERAD guidelines (Mirra et al. 1993). NP density was determined in the MFG, SMTG, and IP lobule and a CERAD age-related plaque score was assigned: 0 = none, A = sparse, B = moderate, C = frequent (Mirra et al. 1993). In combination with the clinical data, a pathological diagnosis Inhibitors,research,lifescience,medical of normal with respect to AD, possible AD, probable AD, or definite AD was BIO GSK-3 molecular weight rendered according to CERAD guidelines. As an additional

approach to assessing the severity of neurodegeneration, the distribution of NFTs was assessed and graded on a scale of 0–VI according to Braak (Braak and Braak 1991). As an adjunct to the standard means of assessing and diagnosing AD, stereologic analysis was performed Oxalosuccinic acid using 10 μm sections of the MFG, middle temporal gyrus (MTG), IP, and precuneus (PreCu) were stained with an antibody for Aβ-amyloid (6E10, Covance, Emeryville, CA, USA, dilution 1:500) and phosphorylated tau (PHF-1 antibody; gift of Dr. P. Davies, dilution, 1:100). Stereological measurements were performed using a Zeiss light microscope equipped with a 100´, NA 1.30, oil Plan neofluor ∞/0.10 objective, and interfaced with a Stereo-Investigator system (MBF bioscience, Williston, VT, USA). The fractional area of immunoreactivity was measured utilizing the area fraction fractionator probe.