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ObjectiveTo test the hypothesis that ApoE isoforms affect mitochondrial structure and function that are related to cognitive impairment in Alzheimer disease (AD), we systematically investigated the effects of ApoE isoforms on mitochondrial biogenesis and dynamics, oxidative stress, synapses, and cognitive performance in AD.MethodsWe obtained postmortem human brain tissues and measured proteins that are responsible for mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1α [PGC-1α] and sirtuin 3 [SIRT3]), for mitochondrial dynamics (mitofusin 1 [MFN1], mitofusin 2 [MFN2], and dynamin-like protein 1 [DLP1]), for oxidative stress (superoxide dismutase 2 [SOD2] and forkhead-box protein O3a [Foxo3a]), and for synapses (postsynaptic density protein 95 [PSD95] and synapsin1 [Syn1]). A total of 46 cases were enrolled, including ApoE-ɛ4 carriers (n = 21) and noncarriers (n = 25).ResultsLevels of these proteins were compared between ApoE-ɛ4 carriers and noncarriers. ApoE-ɛ4 was associated with impaired mitochondrial structure and function, oxidative stress, and synaptic integrity in the human brain. Correlation analysis revealed that mitochondrial proteins and the synaptic protein were strongly associated with cognitive performance.ConclusionApoE isoforms influence mitochondrial structure and function, which likely leads to alteration in oxidative stress, synapses, and cognitive function. These mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.

Objective: To investigate brain β-amyloid binding in subjects with Down syndrome (DS) using [ 18 F]florbetaben PET imaging. Methods: Thirty-nine subjects with DS (46.3 ± 4.7 years) were assessed with [ 18 F]florbetaben PET imaging. Three blinded independent readers assessed the scans to provide a visual analysis. The primary quantitative imaging outcome was a standardized uptake value ratio (SUVR) obtained for 6 brain regions. Cognitive status was evaluated using the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID). Results: [ 18 F]Florbetaben uptake was correlated with age ( p R 2 = 0.39); 90% of scans in subjects with DS aged 50 years or older (SUVR = 1.62 ± 0.26), 53% in those aged 45 to 49 years (SUVR = 1.43 ± 0.16), and 7% in those aged 40 to 45 years (SUVR = 1.27 ± 0.11) were visually assessed as positive. Visual and quantitative assessments were highly related (χ 2 = 11.3823, p = 0.0007; Cohen κ = 0.58). Only 2 of 34 participants were considered to have dementia by the DSQIID. Conclusions: Brain β-amyloid binding, as measured by [ 18 F]florbetaben, increases with age in DS. Subjects with DS who have no evidence of dementia demonstrate brain β-amyloid binding in vivo, suggesting that [ 18 F]florbetaben PET imaging may detect β-amyloid in this at-risk population.

Objective To examine safety, tolerability, and efficacy of PF-04494700, an inhibitor of the receptor for advanced glycation end products (RAGE), in mild to moderate Alzheimer disease (AD). Methods Double-blind, placebo-controlled trial at 40 academic centers (United States). Subjects with AD and Mini-Mental State Examination score 14-26 were randomized to PF-04494700 60 mg/day × 6 days, then 20 mg daily (high dose); 15 mg/day × 6 days, then 5 mg daily (low dose); or placebo, for 18 months. Clinical and laboratory measures were used to evaluate safety and tolerability. The primary efficacy measure was the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog). Secondary measures assessed clinical stage, function, behavior, MRI, and CSF biomarkers. Results A total of 399 subjects were randomized. In a prespecified interim analysis, when 50% of subjects had completed the 6-month visit, the high dose was associated with confusion, falls, and greater ADAS-cog decline and was discontinued. A second prespecified analysis compared low-dose and placebo groups for futility and safety approximately 12 months after all subjects were randomized. This analysis met criteria for futility, and treatment was discontinued. There were no safety concerns in the low-dose group. Analyses including post-futility data showed decreased decline on the ADAS-cog in the low-dose group at month 18. Other clinical and biomarker measures showed no differences between low-dose treatment and placebo. Conclusions PF-04494700 at 20 mg/d was associated with increased adverse events and cognitive decline. At 5 mg/d, PF-04494700 had a good safety profile. A potential benefit for this low dose on the ADAS-cog is not conclusive, because of high dropout and discontinuation rates subsequent to the interim analyses. Classification of evidence This study provides Class I evidence that in patients with AD high-dose PF-04494700 increased cognitive decline at 6 months and Class IV evidence that low-dose PF-04494700 slowed cognitive decline at 18 months.

Objective To assess health care utilization and associated costs among patients with Alzheimer disease (AD), with and without dysphagia. Methods MarketScan Commercial and Medicare databases were analyzed. Patients with a diagnosis of AD with and without dysphagia between October 2006 and September 2010 were included. Acetylcholinesterase inhibitor usage, the number of outpatient and emergency room (ER) visits and hospitalizations, and associated health care costs were assessed. All variables were measured 1 year after the initial diagnosis of AD at the patient level. Patients with dysphagia were matched to patients without dysphagia using propensity score-matching (PSM) methods. Regression models were conducted to compare utilization and costs between the 2 groups. Results A total of 485 patients with dysphagia and 8492 patients without dysphagia were included. Before matching, patients with dysphagia were older (81.1 vs. 79.8 y), and had higher Charlson Comorbidity Index scores (2.4 vs. 1.7). After matching, all baseline covariates were not statistically different between the 2 groups. Multivariate regression results showed that patients with dysphagia had a higher likelihood of all-cause hospitalizations [odds ratio (OR)=2.26, 95% confidence interval (CI)=1.70-2.99, P=0.001] and all-cause ER visits (OR=1.45, 95% CI=1.12-1.87, P=0.007) compared with patients without dysphagia; they also had a higher likelihood for AD-related hospitalizations and ER visits. The difference in all-cause total health care, ER, and hospitalization costs between patients with and without dysphagia were $3620 (95% CI=$2863-$4375), $258 (95% CI=$241-$274), and $3547 (95% CI=$3325-$3770), respectively. Conclusions This study suggests that patients with AD and dysphagia have higher health care utilization and costs compared with patients without dysphagia.

Florbetapir F 18 PET can image amyloid-β (Aβ) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aβ pathology using florbetapir PET in subjects at risk for progressive cognitive decline.A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aβ+) or negative (Aβ-) for pathologic levels of β-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline.In both MCI and CN, baseline Aβ+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog (p0.01) and Clinical Dementia Rating-sum of boxes (CDR-SB) (p0.02). In MCI Aβ+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p0.01), CDR-SB (p0.03), a memory measure, DSS, and MMSE (p0.05). Aβ+ MCI tended to convert to AD dementia at a higher rate than Aβ- subjects (p0.10).Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.

Objective To evaluate the safety and tolerability of PF-04494700, an oral inhibitor of receptor for advanced glycation end products, in patients with mild-to-moderate dementia of the Alzheimer type. Methods Patients aged 50 years and older who met the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria for Alzheimer disease with an Mini-Mental State Examination (MMSE) score between 12 and 26 (inclusive) were randomized to 10 weeks of double-blind treatment with either a 10 mg "low dose" of PF-04494700 (after a 6-d loading dose of 30 mg/d), a 20 mg "high dose" of PF-04494700 (after a loading dose of 60 mg/d), or placebo. Safety measures included adverse events, laboratory tests, vital signs, and 12-lead electrocardiogram. Results Twenty-seven patients received PF-04494700 30/co mg (female: 63%; mean age: 74.6 y; mean MMSE: 21.1), 28 patients received PF-04494700 60/20 mg (female: 57%; mean age: 76.6 y; mean MMSE: 21.6), and 12 patients received placebo (female: 67%; mean age: 74.1 y; mean MMSE: 19.2). A higher proportion of patients completed 10 weeks of double-blind treatment on both the "low-dose" regimen of PF-04494700 (88.9%) and the "high-dose" regimen (85.7%) than patients who were on placebo (66.7%). Discontinuation owing to adverse events and incidence of severe adverse events, respectively, were lower in the "low-dose" regimen (7.4%, 11.1%) and the "high-dose" regimen (3.6%, 10.7%) compared with placebo (25.0%, 16.7%). There were no clinically meaningful differences in vital signs, laboratory test results, or mean electrocardiogram parameters in patients treated with PF-04494700. PF-04494700 had no consistent effect on plasma levels of β-amyloid, inflammatory biomarkers, or secondary cognitive outcomes. Conclusions Ten weeks of treatment with PF-04494700 was safe and well tolerated in patients with mild-to-moderate Alzheimer disease, indicating the feasibility of a larger long-term efficacy trial.

Bapineuzumab, a humanized anti-amyloid-beta (Abeta) monoclonal antibody for the potential treatment of Alzheimer disease (AD), was evaluated in a multiple ascending dose, safety, and efficacy study in mild to moderate AD.The study enrolled 234 patients, randomly assigned to IV bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 infusions, 13 weeks apart, with final assessments at week 78. The prespecified primary efficacy analysis in the modified intent-to-treat population assumed linear decline and compared treatment differences within dose cohorts on the Alzheimer's Disease Assessment Scale-Cognitive and Disability Assessment for Dementia. Exploratory analyses combined dose cohorts and did not assume a specific pattern of decline.No significant differences were found in the primary efficacy analysis. Exploratory analyses showed potential treatment differences (p0.05, unadjusted for multiple comparisons) on cognitive and functional endpoints in study "completers" and APOE epsilon4 noncarriers. Reversible vasogenic edema, detected on brain MRI in 12/124 (9.7%) bapineuzumab-treated patients, was more frequent in higher dose groups and APOE epsilon4 carriers. Six vasogenic edema patients were asymptomatic; 6 experienced transient symptoms.Primary efficacy outcomes in this phase 2 trial were not significant. Potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE epsilon4 carrier status.Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.

Objective To evaluate the efficacy and safety of naproxen and celecoxib for the primary prevention of Alzheimer disease (AD). Methods Randomized, placebo-controlled, double-masked clinical trial conducted at six US dementia research clinics. Volunteers aged 70+ years, with cognitive screening scores above designated cut-offs and a family history of AD, were randomly assigned to celecoxib 200 mg BID, naproxen sodium 220 mg BID, or placebo. Enrollment began in early 2001. The main outcome measure was diagnosis of AD after randomization. Results On December 17, 2004, treatments were suspended. Events while on treatment yielded hazard ratios vs placebo of 1.99 (95% CI 0.80 to 4.97; p = 0.14) for celecoxib and 2.35 (0.95 to 5.77; p = 0.06) for naproxen. Imperfect screening measures led to enrollment of 7 individuals with dementia and 46 others with milder cognitive syndromes. Their (prevalent) illness was detected at enrollment and diagnosed within 6 months following randomization. Secondary analyses that excluded the 7 cases of prevalent dementia showed increased hazard ratios for AD with both treatments. Neither treatment produced a notable effect on the incidence of milder cognitive syndromes. Conclusions These results do not support the hypothesis that celecoxib or naproxen prevent Alzheimer dementia, at least within the early years after initiation of treatment. Masked long-term follow-up of these participants will be essential.

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

Subjects with Parkinson disease (PD) frequently develop dementia with greater than one-third meeting neuropathologic diagnostic criteria for Alzheimer disease (AD). The objective is to identify clinical and neuropathologic differences between Parkinson disease with dementia (PDD) subjects, with and without coexistent AD pathology. Neuropathologic examination was available on subjects diagnosed by clinicopathologic criteria with PDD ― AD (N = 23) and PDD + AD (N = 28). A small subset of subjects with PDD ― AD and PDD + AD had received at least 1 standardized neuropsychologic assessment. PDD + AD subjects were significantly older at age of PD onset and death, progressed to onset of dementia in less time, and had a shorter duration of PD symptoms before the onset of dementia. Education, responsiveness of L-dopa and dopaminergic medications, presence of cognitive fluctuations and hallucinations, and mean Mini-Mental State Examination, Global Deterioration Scale, Functional Assessment Staging, and Unified Parkinson Disease Rating Scale scores did not differ significantly between the 2 groups. The PDD+AD group had significantly greater total plaques, neuritic plaques, total tangles, and Braak stages compared with PDD ― AD. This study suggests that it is difficult to distinguish PDD + AD and PDD ― AD on the basis of movement, clinical, and neuropsychologic assessment. PDD ― AD and PDD + AD have similar degrees of dementia and approximately half of PDD subjects have enough AD pathology to attain a neuropathologic diagnosis of AD. PDD can develop in the absence of significant Alzheimer pathology.

Objective: We tested the hypothesis that the apolipoprotein E ϵ4 (apoE4) allele is associated with an increased proportion of vascular-related mortality in Alzheimer's disease (AD).Background: ApoE4 is associated with an increased risk of developing AD, with an earlier onset, and may predispose to vascular dementia as well. In the general population, apoE4 has been associated with increased coronary artery disease and shorter lifespan. There is a paucity of data regarding the effect of the apolipoprotein E (apoE) genotype upon the contributing causes of death in AD.Methods: Death certificates of 114 AD cases were reviewed blind to apoE genotype. Deaths due to ischemic heart disease (IHD), cerebrovascular disease (CVD), vascular disease (either IHD or CVD), pneumonia, and other causes were analyzed as a function of apoE genotype. Logistic regression analyses were employed to control for age and gender effects.Results: The likelihood of vascular disease contributing to death increased in association with the ϵ4 allele (29% in cases without an ϵ4 allele, 43% in cases with one ϵ4 allele, 53% in ϵ4/4 homozygous cases;p = 0.035 after corrections for age and gender). This increase appeared largely due to an increase in ischemic heart disease, which was reported more frequently on death certificates of cases with one or moreϵ4 allele (adjusted odds ratio [OR] = 1.85 per ϵ4 allele;p < 0.05). There were nonsignificant trends for apoE4 to be associated with increased mortality related to cerebrovascular disease (OR = 1.45) and decreased mortality related to pneumonia (OR = 0.77) and AD itself(OR = 0.72). The ϵ4/4 cases had significantly earlier age of onset (mean= 64.5 yr), earlier death, and longer duration of disease (mean = 10.1 yr). Cases with one or more ϵ4 allele tended to have lower mean MMSE scores prior to death (6.6 versus 9.5) and were more often female (54% versus 45%).Conclusions: The apoE4 allele appears to increase the risk of vascular and ischemic heart disease-related death in patients with AD.

Because epidemiologic and in vitro evidence conflict, the authors studied the association between smoking and Alzheimer disease (AD) in 46 never, 47 former, and 15 active smokers with AD followed to autopsy. Disease parameters were examined by smoking status and amount smoked in bivariate tests and in multivariate models controlling for age, sex, education, and APOE status. Smoking status was not associated with cognitive or neuropathologic measures. However, active smokers were significantly younger at death and higher levels of smoking were associated with shorter disease duration.

Although consensus is rare in the Alzheimer disease (AD) research community, there is widespread agreement that the development of AD prevention strategies is of paramount importance. However, primary prevention trials relying on clinical outcome measures are exceedingly time and labor-intensive, requiring thousands of subjects followed over several years. One approach to accelerating the process is to validate surrogate markers of AD pathology for use in prevention studies. Three surrogate markers, namely CSF total tau, phosphorylated tau, and the lipid peroxidation product F2-isoprostanes, have been identified and validated as markers that are elevated in CSF in established AD,1 while CSF beta amyloid (Aβ)1-42 is lower in established AD compared to control subjects.1 The sensitivity of these CSF markers for detecting presymptomatic pathologic changes, however, has not been established. The utility of plasma levels of these biomarkers is less clear. Tau and p-tau are not measurable in plasma, while Aβ and isoprostanes are detectable in picomolar concentrations. Reports on the ability of systemic isoprostanes to distinguish AD from control subjects are not consistent. …

In this issue of Neurology ®, two independent reports1,2 once again confirm the saliency of the apolipoprotein epsilon 4 (APOE4) allele as a risk factor for Alzheimer disease (AD) or dementia. However, these studies go on to evaluate how APOE4 may be influenced by two other well-known AD/dementia risk factors, one of which, stroke, has been suggested to increase dementia risk,3 and one of which, nonsteroidal anti-inflammatory drug (NSAID) use, has been suggested to decrease AD risk.4 In a relatively large cohort, Szekely et al.1 show that the putative AD protective effects of prior NSAID exposure may owe almost exclusively to decreased risk in APOE4 carriers, with little to no reduction of the ORs for AD among NSAID-using, non-APOE4 subjects. This finding confirms earlier epidemiologic work by Hayden et al.,5 who also observed a significant AD protective effect of NSAIDs that was most notable in APOE4 subjects. Collectively, these studies could go far to explaining several paradoxes surrounding the now voluminous literature on inflammation and AD. The AD cortex (and its embedded vasculature) are clearly subject to chronic, innate inflammatory responses,6 yet AD treatment trials with NSAIDs have been equivocal at best.7 Perhaps beneficial effects in APOE4 subjects have been masked by an absence of benefit in non-APOE4 carriers—a possibility given that only one previous AD/NSAID treatment trial8 included APOE status as a covariate. …