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1.  Detecting When “Quality of Life” Has Been “Enhanced”: Estimating Change in Quality of Life Ratings 
Open journal of philosophy  2013;3(4A):24-31.
To demonstrate challenges in the estimation of change in quality of life (QOL).
Data were taken from a completed clinical trial with negative results. Responses to 13 QOL items were obtained 12 months apart from 258 persons with Alzheimer’s disease (AD) participating in a randomized, placebo-controlled clinical trial with two treatment arms. Two analyses to estimate whether “change” in QOL occurred over 12 months are described. A simple difference (later - earlier) was calculated from total scores (standard approach). A Qualified Change algorithm (novel approach) was applied to each item: differences in ratings were classified as either: improved, worsened, stayed poor, or stayed “positive” (fair, good, excellent). The strengths of evidence supporting a claim that “QOL changed”, derived from the two analyses, were compared by considering plausible alternative explanations for, and interpretations of, results obtained under each approach.
Total score approach: QOL total scores decreased, on average, in the two treatment (both −1.0, p < 0.05), but not the placebo (=−0.59, p > 0.3) groups. Qualified change approach: Roughly 60% of all change in QOL items was worsening in every arm; 17% - 42% of all subjects experienced change in each item.
Totalling the subjective QOL item ratings collapses over items, and suggests a potentially misleading “overall” level of change (or no change, as in the placebo arm). Leaving the items as individual components of “quality” of life they were intended to capture, and qualifying the direction and amount of change in each, suggests that at least 17% of any group experienced change on every item, with 60% of all observed change being worsening.
Summarizing QOL item ratings as a total “score” collapses over the face-valid, multi-dimensional components of the construct “quality of life”. Qualified Change provides robust evidence of changes to QOL or “enhancements of” life quality.
PMCID: PMC4514524  PMID: 26213645
Longitudinal Analysis; Statistical Method; Scale Type; Data Interpretation
2.  Comparing recruitment, retention, and safety reporting among geographic regions in multinational Alzheimer’s disease clinical trials 
Most Alzheimer’s disease (AD) clinical trials enroll participants multinationally. Yet, few data exist to guide investigators and sponsors regarding the types of patients enrolled in these studies and whether participant characteristics vary by region.
We used data derived from four multinational phase III trials in mild to moderate AD to examine whether regional differences exist with regard to participant demographics, safety reporting, and baseline scores on the Mini Mental State Examination (MMSE), the 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-cog11), the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL), and the Neuropsychiatric Inventory (NPI). We assigned 31 participating nations to 7 geographic regions: North America, South America/Mexico, Western Europe/Israel, Eastern Europe/Russia, Australia/South Africa, Asia, and Japan.
North America, Western Europe/Israel, and Australia/South Africa enrolled similar proportions of men, apolipoprotein E ε4 carriers, and participants with spouse study partners, whereas Asia, Eastern Europe/Russia, and South America/Mexico had lower proportions for these variables. North America and South America/Mexico enrolled older subjects, whereas Asia and South America/Mexico enrolled less-educated participants than the remaining regions. Approved AD therapy use differed among regions (range: 73% to 92%) and was highest in North America, Western Europe/Israel, and Japan. Dual therapy was most frequent in North America (48%). On the MMSE, North America, Western Europe/Israel, Japan, and Australia/South Africa had higher (better) scores, and Asia, South America/Mexico, and Eastern Europe/Russia had lower scores. Eastern Europe/Russia had more impaired ADAS-cog11 scores than all other regions. Eastern Europe/Russia and South America/Mexico had more impaired scores for the ADCS-ADL and the CDR-SB. Mean scores for the CDR-SB in Asia were milder than all regions except Japan. NPI scores were lower in Asia and Japan than in all other regions. Participants in North America and Western Europe/Israel reported more adverse events than those in Eastern Europe/Russia and Japan.
These findings suggest that trial populations differ across geographic regions on most baseline characteristics and that multinational enrollment is associated with sample heterogeneity. The data provide initial guidance with regard to the regional differences that contribute to this heterogeneity and are important to consider when planning global trials.
PMCID: PMC4481112  PMID: 26120368
3.  Alzheimer’s disease progression by geographical region in a clinical trial setting 
To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer’s disease (AD) studies. Geographic regions vary on many dimensions that may affect disease progression or its measurement. To aid researchers designing and implementing Phase 3 AD trials, we assessed disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology.
Four similarly-designed 76 to 80 week, randomized, double-blind placebo-controlled trials with nearly identical entry criteria enrolled patients aged ≥55 years with mild or moderate NINCDS/ADRDA probable AD. Descriptive analyses were performed for observed mean score and observed mean change in score from baseline at each scheduled visit. Data included in the analyses were pooled from the intent-to-treat placebo-assigned overall (mild and moderate) AD dementia populations from all four studies. Disease progression was assessed as change from baseline for each of 5 scales - the AD Assessment Scale-cognitive subscale (ADAS-cog11), the AD Cooperative Study- Activities of Daily Living Scale (ADCS-ADL), Mini-Mental State Examination (MMSE), the Clinical Dementia Rating scored by the sum of boxes method (CDR-SB), and the Neuropsychiatric Inventory (NPI).
Regions were heterogeneous at baseline. At baseline, disease severity as measured by ADAS-cog11, ADCS-ADL, and CDR-SB was numerically worse for Eastern Europe/Russia compared with other regions. Of all regional populations, Eastern Europe/Russia showed the greatest cognitive and functional decline from baseline; Japan, Asia and/or S. America/Mexico showed the least cognitive and functional decline.
These data suggest that in multi-national clinical trials, AD progression or its measurement may differ across geographic regions; this may be in part due to heterogeneity across populations at baseline. The observed differences in AD progression between outcome measures across geographic regions may generalize to 'real-world' clinic populations, where heterogeneity is the norm.
Trial registrations NCT00594568 – IDENTITY. Registered 11 January 2008. NCT00762411 – IDENTITY2. Registered 26 September 2008 NCT00905372 – EXPEDITION. Registered 18 May 2009 NCT00904683 – EXPEDITION2. Registered 18 May 2009
PMCID: PMC4481070  PMID: 26120369
4.  Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer’s disease 
The negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer’s disease (AD) included a number of biomarkers of the disease as well as safety outcomes. We analyzed these data to explore relationships between drug exposure and pharmacodynamic effects and to examine the correlations among outcome measures.
The study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a placebo administered for 18 months to individuals with mild to moderate AD. Changes in measures of central and peripheral drug activity were compared between the three treatment groups using one-way analysis of variance. The relationship between changes in each of the outcome measures and measures of drug exposure and peripheral pharmacodynamic effect were assessed using Spearman’s correlation coefficient.
Assignment to the active treatment arms was associated with reduction in plasma amyloid-β (Aβ) peptides, increase in ventricular volume, decrease in cerebrospinal fluid phosphorylated tau (p-tau) and several other laboratory measures and adverse event categories. Within the active arms, exposure to drug, as indicated by area under the concentration curve (AUC) of blood concentration, was associated with reduction in plasma Aβ peptides and a subset of laboratory changes and adverse event rates. Ventricular volume increase, right hippocampal volume loss and gastrointestinal symptoms were related to change in plasma Aβ peptide but not AUC, supporting a link to inhibition of γ-secretase cleavage of the amyloid precursor protein. Cognitive decline correlated with ventricular expansion and reduction in p-tau.
These findings may inform future studies of drugs targeting secretases involved in Aβ generation.
Trial registration Identifier: NCT00594568. Registered 11 January 2008.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-015-0121-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4461930  PMID: 26064192
5.  The Preclinical Alzheimer Cognitive Composite 
JAMA neurology  2014;71(8):961-970.
As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes.
To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study).
With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies.
For the 2 studies that collected data on Aβ levels (ADNI and AIBL), we estimate decline in a preclinical AD “Aβ-positive” placebo group and compare them with an “Aβ-negative” group. For the study that did not include data on Aβ levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-ɛ4 and by clinical progression.
In ADNI, Aβ-positive participants showed more decline than did Aβ-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, −1.239 [0.522] [95% CI, −2.263 to −0.215]; P = .02). In AIBL, the mean (SE) difference is significant at both 18 months (−1.009 [0.406] [95% CI, −1.805 to −0.213]; P = .01) and 36 months (−1.404 [0.452] [95% CI, −2.290 to −0.519]; P = .002). In the ADCS-PI study, APOE-ɛ4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, −0.742 [0.294] [95% CI, −1.318 to −0.165]; P = .01) and 36 months (−1.531 [0.469] [95% CI, −2.450 to −0.612]; P = .001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, −4.471 [0.702] [95% CI, −5.848 to −3.094]; P < .001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% α level, we project 80% power to detect effects in the range of Δ = 0.467 to 0.733 on the ADCS-PACC.
Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials.
PMCID: PMC4439182  PMID: 24886908
6.  A simple method to rule out dementia with temporal orientation 
To explore the performance of a test of temporal orientation (TTO) comprising four items derived from the Mini-Mental State Examination over 4 years.
Responses were obtained from two large cohorts participating in longitudinal studies of aging in the United States (352 normal elderly, 98 persons with very mild probable or possible Alzheimer’s disease). Sensitivity, specificity, and predictive value (positive, PV+, negative, PV−) of the TTO were estimated for each of four annual visits.
When four correct answers were treated as “oriented to time” and 0 to 3 correct answers were treated as “not oriented to time,” sensitivity (to the presence of AD) ranged from 46.0% to 69.2% and PV+ ranged from 32.1% to 49.5%. Specificity (for normal cognition) decreased from 93.2% at the first visit to 81.3% at the fourth visit; TTO performed most reliably in terms of PV−, the probability of normal cognitive function given orientation to time (TTO = 4), which ranged from 92.8% to 95.4%.
Given the stability and strength of the predictive negative value of a dichotomized TTO over time, a TTO could contribute to monitoring normal cognitive functioning in longitudinal studies in which cognitive status is not the primary focus. Prospective validation of the TTO is warranted.
PMCID: PMC4420176  PMID: 19595914
Aged; Orientation; Dementia; Longitudinal; Epidemiologic methods
8.  Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease 
Neurology  2014;82(17):1536-1542.
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).
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.
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.
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.
PMCID: PMC4011464  PMID: 24696507
9.  Tracking early decline in cognitive function in older individuals at risk for Alzheimer's disease dementia: the Alzheimer's Disease Cooperative Study Cognitive Function Instrument 
JAMA neurology  2015;72(4):446-454.
Several large-scale Alzheimer's disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic.
To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline.
Design, Setting, and Participants
Longitudinal study over the course of 48 months at participating Alzheimer's Disease Cooperative Study (ADCS) sites. The study included 468 healthy older individuals (Clinical Dementia Rating Scale [CDR] Global = 0, above cut-off on modified Mini-Mental State Exam and Free and Cued Selective Reminding Test) (mean age= 79.4 years ±3.6). All subjects and their study partners completed the Self and Partner CFI annually. Subjects also underwent concurrent annual neuropsychological assessment and apolipoprotein E (APOE) genotyping.
Main outcomes and measures
Comparison of CFI scores between clinical progressors (Clinical Dementia Rating Scale [CDR] ≥ 0.5) and non-progressors (CDR remained = 0), as well as between APOE ε4 carriers and non-carriers were performed. Correlations of change between the CFI and neuropsychological performance were assessed longitudinally.
At 48 months, group differences between clinical progressors and non-progressors were significant for CFI Self, CFI Partner, and CFI Self+Partner total scores. At month 48, APOE ε4 carriers showed greater progression than non-carriers on CFI Partner and CFI Self+Partner scores. Both CFI Self and CFI Partner scores were associated with longitudinal cognitive decline, although findings suggest self report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment.
Conclusions and Relevance
Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, yet informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease.
PMCID: PMC4397164  PMID: 25706191
10.  Effects of traumatic brain injury and posttraumatic stress disorder on Alzheimer’s disease in veterans, using the Alzheimer’s Disease Neuroimaging Initiative 
Both traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are common problems resulting from military service, and both have been associated with increased risk of cognitive decline and dementia resulting from Alzheimer’s disease (AD) or other causes. This study aims to use imaging techniques and biomarker analysis to determine whether traumatic brain injury (TBI) and/or PTSD resulting from combat or other traumas increase the risk for AD and decrease cognitive reserve in Veteran subjects, after accounting for age. Using military and Department of Veterans Affairs records, 65 Vietnam War veterans with a history of moderate or severe TBI with or without PTSD, 65 with ongoing PTSD without TBI, and 65 control subjects are being enrolled in this study at 19 sites. The study aims to select subject groups that are comparable in age, gender, ethnicity, and education. Subjects with mild cognitive impairment (MCI) or dementia are being excluded. However, a new study just beginning, and similar in size, will study subjects with TBI, subjects with PTSD, and control subjects with MCI. Baseline measurements of cognition, function, blood, and cerebrospinal fluid bio-markers; magnetic resonance images (structural, diffusion tensor, and resting state blood-level oxygen dependent (BOLD) functional magnetic resonance imaging); and amyloid positron emission tomographic (PET) images with florbetapir are being obtained. One-year follow-up measurements will be collected for most of the baseline procedures, with the exception of the lumbar puncture, the PET imaging, and apolipoprotein E genotyping. To date, 19 subjects with TBI only, 46 with PTSD only, and 15 with TBI and PTSD have been recruited and referred to 13 clinics to undergo the study protocol. It is expected that cohorts will be fully recruited by October 2014. This study is a first step toward the design and statistical powering of an AD prevention trial using at-risk veterans as subjects, and provides the basis for a larger, more comprehensive study of dementia risk factors in veterans.
PMCID: PMC4392759  PMID: 24924673
Traumatic brain injury; Posttraumatic stress disorder; Alzheimer’s disease; Veterans; Neuroimaging
11.  One-trial 10-item free-recall performance in Taiwanese elderly and near-elderly: A potential screen for cognitive decline 
To explore a one-trial 1 0-item free-recall test as a potential dementia screening tool, we analyzed recall scores and individualized serial position effects in near-elderly (N = 2,336) and elderly (N = 2,371) participants in a population-based survey in Taiwan. Age and sex were significantly associated with recall score [younger> older(p < 0.001); men> women (p < 0.001)]; after controlling for gender and age group, weak association between recall and education was still observed. By contrast, serial position effects (SPEs), defined for each participant and analyzed aggregated over each age group, were not associated with education and tended not to be associated with sex. Primacy effects were observed in 67 to 80 percent, and recency effects were observed in 41 to 54 percent of respondents. Because SPEs were defined for each respondent, we could determine that loss of the primacy effect was associated with significantly larger losses in total recall score in elderly persons who had exhibited both SPEs at the first survey, as compared to those who maintained both SPEs at successive surveys (p < 0.01). Elderly subjects showed slight longitudinal decline infree recall. A one-trial10-itemfree-recall test demonstrated age-related cognitive decline in this Taiwanese population survey cohort; SPEs at the individual level may be useful markers for important cognitive change and warrant further study and benchmarking against valid and reliable tests of memory and cognitive decline.
PMCID: PMC4375550  PMID: 16136848
serial position effects; cognitive decline; primacy effect; dementia; education
12.  Advances in Alzheimer’s Disease Drug Development 
BMC Medicine  2015;13:62.
Alzheimer’s disease (AD) is the foremost cause of dementia worldwide. Clinically, AD manifests as progressive memory impairment followed by a gradual decline in other cognitive abilities leading to complete functional dependency. Recent biomarker studies indicate that AD is characterized by a long asymptomatic phase, with the development of pathology occurring at least a decade prior to the onset of any symptoms. Current FDA-approved treatments target neurotransmitter abnormalities associated with the disease but do not affect what is believed to be the underlying etiology. In this review, we briefly discuss the most recent therapeutic strategies being employed in AD clinical trials, as well the scientific rationale with which they have been developed.
PMCID: PMC4373002  PMID: 25857341
Alzheimer’s disease; Beta-amyloid; Clinical trials
13.  Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease 
To find the combination of candidate biomarkers and cognitive endpoints to maximize statistical power and minimize cost of clinical trials of healthy elders at risk for cognitive decline due to Alzheimer's disease.
Four-hundred and twelve cognitively normal participants were followed over 7 years. Nonlinear methods were used to estimate the longitudinal trajectories of several cognitive outcomes including delayed memory recall, executive function, processing speed, and several cognitive composites by subgroups selected on the basis of biomarkers, including APOE-ε4 allele carriers, cerebrospinal fluid biomarkers (Aβ42, total tau, and phosphorylated tau), and those with small hippocampi.
Derived cognitive composites combining Alzheimer's Disease Assessment Scale (ADAS)-cog scores with additional delayed memory recall and executive function components captured decline more robustly across biomarker groups than any measure of a single cognitive domain or ADAS-cog alone. Substantial increases in power resulted when including only participants positive for three or more biomarkers in simulations of clinical trials.
Clinical trial power may be improved by selecting participants on the basis of amyloid and neurodegeneration biomarkers and carefully tailoring primary cognitive endpoints to reflect the expected decline specific to these individuals.
PMCID: PMC4435707  PMID: 26000325
14.  Longitudinal plasma amyloid beta as a biomarker of Alzheimer’s disease 
Alzheimer’s disease (AD) affects more than twenty-five million people worldwide and is the most common form of dementia. Symptomatic treatments have been developed, but effective intervention to alter disease progression is needed. Targets have been identified for disease-modifying drugs, but the results of clinical trials have been disappointing. Peripheral biomarkers of disease state may improve clinical trial design and analysis, increasing the likelihood of successful drug development. Amyloid-related measures, presumably reflecting principal pathology of AD, are among the leading cerebrospinal fluid and neuroimaging biomarkers, and measurement of plasma levels of amyloid peptides has been the focus of much investigation. In this review, we discuss recent data on plasma β-amyloid (Aβ) and examine the issues that have arisen in establishing it as a reliable biomarker of AD.
PMCID: PMC4305447  PMID: 22354745
Alzheimer’s disease; Protein biomarker; Plasma amyloid
15.  Developing a national strategy to prevent dementia: Leon Thal Symposium 2009 
Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27–28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia. The deliberations of LTS'09 included presentations and reviews of different approaches (algorithms, biomarkers, or measures) for identifying asymptomatic individuals at elevated risk for AD who would be candidates for longitudinal or prevention studies. The key nested recommendations of LTS'09 included: (1) establishment of a National Database for Longitudinal Studies as a shared research core resource; (2) launch of a large collaborative study that will compare multiple screening approaches and biomarkers to determine the best method for identifying asymptomatic people at risk for AD; (3) initiation of a Global Database that extends the concept of the National Database for Longitudinal Studies for longitudinal studies beyond the United States; and (4) development of an educational campaign that will address public misconceptions about AD and promote healthy brain aging.
PMCID: PMC4298995  PMID: 20298968
Alzheimer's disease; Dementia; Mild cognitive impairment; Prevention; Biomarkers; Diagnosis; Screening; Clinical trials; MCI; Asymptomatic; Risk factors; Registry; Longitudinal studies; Database; PAD2020; Leon Thal Symposium; Treatment; Drug development; Health policy
16.  Symptom onset in autosomal dominant Alzheimer disease 
Neurology  2014;83(3):253-260.
To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD.
We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study.
We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10−16, r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex.
Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research.
PMCID: PMC4117367  PMID: 24928124
17.  Association of plasma and cortical beta-amyloid is modulated by APOE ε4 status 
APOE ε4’s role as a modulator of the relationship between soluble plasma beta-amyloid (Aβ) and fibrillar brain Aβ measured by Pittsburgh Compound-B positron emission tomography ([11C]PiB PET) has not been assessed.
Ninety-six Alzheimer’s Disease Neuroimaging Initiative participants with [11C]PiB scans and plasma Aβ1-40 and Aβ1-42 measurements at time of scan were included. Regional and voxel-wise analyses of [11C]PiB data were used to determine the influence of APOE ε4 on association of plasma Aβ1-40, Aβ1-42, and Aβ1-40/Aβ1-42 with [11C]PiB uptake.
In APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ1-40/Aβ1-42 and [11C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ1-40/Aβ1-42 improved the explained variance in [11C]PiB binding compared to using APOE and plasma Aβ1-40/Aβ1-42 as separate terms.
The results suggest that plasma Aβ is a potential Alzheimer’s disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.
PMCID: PMC3750076  PMID: 23541187
Alzheimer’s disease (AD); mild cognitive impairment (MCI); Alzheimer’s Disease Neuroimaging Initiative (ADNI); beta-amyloid (Aβ); plasma beta-amyloid; positron emission tomography (PET); Pittsburgh Compound-B ([11C]PiB); Apolipoprotein E (APOE)
18.  The Alzheimer's Disease Cooperative Study Prevention Instrument Project: Longitudinal Outcome of Behavioral Measures as Predictors of Cognitive Decline 
The Alzheimer's Disease Cooperative Study Prevention Instrument Project is a longitudinal study that recruited 644 cognitively healthy older subjects (aged between 75 and 93 years, 58% women) at baseline and evaluated their cognitive change over 4 years. The study was structured like a clinical trial to anticipate a prevention trial and to determine the performance of novel trial instruments in a longitudinal non-interventional trial framework. Behavioral symptoms were assessed at baseline.
The existence of participant-reported behavioral symptoms at baseline predicted conversion to Clinical Dementia Rating scale score ≥0.5 over the 4-year period.
The results imply that early anxiety and depression may be harbingers of future cognitive decline, and that patients exhibiting such symptoms, even in the absence of co-occurring cognitive symptoms, should be closely followed over time.
PMCID: PMC4307008  PMID: 25685141
Aging; Depression; Anxiety; Mild cognitive impairment; Alzheimer's disease
19.  Focal Hemosiderin Deposits and β-Amyloid Load in the ADNI Cohort 
Prevalence and risk factors for focal hemosiderin deposits are important considerations when planning amyloid–modifying trials for treatment and prevention of Alzheimer’s disease (AD).
Subjects were cognitively normal (n=171), early-mild cognitive impairment (MCI) (n=240), late-MCI (n=111) and AD (n=40) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Microhemorrhages and superficial siderosis were assessed at baseline and on all available MRIs at 3, 6 and 12 months. β-amyloid load was assessed with 18F-florbetapir PET.
Prevalence of superficial siderosis was 1% and prevalence of microhemorrhages was 25% increasing with age (p<0.001) and β-amyloid load (p<0.001). Topographic densities of microhemorrhages were highest in the occipital lobes and lowest in the deep/infratentorial regions. A greater number of microhemorrhages at baseline was associated with a greater annualized rate of additional microhemorrhages by last follow-up (rank correlation=0.49;P<0.001).
Focal hemosiderin deposits are relatively common in the ADNI cohort and are associated with β-amyloid load.
PMCID: PMC3770782  PMID: 23375568
ADNI; microhemorrhage; superficial siderosis; MRI; Amyloid; PET; Florbetapir; Alzheimer’s disease; mild cognitive impairment; early mild cognitive impairment
20.  Developing Dementia Prevention Trials: Baseline Report of the Home-Based Assessment Study 
This report describes the baseline experience of the multi-center, Home Based Assessment (HBA) study, designed to develop methods for dementia prevention trials using novel technologies for test administration and data collection. Non-demented individuals ≥ 75 years old were recruited and evaluated in-person using established clinical trial outcomes of cognition and function, and randomized to one of 3 assessment methodologies: 1) mail-in questionnaire/live telephone interviews (MIP); 2) automated telephone with interactive voice recognition (IVR); and 3) internet-based computer Kiosk (KIO). Brief versions of cognitive and non-cognitive outcomes, were adapted to each methodology and administered at baseline and repeatedly over a 4-year period. “Efficiency” measures assessed the time from screening to baseline, and staff time required for each methodology. 713 individuals signed consent and were screened; 640 met eligibility and were randomized to one of 3 assessment arms and 581 completed baseline. Drop out, time from screening to baseline and total staff time were highest among those assigned to KIO. However efficiency measures were driven by non-recurring start-up activities suggesting that differences may be mitigated over a long trial. Performance among HBA instruments collected via different technologies will be compared to established outcomes over this 4 year study.
PMCID: PMC3943465  PMID: 23151596
Alzheimer’s disease; clinical trials; in-home assessment; prevention studies
21.  APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study 
Molecular psychiatry  2013;19(3):351-357.
Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer’s disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir (18F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender, and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (rs429358, p = 5.5 × 10−14) and on chromosome 3 upstream of BCHE (rs509208, p = 2.7 × 10−8) in a region previously associated with serum butyrylcholinesterase activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB, and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. Butyrylcholinesterase has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of butyrylcholinesterase-modulating agents in the AD spectrum.
PMCID: PMC3661739  PMID: 23419831
Alzheimer’s disease (AD); amyloid; apolipoprotein E (APOE); butyrylcholinesterase (BCHE); florbetapir (AV-45); genome-wide association study (GWAS)
22.  The Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception 
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151–3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [18F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.
PMCID: PMC4108198  PMID: 23932184
Alzheimer's disease; Mild cognitive impairment; Amyloid; Tau; Biomarker
23.  Criteria for Mild Cognitive Impairment Due to Alzheimer’s Disease in the Community 
Annals of neurology  2013;74(2):199-208.
The newly proposed National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria for mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) suggest a combination of clinical features and biomarker measures, but their performance in the community is not known.
The Mayo Clinic Study of Aging (MCSA) is a population-based longitudinal study of non-demented subjects in Olmsted County, Minnesota. A sample of 154 MCI subjects from the MCSA was compared to a sample of 58 amnestic MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI 1) to assess the applicability of the criteria in both settings and to assess their outcomes.
In the MCSA, 14% and in ADNI 1 16% of subjects were biomarker negative. In addition, 14% of the MCSA and 12% of ADNI 1 subjects had evidence for amyloid deposition only, while 43% of MCSA and 55% of ADNI 1 subjects had evidence for amyloid deposition plus neurodegeneration (MRI atrophy, FDG PET hypometabolism or both). However, a considerable number of subjects had biomarkers inconsistent with the proposed AD model, e.g., 29% of MCSA subjects and 17% of the ADNI 1 subjects had evidence for neurodegeneration without amyloid deposition. These subjects may not be on an AD pathway. Neurodegeneration appears to be a key factor in predicting progression relative to amyloid deposition alone.
The NIA-AA criteria apply to most MCI subjects in both the community and clinical trials settings however, a sizeable proportion of subjects had conflicting biomarkers which may be very important and need to be explored.
PMCID: PMC3804562  PMID: 23686697
24.  Age and APOE genotype influence rate of cognitive decline in non-demented elderly 
Neuropsychology  2013;27(4):10.1037/a0032707.
This study examined the impact of age and apolipoprotein E (APOE) genotype on the rate of cognitive decline in non-demented elderly participants in a simulated Alzheimer’s disease (AD) primary prevention treatment trial carried out by the Alzheimer’s Disease Cooperative Study.
Cognitive tests were administered at baseline and at four subsequent annual evaluations to 417 non-demented participants (172 men, 245 women) between the ages of 74 and 93 (mean=79.13 ± 3.34). APOE genotyping was available for 286 of the participants.
Four-year decline was evident on measures of orientation, memory, executive function and language. Faster decline was evident in APOE ε4+ (a genetic risk factor for AD; n=73) than ε4− participants (n=213), even after controlling for education, gender, ethnicity, and baseline functional and cognitive abilities. This discrepancy increased with increasing age indicating an age X genotype interaction.
These results are consistent with population-based studies, and extend the findings to a carefully-screened sample that meets inclusion and exclusion criteria for an AD primary prevention trial. The interaction between age and APOE genotype on rate of decline suggests that preclinical disease may be over represented in olderε4+ individuals. Thus, APOE genotype and age should be considered in the design of AD primary prevention treatment trials.
PMCID: PMC3831285  PMID: 23876113
Cognitive decline; Apolipoprotein E; Aging
25.  The A4 Study: Stopping AD before Symptoms Begin? 
Science translational medicine  2014;6(228):228fs13.
A secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer’s disease dementia should provide insights into whether anti-amyloid therapy can delay cognitive decline.
PMCID: PMC4049292  PMID: 24648338

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