Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study.

IMPORTANCE: Age-associated changes in brain imaging and fluid biomarkers are characterized and compared in presenilin 1 (PSEN1)E280A mutation carriers and noncarriers from the world's largest known autosomal dominant Alzheimer disease (AD) kindred. OBJECTIVE: To characterize and compare age-associated changes in brain imaging and fluid biomarkers in PSEN1 E280A mutation carriers and noncarriers. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional measures of 18F-florbetapir positron emission tomography, 18F-fludeoxyglucose positron emission tomography, structural magnetic resonance imaging, cerebrospinal fluid (CSF), and plasma biomarkers of AD were assessed from 54 PSEN1 E280A kindred members (age range, 20-59 years). MAIN OUTCOMES AND MEASURES: We used brain mapping algorithms to compare regional cerebral metabolic rates for glucose and gray matter volumes in cognitively unimpaired mutation carriers and noncarriers. We used regression analyses to characterize associations between age and the mean cortical to pontine 18F-florbetapir standard uptake value ratios, precuneus cerebral metabolic rates for glucose, hippocampal gray matter volume, CSF Aß1-42, total tau and phosphorylated tau181, and plasma Aß measurements. Age at onset of progressive biomarker changes that distinguish carriers from noncarriers was estimated using best-fitting regression models. RESULTS: Compared with noncarriers, cognitively unimpaired mutation carriers had significantly lower precuneus cerebral metabolic rates for glucose, smaller hippocampal volume, lower CSF Aß1-42, higher CSF total tau and phosphorylated tau181, and higher plasma Aß1-42 measurements. Sequential changes in biomarkers were seen at age 20 years (95% CI, 14-24 years) for CSF Aß1-42, age 16 years (95% CI, 11-24 years) for the mean cortical 18F-florbetapir standard uptake value ratio, age 15 years (95% CI, 10-24 years) for precuneus cerebral metabolic rate for glucose, age 15 years (95% CI, 7-20 years) for CSF total tau, age 13 years (95% CI, 8-19 years) for phosphorylated tau181, and age 6 years (95% CI, 1-10 years) for hippocampal volume, with cognitive decline up to 6 years before the kindred's estimated median age of 44 years (95% CI, 43-45 years) at mild cognitive impairment diagnosis. No age-associated findings were seen in plasma Aß1-42 or Aß1-40. CONCLUSIONS AND RELEVANCE: This cross-sectional study provides additional information about the course of different AD biomarkers in the preclinical and clinical stages of autosomal dominant AD.

Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers.

OBJECTIVE: To identify a cognitive composite that is sensitive to tracking preclinical Alzheimer's disease decline to be used as a primary end point in treatment trials. METHOD: We capitalized on longitudinal data collected from 1995 to 2010 from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world's largest known early-onset autosomal dominant Alzheimer's disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimer's disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimer's Prevention Initiative's (API) preclinical Alzheimer's disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top-performing combinations, and representation of relevant cognitive domains. RESULTS: The optimal test combination included Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Recall, CERAD Boston Naming Test (high frequency items), Mini-Mental State Examination (MMSE) Orientation to Time, CERAD Constructional Praxis, and Raven's Progressive Matrices (Set A), with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR = 0.38) or the entire CERAD-Col battery (MSDR = 0.76). A sample size of 75 cognitively normal PSEN1 E280A mutation carriers aged 30 years and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, P = .05). CONCLUSIONS: We have identified a composite cognitive test score representing multiple cognitive domains that, compared to the most sensitive single test item, has improved power to track preclinical Alzheimer's disease decline in autosomal dominant Alzheimer's disease mutation carriers and to evaluate preclinical Alzheimer's disease treatments. This API composite cognitive test score will be used as the primary end point in the first API trial in cognitively unimpaired autosomal dominant Alzheimer's disease carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset Alzheimer's disease, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytic approaches.

Association between an Alzheimer's Disease-Related Index and APOE ε4 Gene Dose.

BACKGROUND: We introduced a hypometabolic convergence index (HCI) to characterize in a single measurement the extent to which a person's fluorodeoxyglucose positron emission tomogram (FDG PET) corresponds to that in Alzheimer's disease (AD). Apolipoprotein E ε4 (APOE ε4) gene dose is associated with three levels of risk for late-onset AD. We explored the association between gene dose and HCI in cognitively normal ε4 homozygotes, heterozygotes, and non-carriers. METHODS: An algorithm was used to characterize and compare AD-related HCIs in cognitively normal individuals, including 36 ε4 homozygotes, 46 heterozygotes, and 78 non-carriers. RESULTS: These three groups differed significantly in their HCIs (ANOVA, p = 0.004), and there was a significant association between HCIs and gene dose (linear trend, p = 0.001). CONCLUSIONS: The HCI is associated with three levels of genetic risk for late-onset AD. This supports the possibility of using a single FDG PET measurement to help in the preclinical detection and tracking of AD.

Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease.

OBJECTIVE: To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ε4 allele, reflecting 3 levels of risk for late-onset Alzheimer disease. DESIGN: Cross-sectional comparison of measurements of cerebral glucose metabolism using 18F-fluorodeoxyglucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal ε4 homozygotes, ε4 heterozygotes, and noncarriers. SETTING: Academic medical center. PARTICIPANTS: A total of 31 ε4 homozygotes, 42 ε4 heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level. MAIN OUTCOME MEASURES: The measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were characterized using a semiautomated algorithm and normalized for total intracranial volume. RESULTS: Although there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P = .60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P = .001). The APOE ε4 gene dose was significantly associated with posterior cingulate glucose metabolism (r = 0.29, P = .0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (P < .05, determined by use of pairwise Fisher z tests). CONCLUSIONS: Although our findings may depend in part on the analysis algorithms used, they suggest that a reduction in posterior cingulate glucose metabolism precedes a reduction in hippocampal volume or metabolism in cognitively normal persons at increased genetic risk for Alzheimer disease.

Memory training in the ACTIVE study: how much is needed and who benefits?

OBJECTIVE AND METHOD: Data from the memory training arm (n = 629) of the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial were examined to characterize change in memory performance through 5 years of follow-up as a function of memory training, booster training, adherence to training, and other characteristics. RESULTS: Latent growth model analyses revealed that memory training was associated with improved memory performance through Year 5 but that neither booster training nor training adherence significantly influenced this effect. Baseline age was associated with change in memory performance attributable to the passage of time alone (i.e., to aging). Higher education and better self-rated health were associated with greater change in memory performance after training. DISCUSSION: These findings confirm that memory training can aid in maintaining long-term improvements in memory performance. Booster training and adherence to training do not appear to attenuate rates of normal age-related memory decline.

Identification of mild cognitive impairment in ACTIVE: algorithmic classification and stability.

Rates of mild cognitive impairment (MCI) have varied substantially, depending on the criteria used and the samples surveyed. The present investigation used a psychometric algorithm for identifying MCI and its stability to determine if low cognitive functioning was related to poorer longitudinal outcomes. The Advanced Cognitive Training of Independent and Vital Elders (ACTIVE) study is a multi-site longitudinal investigation of long-term effects of cognitive training with older adults. ACTIVE exclusion criteria eliminated participants at highest risk for dementia (i.e., Mini-Mental State Examination < 23). Using composite normative for sample- and training-corrected psychometric data, 8.07% of the sample had amnestic impairment, while 25.09% had a non-amnestic impairment at baseline. Poorer baseline functional scores were observed in those with impairment at the first visit, including a higher rate of attrition, depressive symptoms, and self-reported physical functioning. Participants were then classified based upon the stability of their classification. Those who were stably impaired over the 5-year interval had the worst functional outcomes (e.g., Instrumental Activities of Daily Living performance), and inconsistency in classification over time also appeared to be associated increased risk. These findings suggest that there is prognostic value in assessing and tracking cognition to assist in identifying the critical baseline features associated with poorer outcomes.

Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study.

BACKGROUND: We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. METHODS: Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aß(1-42), total tau and phospho-tau(181) concentrations, and plasma Aß(1-42) concentrations and Aß(1-42):Aß(1-40) ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. FINDINGS: 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aß(1-42) concentrations (p=0·008) and plasma Aß(1-42) concentrations (p=0·01) than non-carriers. INTERPRETATION: Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aß(1-42) overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. FUNDING: Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.

Florbetapir PET analysis of amyloid-ß deposition in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional study.

BACKGROUND: Fibrillar amyloid-ß (Aß) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer's disease. By assessing the accumulation of Aß in people at risk of genetic forms of Alzheimer's disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of Aß deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease. METHODS: Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer's disease Colombian kindred aged 18-60 years were recruited from the Alzheimer's Prevention Initiative's registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer's Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions.was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar Aß deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar Aß deposition. FINDINGS: We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar Aß began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3-33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively. (18)F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3-40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions. INTERPRETATION: These findings contribute to the understanding of preclinical familial Alzheimer's disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer's disease. FUNDING: Avid Radiopharmaceuticals, Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.

Correlations between FDG PET glucose uptake-MRI gray matter volume scores and apolipoprotein E ε4 gene dose in cognitively normal adults: a cross-validation study using voxel-based multi-modal partial least squares.

We previously introduced a voxel-based, multi-modal application of the partial least square algorithm (MMPLS) to characterize the linkage between patterns in a person's complementary complex datasets without the need to correct for multiple regional comparisons. Here we used it to demonstrate a strong correlation between MMPLS scores to characterize the linkage between the covarying patterns of fluorodeoxyglucose positron emission tomography (FDG PET) measurements of regional glucose metabolism and magnetic resonance imaging (MRI) measurements of regional gray matter associated with apolipoprotein E (APOE) ε4 gene dose (i.e., three levels of genetic risk for late-onset Alzheimer's disease (AD)) in cognitively normal, late-middle-aged persons. Coregistered and spatially normalized FDG PET and MRI images from 70% of the subjects (27 ε4 homozygotes, 36 ε4 heterozygotes and 67 ε4 non-carriers) were used in a hypothesis-generating MMPLS analysis to characterize the covarying pattern of regional gray matter volume and cerebral glucose metabolism most strongly correlated with APOE-ε4 gene dose. Coregistered and spatially normalized FDG PET and MRI images from the remaining 30% of the subjects were used in a hypothesis-testing MMPLS analysis to generate FDG PET-MRI gray matter MMPLS scores blind to their APOE genotype and characterize their relationship to APOE-ε4 gene dose. The hypothesis-generating analysis revealed covarying regional gray matter volume and cerebral glucose metabolism patterns that resembled those in traditional univariate analyses of AD and APOE-ε4 gene dose and PET-MRI scores that were strongly correlated with APOE-ε4 gene dose (p<1 × 10(-16)). The hypothesis-testing analysis results showed strong correlations between FDG PET-MRI gray matter scores and APOE-ε4 gene dose (p = 8.7 × 10(-4)). Our findings support the possibility of using the MMPLS to analyze complementary datasets from the same person in the presymptomatic detection and tracking of AD.

Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons.

Epidemiological studies suggest that elevated blood pressure (BP) in midlife is associated with increased risk of Alzheimer's disease (AD) in late life. In this preliminary study, we investigated the extent to which BP measurements are related to positron emission tomography (PET) measurements of fibrillar amyloid-beta burden using Pittsburgh Compound-B (PiB) and fluorodeoxyglucose (FDG) PET measures of cerebral metabolic rate for glucose metabolism (CMRgl) in cognitively normal, late middle-aged to older adult apolipoprotein E (APOE) ε4 homozygotes, heterozygotes and noncarriers. PiB PET results revealed that systolic BP (SBP) and pulse pressure (PP) were each positively correlated with cerebral-to-cerebellar PiB distribution volume ratio (DVR) in frontal, temporal, and posterior-cingulate/precuneus regions, whereas no significant positive correlations were found between PiB distribution volume ratios and diastolic BP (DBP). FDG PET results revealed significant inverse correlations between each of the BP measures and lower glucose metabolism in frontal and temporal brain regions. These preliminary findings provide additional evidence that higher BP, likely a reflection of arterial stiffness, during late midlife may be associated with increased risk of presymptomatic AD.

Alzheimer's Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments.

There is an urgent need to find effective presymptomatic Alzheimer's disease (AD) treatments that reduce the risk of AD symptoms or prevent them completely. It currently takes too many healthy people, too much money and too many years to evaluate the range of promising presymptomatic treatments using clinical endpoints. We have used brain imaging and other measurements to track some of the earliest changes associated with the predisposition to AD. We have proposed the Alzheimer's Prevention Initiative (API) to evaluate investigational amyloid-modifying treatments in healthy people who, based on their age and genetic background, are at the highest imminent risk of developing symptomatic AD using brain imaging, cerebrospinal fluid (CSF), and cognitive endpoints. In one trial, we propose to study AD-causing presenilin 1 [PS1] mutation carriers from the world's largest early-onset AD kindred in Antioquia, Colombia, close to their estimated average age at clinical onset. In another trial, we propose to study apolipoprotein E (APOE) ε4 homozygotes (and possibly heterozygotes) close to their estimated average age at clinical onset. The API has several goals: 1) to evaluate investigational AD-modifying treatments sooner than otherwise possible; 2) to determine the extent to which the treatment's brain imaging and other biomarker effects predict a clinical benefit-information needed to help qualify biomarker endpoints for use in pivotal prevention trials; 3) to provide a better test of the amyloid hypothesis than clinical trials in symptomatic patients, when these treatments may be too little too late to exert their most profound effect; 4) to establish AD prevention registries needed to support these and other presymptomatic AD trials; and 5) to give those individuals at highest imminent risk of AD symptoms access to the most promising investigational treatments in clinical trials.

Modeling change in memory performance and memory perceptions: findings from the ACTIVE study.

Within the context of the ACTIVE study, the current investigation explored the relationships between objective memory and two components of subjective memory (frequency of forgetting and use of external aids) over a five-year period. Relationships were assessed using parallel process latent growth curve models. Results indicated that changes in objective memory were associated with changes in perceived frequency of forgetting, but not with use of external aids (calendars, reminder notes) over time. Findings suggest that memory complaints may accurately reflect decline in objective memory performance, but that these memory changes are not necessarily related to compensatory behaviors.

Characterizing Alzheimer's disease using a hypometabolic convergence index.

This article introduces a hypometabolic convergence index (HCI) for the assessment of Alzheimer's disease (AD); compares it to other biological, cognitive and clinical measures; and demonstrates its promise to predict clinical decline in mild cognitive impairment (MCI) patients using data from the AD Neuroimaging Initiative (ADNI). The HCI is intended to reflect in a single measurement the extent to which the pattern and magnitude of cerebral hypometabolism in an individual's fluorodeoxyglucose positron emission tomography (FDG-PET) image correspond to that in probable AD patients, and is generated using a fully automated voxel-based image-analysis algorithm. HCIs, magnetic resonance imaging (MRI) hippocampal volume measurements, cerebrospinal fluid (CSF) assays, memory test scores, and clinical ratings were compared in 47 probable AD patients, 21 MCI patients who converted to probable AD within the next 18months, 76 MCI patients who did not, and 47 normal controls (NCs) in terms of their ability to characterize clinical disease severity and predict conversion rates from MCI to probable AD. HCIs were significantly different in the probable AD, MCI converter, MCI stable and NC groups (p=9e-17) and correlated with clinical disease severity. Using retrospectively characterized threshold criteria, MCI patients with either higher HCIs or smaller hippocampal volumes had the highest hazard ratios (HRs) for 18-month progression to probable AD (7.38 and 6.34, respectively), and those with both had an even higher HR (36.72). In conclusion, the HCI, alone or in combination with certain other biomarker measurements, has the potential to help characterize AD and predict subsequent rates of clinical decline. More generally, our conversion index strategy could be applied to a range of imaging modalities and voxel-based image-analysis algorithms.

Association between GAB2 haplotype and higher glucose metabolism in Alzheimer's disease-affected brain regions in cognitively normal APOEε4 carriers.

In a genome-wide association study (GWAS) of late-onset Alzheimer's disease (AD), we found an association between common haplotypes of the GAB2 gene and AD risk in carriers of the apolipoprotein E (APOE) ε4 allele, the major late-onset AD susceptibility gene. We previously proposed the use of fluorodeoxyglucose positron emission tomography (FDG-PET) measurements as a quantitative pre-symptomatic endophenotype, more closely related to disease risk than the clinical syndrome itself, to help evaluate putative genetic and non-genetic modifiers of AD risk. In this study, we examined the relationship between the presence or absence of the relatively protective GAB2 haplotype and PET measurements of regional-to-whole brain FDG uptake in several AD-affected brain regions in 158 cognitively normal late-middle-aged APOEε4 homozygotes, heterozygotes, and non-carriers. GAB2 haplotypes were characterized using Affymetrix Genome-Wide Human SNP 6.0 Array data from each of these subjects. As predicted, the possibly protective GAB2 haplotype was associated with higher regional-to-whole brain FDG uptake in AD-affected brain regions in APOEε4 carriers. While additional studies are needed, this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset AD in APOEε4 carriers. It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk.

Assessing the reliability to detect cerebral hypometabolism in probable Alzheimer's disease and amnestic mild cognitive impairment.

Fluorodeoxyglucose positron emission tomography (FDG-PET) studies report characteristic patterns of cerebral hypometabolism in probable Alzheimer's disease (pAD) and amnestic mild cognitive impairment (aMCI). This study aims to characterize the consistency of regional hypometabolism in pAD and aMCI patients enrolled in the AD neuroimaging initiative (ADNI) using statistical parametric mapping (SPM) and bootstrap resampling, and to compare bootstrap-based reliability index to the commonly used type-I error approach with or without correction for multiple comparisons. Batched SPM5 was run for each of 1000 bootstrap iterations to compare FDG-PET images from 74 pAD and 142 aMCI patients, respectively, to 82 normal controls. Maps of the hypometabolic voxels detected for at least a specific percentage of times over the 1000 runs were examined and compared to an overlap of the hypometabolic maps obtained from 3 randomly partitioned independent sub-datasets. The results from the bootstrap derived reliability of regional hypometabolism in the overall data set were similar to that observed in each of the three non-overlapping sub-sets using family-wise error. Strong but non-linear association was found between the bootstrap-based reliability index and the type-I error. For threshold p=0.0005, pAD was associated with extensive hypometabolic voxels in the posterior cingulate/precuneus and parietotemporal regions with reliability between 90% and 100%. Bootstrap analysis provides an alternative to the parametric family-wise error approach used to examine consistency of hypometabolic brain voxels in pAD and aMCI patients. These results provide a foundation for the use of bootstrap analysis characterize statistical ROIs or search regions in both cross-sectional and longitudinal FDG-PET studies. This approach offers promise in the early detection and tracking of AD, the evaluation of AD-modifying treatments, and other biologically or clinical important measurements using brain images and voxel-based data analysis techniques.

Alzheimer's prevention initiative: a proposal to evaluate presymptomatic treatments as quickly as possible.

Now is the time to launch the era of Alzheimer's disease (AD) prevention research, establish the methods and infrastructure to rapidly evaluate presymptomatic AD treatments and evaluate them rigorously and rapidly in randomized clinical trials. This article is a call to arms. It contends that the evaluation of presymptomatic AD treatments must become an urgent priority, it identifies what is holding us back and proposes new public policies and scientific strategies to overcome these roadblocks. It defines the term 'presymptomatic AD treatment', notes the best established biomarkers of AD progression and pathology and suggests how they could be used to rapidly evaluate presymptomatic AD treatments in the people at risk. It introduces an approach to evaluate presymptomatic AD treatments in asymptomatic people at the highest risk of imminent clinical onset and determines the extent to which the treatment's biomarker predicts a clinical outcome. We propose an Alzheimer's Prevention Initiative, which is now being reviewed and refined in partnership with leading academic and industry investigators. It is intended to evaluate the most promising presymptomatic AD treatments, help develop a regulatory pathway for their accelerated approval using reasonably likely surrogate end points and find demonstrably effective presymptomatic AD treatments as quickly as possible.

Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E epsilon4 allele.

OBJECTIVE: To investigate with fluorodeoxyglucose positron emission tomography whether regional reductions in the cerebral metabolic rate for glucose (CMRgl) previously found in cognitively healthy late-middle-aged apolipoprotein E (APOE) epsilon4 carriers extend to members of the Latino Mexican American community. DESIGN: Prospective cohort study. SETTING: Banner Alzheimer's Institute, Phoenix, Arizona. PATIENTS OR OTHER PARTICIPANTS: Eleven APOE epsilon4 carriers and 16 noncarriers from Arizona's Latino community (mean [SD] age, 54.6 [6.4] years) matched for sex, mean age, and educational level and who were predominantly of self-designated Mexican origin. MAIN OUTCOME MEASURE: A brain mapping algorithm was used to compare cross-sectional regional CMRgl in Latino APOE epsilon4 carriers vs noncarriers. RESULTS: Participant groups had similar distributions for age, sex, education, family history of dementia, clinical ratings, and neuropsychological test scores. Latino APOE epsilon4 carriers had lower CMRgl than the noncarriers in the posterior cingulate, precuneus, and parietal regions previously found to be preferentially affected in patients with Alzheimer disease (AD) and cognitively healthy non-Latino APOE epsilon4 carriers. Additionally, the Latino APOE epsilon4 carriers had lower CMRgl in the middle and anterior cingulate cortex, hippocampus, and thalamus. CONCLUSIONS: This study provides support for the relationship between APOE epsilon4 and risk of AD in Latino individuals. It illustrates the role of positron emission tomography as a presymptomatic endophenotype for the assessment of AD risk factors and supports the inclusion of Latino APOE epsilon4 carriers in proof-of-concept studies using fluorodeoxyglucose PET to evaluate promising presymptomatic treatments in cognitively healthy carriers of this common AD susceptibility gene.

Twelve-month metabolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment assessed using an empirically pre-defined statistical region-of-interest: findings from the Alzheimer's Disease Neuroimaging Initiative.

Alzheimer's disease (AD) is characterized by specific and progressive reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose (CMRgl), some of which may precede the onset of symptoms. In this report, we describe twelve-month CMRgl declines in 69 probable AD patients, 154 amnestic mild cognitive impairment (MCI) patients, and 79 cognitively normal controls (NCs) from the AD Neuroimaging Initiative (ADNI) using statistical parametric mapping (SPM). We introduce the use of an empirically pre-defined statistical region-of-interest (sROI) to characterize CMRgl declines with optimal power and freedom from multiple comparisons, and we estimate the number of patients needed to characterize AD-slowing treatment effects in multi-center randomized clinical trials (RCTs). The AD and MCI groups each had significant twelve-month CMRgl declines bilaterally in posterior cingulate, medial and lateral parietal, medial and lateral temporal, frontal and occipital cortex, which were significantly greater than those in the NC group and correlated with measures of clinical decline. Using sROIs defined based on training sets of baseline and follow-up images to assess CMRgl declines in independent test sets from each patient group, we estimate the need for 66 AD patients or 217 MCI patients per treatment group to detect a 25% AD-slowing treatment effect in a twelve-month, multi-center RCT with 80% power and two-tailed alpha=0.05, roughly one-tenth the number of the patients needed to study MCI patients using clinical endpoints. Our findings support the use of FDG PET, brain-mapping algorithms and empirically pre-defined sROIs in RCTs of AD-slowing treatments.

Higher serum total cholesterol levels in late middle age are associated with glucose hypometabolism in brain regions affected by Alzheimer's disease and normal aging.

Epidemiological studies suggest that higher midlife serum total cholesterol levels are associated with an increased risk of Alzheimer's disease (AD). Using fluorodeoxyglucose positron emission tomography (PET) in the study of cognitively normal late middle-aged people, we demonstrated an association between apolipoprotein E (APOE) epsilon4 gene dose, the major genetic risk factor for late-onset AD, and lower measurements of the cerebral metabolic rate for glucose (CMRgl) in AD-affected brain regions, we proposed using PET as a pre-symptomatic endophenotype to evaluate other putative AD risk modifiers, and we then used it to support an aggregate cholesterol-related genetic risk score in the risk of AD. In the present study, we used PET to investigate the association between serum total cholesterol levels and cerebral metabolic rate for glucose metabolism (CMRgl) in 117 cognitively normal late middle-aged APOE epsilon4 homozygotes, heterozygotes and non-carriers. Higher serum total cholesterol levels were associated with lower CMRgl bilaterally in precuneus, parietotemporal and prefrontal regions previously found to be preferentially affected by AD, and in additional frontal regions previously found to be preferentially affected by normal aging. The associations were greater in APOE epsilon4 carriers than non-carriers in some of the AD-affected brain regions. We postulate that higher midlife serum total cholesterol levels accelerate brain processes associated with normal aging and conspire with other risk factors in the predisposition to AD. We propose using PET in proof-of-concept randomized controlled trials to rapidly evaluate the effects of midlife cholesterol-lowering treatments on the brain changes associated with normal aging and AD.