Dominant Alzheimer Research Articles

A survey of attitudes toward clinical trials and genetic disclosure in autosomal dominant Alzheimer's disease.

IntroductionBecause of its genetic underpinnings and consistent age of onset within families, autosomal dominant Alzheimer’s disease (ADAD) provides a unique opportunity to conduct clinical trials of investigational agents as preventative or symptom-delaying treatments. The design of such trials may be complicated by low rates of genetic testing and disclosure among persons at risk of inheriting disease-causing mutations.MethodsTo better understand the attitudes toward genetic testing and clinical trials of persons at risk for ADAD, we surveyed participants in the Dominantly Inherited Alzheimer’s Network (DIAN), a multisite longitudinal study of clinical and biomarker outcomes in ADAD that does not require learning genetic status to participate.ResultsEighty participants completed a brief anonymous survey by mail or on-line; 40 % reported knowing if they carried a gene mutation, 15 % did not know but expressed a desire to learn their genetic status, and 45 % did not know and did not desire to know their genetic status. Among participants who knew or wished to know their genetic status, 86 % were interested in participating in a clinical trial. Seventy-two percent of participants who did not wish to learn their genetic status reported that they would change their mind, if learning that they carried a mutation gave them the opportunity to participate in a clinical trial. Nearly all participants responded that they would be interested if an open-label extension were offered.ConclusionsThese results suggest that the availability of clinical trials to prevent ADAD can affect persons’ desire to undergo genetic testing and that consideration can be given to performing studies in which such testing is required.

William Klunk: imaging Alzheimer's disease in vivo

William Klunk: imaging Alzheimer's disease in vivo

Early frame of PiB and FDG in autosomal dominant Alzheimer's disease: Similarity, discrepancy, and clinical implication

Alzheimer's disease (AD), the leading cause of dementia in the elderly, can affect individuals in their thirties in autosomal dominant form. The Imaging Core of the Dominantly Inherited Alzheimer Network (DIAN) aims to characterize transition from preclinical to symptomatic disease using imaging biomarkers. Decreases in cerebral glucose metabolism in the parietal lobe are detectable 10 years before the estimated year of symptom onset (EYO) (Benzinger, Blazey et al., 2013) and may represent synaptic dysfunction. In sporadic AD, studies have shown that early perfusion frames of amyloid imaging with [11C]-Pittsburgh Compound B PiB (ePiB) correlate well with glucose metabolism (Rostomian et al., 2011). Here, we evaluated whether ePiB is a reasonable surrogate marker for synaptic dysfunction, in comparison to glucose metabolism hypometabolism, and how ePiB changes with the disease progression. DIAN participants (n=110), including 65 asymptomatic and symptomatic mutation carriers (MC), underwent full dynamic PiB-PET and also had [18F]-fluorodeoxyglucose (FDG) PET and volumetric brain MRI. The MRI was used to register the PET images. A standardized uptake value ratio (SUVR) from MR segmented PiB and FDG regions. An ePiB image with 1-9 min time frames was selected. Voxel-wise spatial correlation between FDG and ePiB was performed for each participant. The mutation and cognitive status were taken into account in the analyses. For each imaging modality, relationship with EYO was evaluated with linear mixed models on specific regions such as inferior parietal and precuneus cortices. FDG and ePiB were visually similar and showed high spatial correlation with an average of 0.8±0.04 regardless of the mutation or cognitive status. As we have previously found, the association between FDG and EYO significantly differs between MC and non-carrier groups (p-value<0.001 and p-value<0.01 for inferior parietal and precuneus, respectively). However, these associations were not significant between ePiB and EYO. Our findings show that ePiB is strongly correlated with FDG within the same individual. However, ePiB does not display the same sensitivity as FDG to reflect disease progression in this population. Further studies are needed to fully determine the utility of ePiB measurements in clinic.

Amyloid load increase and cerebral microbleed prevalence differ as a function of the position of the mutation within the PSEN1 coding sequence

Autosomal dominant Alzheimer's disease (ADAD) is a rare familial form of AD caused by mutations that alter metabolism of the β-amyloid protein. Most ADAD mutations concern the PSEN1 gene with more than 185 mutations currently reported. Mann and colleagues have reported histological differences in terms of amyloidosis and angiopathy when PSEN1mutations are located before or after the codon 200 (Mann et al., 2001). The Dominantly Inherited Alzheimer Network (DIAN) aims to understand the changes occurring in the ADAD population. Here, we investigated amyloid PiB-PET retention and prevalence of microbleeds as imaging biomarkers, taking into account the mutation position relative to the codon 200. Carriers of a mutation on the PSEN1gene (n=119), before (n=34) or after (n=85) codon 200, underwent PiB-PET scan to quantify amyloid brain deposition, susceptibility-weighted imaging MR scan to detect microbleeds, and volumetric MRI. The volumetric MRI was used to register the PET images and calculate standardized uptake values ratio (SUVR) from segmented regions. Cross-sectional analyses with linear models were performed to evaluate the amyloid retention in function of estimated year of onset (EYO) of the symptoms. Prevalence of microbleeds in the participants and per group of mutation position was also analyzed. Cross-sectionally estimated slopes of amyloid accumulation differed as a function of the mutation position. The group with mutations before codon 200 showed greater slope of amyloid accumulation at the mean cortical and caudate levels (p-value<0.005 and p-value<0.0005, respectively). Concerning microbleed evaluation, 12% of our cohort displayed one or more microbleeds. The percentage of carriers with microbleeds was up to 75% in the group carrying a mutation located after codon 200 compare to 25% in the group carrying a mutation located before codon 200. Our imaging findings are concordant with the previous histological description of particular phenotypes due to the position of the PSEN1 mutation. They give new insights into the ADAD population who often display high subcortical, basal ganglia amyloidosis. These outcomes can be taken into account to address specific treatment trial designs, including screening participants likely to develop microbleeds during clinical trials.

Early frame of PiB and FDG in autosomal dominant Alzheimer's disease: Similarity, discrepancy, and clinical implication

Early frame of PiB and FDG in autosomal dominant Alzheimer's disease: Similarity, discrepancy, and clinical implication

CSF proteomic discovery in persons with autosomal dominant Alzheimer's disease mutations

The identification of protein differences in the cerebrospinal fluid (CSF) from individuals with incipient or early Alzheimer's disease (AD) may assist in both early diagnosis and the identification of novel therapeutic targets. Proteomic CSF studies in individuals carrying fully-penetrant autosomal dominant Alzheimer's Disease (ADAD) mutations provide the opportunity to identify early changes in persons in whom the future diagnosis of AD is certain. We performed clinical evaluations and obtained CSF from 43 individuals either symptomatic from ADAD mutations (n=18, CDR = 0.5 in 12) or at 50% risk for inheriting such mutations (n=25). Among the 31 mutation carriers (MCs), 26 had PSEN1 mutations and 5 had the V717I APP mutation. CSF was depleted of 14 high abundance proteins, digested with trypsin and the resulting peptides were analyzed by liquid chromatography-mass spectrometry (LCMS). Peptides were identified by shotgun sequencing and clustered into their parent proteins. Peptide peaks were aligned across all samples and peak intensities were measured and compared to determine relative peptide and protein abundance in each sample. Protein levels were separately compared between mutation non-carriers (NCs, n=12) versus all ADAD MCs and versus all presymptomatic MCs (n=13). 1,018 proteins were differentially quantified and identified. Using an intensity difference of 2-fold, and p- and q-values (false discovery rate) of 0.05 as cut-offs for significance, we identified 12 proteins that were differentially expressed between ADAD MCs and NCs. Thrombospondin-2, LRP 11, NPDC1, Complement factor H, Fibronectin, Complement component C7, Transcription factor SOX-13, Clusterin, Fatty acid-binding protein, and APP were increased and Folate receptor alpha and CRP were decreased in ADAD MCs. An additional 22 proteins were differentially expressed with significant but smaller differences. When only presymptomatic ADAD mutation carriers were included, no protein was expressed with a 2-fold difference and only one (LRP1) was elevated with p- and q-values 0.05. Proteins associated with the cell matrix, inflammation, vascular remodeling, and Abeta transport are elevated in ADAD MCs Only LRP1 was elevated in presymptomatic MCs, suggesting that its overexpression represents an adaptive response to Abeta overproduction.

Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort study

The biomarker model of Alzheimer's disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimer's disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed. For this prospective cohort study, carriers of autosomal dominant Alzheimer's disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2, or APP were assessed at the University of Pittsburgh Alzheimer's Disease Research Center every 1-2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid β (Aβ) load using (11)C-Pittsburgh Compound-B PET, posterior cortical metabolism with (18)F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimer's Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65-89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls). 16 people with mutations in PSEN1, PSEN2, or APP, aged 28-56 years, completed between two and eight assessments (a total of 83 assessments) over 2-11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6-11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline. Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimer's disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimer's disease-active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline-indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimer's disease. National Institutes of Health and Howard Hughes Medical Institute.

Fast-forwarding treatment for neurodegenerative disorders

Fast-forwarding treatment for neurodegenerative disorders

More than a FAD: The In Vivo Effects of Disease-Linked Presenilin-1 Mutations

Mutations in presenilins are linked to familial autosomal dominant Alzheimer's disease. In this issue of Neuron, Xia et al. (2015) show that a disease-linked mutation leads to loss of γ-secretase function, cognitive decline, and neurodegeneration when knocked into the mouse genome.

Early behavioural changes in familial Alzheimer's disease in the Dominantly Inherited Alzheimer Network.

Prior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer's disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer's disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer's disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer's disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety-seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer's disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26-0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and the degree of self-rated depression more severe (mean Geriatric Depression Scale score of 2.8 versus 1.4, P = 0.006) in mildly symptomatic mutation carriers relative to non-carriers. Anxiety, appetite changes, delusions, and repetitive motor activity were additionally more common in overtly impaired mutation carriers. Similar to studies of late-onset Alzheimer's disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer's disease that increased with disease severity. We did not identify any increased psychopathology in mutation carriers over non-carriers during the presymptomatic stage, suggesting these symptoms result when a threshold of neurodegeneration is reached rather than as life-long qualities. Unexpectedly, we found lower rates of depressive symptoms in cognitively asymptomatic mutation carriers.

Structural biology of presenilin 1 complexes.

The presenilin genes were first identified as the site of missense mutations causing early onset autosomal dominant familial Alzheimer's disease. Subsequent work has shown that the presenilin proteins are the catalytic subunits of a hetero-tetrameric complex containing APH1, nicastrin and PEN-2. This complex (variously termed presenilin complex or gamma-secretase complex) performs an unusual type of proteolysis in which the transmembrane domains of Type I proteins are cleaved within the hydrophobic compartment of the membrane. This review describes some of the molecular and structural biology of this unusual enzyme complex. The presenilin complex is a bilobed structure. The head domain contains the ectodomain of nicastrin. The base domain contains a central cavity with a lateral cleft that likely provides the route for access of the substrate to the catalytic cavity within the centre of the base domain. There are reciprocal allosteric interactions between various sites in the complex that affect its function. For instance, binding of Compound E, a peptidomimetic inhibitor to the PS1 N-terminus, induces significant conformational changes that reduces substrate binding at the initial substrate docking site, and thus inhibits substrate cleavage. However, there is a reciprocal allosteric interaction between these sites such that prior binding of the substrate to the initial docking site paradoxically increases the binding of the Compound E peptidomimetic inhibitor. Such reciprocal interactions are likely to form the basis of a gating mechanism that underlies access of substrate to the catalytic site. An increasingly detailed understanding of the structural biology of the presenilin complex is an essential step towards rational design of substrate- and/or cleavage site-specific modulators of presenilin complex function.

A novel mutation in the PSEN2 gene (N141Y) associated with early-onset autosomal dominant Alzheimer's disease in a Chinese Han family

The mutations in the presenilin 2 (PSEN2) gene as causes of early-onset familial Alzheimer's disease (AD) have never been reported in Asia. We conducted a phenotype and pedigree study by performing neuropathological examination and target region sequencing in a family of 3 generations. Six members in this family developed dementia in their fifth decade and died in their sixth decade. The proband was diagnosed clinically with AD, which was confirmed by an autopsy. Target region sequencing showed a novel missense mutation at codon 141 (N141Y) of the PSEN2 gene that predicts an Asparagine-to-Tyrosine substitution in the affected individuals. The result was validated by Sanger sequencing in 7 family members (2 affected and 5 unaffected). The mutation was absent in the 5 clinically unaffected relatives and 188 control subjects. No influence of the APOE genotype was observed. We are the first to demonstrate a novel PSEN2 N141Y mutation in a Chinese Han family with early-onset AD.

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.

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. 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. 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). 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.

A Novel PSEN1 Mutation (I238M) associated with Early-Onset Alzheimer's Disease in an African-American Woman

Mutations in PSEN1 are the most common cause of autosomal dominant familial Alzheimer's disease (FAD). We describe an African-American woman with a family history consistent with FAD who began to experience cognitive decline at age 50. Her clinical presentation, MRI, FDG-PET, and PIB-PET scan findings were consistent with AD and she was found to have a novel I238M substitution in PSEN1. As this mutation caused increased production of Aβ42 in an in vitro assay, was not present in two population databases, and is conserved across species, it is likely to be pathogenic for FAD.

Clinical and psychological characteristics of the initial cohort of the Dominantly Inherited Alzheimer Network (DIAN).

The purpose was to describe clinical, cognitive, and personality characteristics at baseline assessment of 249 participants, 19 to 60 years of age, in a multinational longitudinal study of autosomal dominant Alzheimer's disease (ADAD). Participants (74% cognitively normal) were from ADAD families with mutations in 1 of 3 genes (APP, PSEN1, or PSEN2). Mixed model analyses, including family as a random variable and controlling for years from expected time of symptomatic onset of ADAD based on parental age at onset, compared 3 groups (cognitively normal mutation noncarriers, cognitively normal mutation carriers, very mildly impaired mutation carriers). Global cognitive deficits similar to those observed in late-life sporadic Alzheimer's disease (AD) existed in very mild ADAD compared with cognitively normal carriers and noncarriers on all but 2 measures (Digit Span Backward, Letter Fluency for FAS) of episodic memory, semantic memory, working memory, attention, and speeded visuospatial abilities. Demented individuals were less extraverted, open, and conscientious than cognitively normal participants on the International Personality Item Pool. Differences in the relation between 3 measures (Logical Memory, Digit Symbol, attention switching) and time to expected age at symptomatic onset indicate that cognitive deficits on some measures can be detected in mutation carriers prior to symptomatic AD, and hence should be useful markers in subsequent longitudinal follow-up. Overall cognitive and personality deficits in very mild ADAD are similar to those seen in sporadic AD. Cognitive deficits also occur in asymptomatic mutation carriers who are closer to the expected time of dementia onset.

Autosomal‐dominant Alzheimer's disease mutations at the same codon of amyloid precursor protein differentially alter Aβ production

Autosomal-dominant Alzheimer's disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studying the mechanisms underlying these mutations can provide insight into the pathways that lead to AD pathology. The majority of biochemical studies on APP mutations to-date have focused on comparing mechanisms between mutations at different codons. It has been assumed that amino acid position is a major determinant of protein dysfunction and clinical phenotype. However, the differential effect of mutations at the same codon has not been sufficiently addressed. In the present study we compared the effects of the aggressive ADAD-associated APP I716F mutation with I716V and I716T on APP processing in human neuroglioma and CHO-K1 cells. All APP I716 mutations increased the ratio of Aβ42/40 and changed the product line preference of γ-secretase towards Aβ38 production. In addition, the APP I716F mutation impaired the ε-cleavage and the fourth cleavage of γ-secretase and led to abnormal APP β-CTF accumulation at the plasma membrane. Taken together, these data indicate that APP mutations at the same codon can induce diverse abnormalities in APP processing, some resembling PSEN1 mutations. These differential effects could explain the clinical differences observed among ADAD patients bearing different APP mutations at the same position. The amyloid precursor protein (APP) I716F mutation is associated with autosomal dominant Alzheimer's disease with the youngest age-at-onset for the APP locus. Here, we describe that this mutation, when compared to two other familial Alzheimer's disease mutations at the same codon (I716V and I716T), interfered distinctly with γ-secretase cleavage. While all three mutations direct γ-secretase cleavage towards the 48→38 production line, the APP I716F mutation also impaired the ε-cleavage and the fourth cleavage of γ-secretase, resembling a PSEN1 mutation. These features may contribute to the aggressiveness of this mutation.

Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial

The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described.

The impact of the availability of prevention studies on the desire to undergo predictive testing in persons at risk for autosomal dominant Alzheimer's disease

Persons at risk for autosomal dominant neurodegenerative diseases provide the opportunity to efficiently test preventive interventions. Only a minority of such persons, however, choose to undergo revealing genetic testing, presenting a challenge to enrollment. Thirty-four preclinical Latinos (n=26) and non-Latinos at risk for familial Alzheimer's disease (FAD) unaware of their genetic status were administered a questionnaire exploring their interest in undergoing revealing genetic testing at baseline and in the context of eligibility for four prevention trials of increasing invasiveness. Forty-four percent of subjects expressed a baseline interest in undergoing revealing testing which increased to 85% in order to be eligible for a study of an oral drug “felt to be very safe.” If there were a 50% chance of receiving placebo, this number dropped to 62% (p=0.02). Among those not interested in a study involving a 50% chance of receiving placebo, a range of 5% to 40% chance of receiving placebo was given as acceptable. For more invasive studies, living in the United States (as opposed to Mexico) positively influenced the likelihood of participating. Our data suggest that clinical trial designs in which persons must confront their genetic status prior to enrollment are feasible. Study designs to minimize the likelihood of being placed on placebo or provide the eventual administration of the drug through open-label extensions should be considered.

Cerebral amyloid-associated changes in brain perfusion in autosomal dominant Alzheimer's disease

Cerebral amyloid-associated changes in brain perfusion in autosomal dominant Alzheimer's disease

Prevalence and growth of cerebral microhemorrhages in autosomal dominant Alzheimer's disease

Prevalence and growth of cerebral microhemorrhages in autosomal dominant Alzheimer's disease