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Publications in Dementia by NOMIS researchers

NOMIS Researcher(s)

September 26, 2023

The SARS-CoV2 global pandemic impacted participants in the Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) clinical trial, who faced three stressors: 1) fear of developing dementia; 2) concerns about missing treatment; and 3) risk of SARS-CoV2 infection. Objective: To describe the frequency of psychological disorders among the participants of the API ADAD Colombia clinical study, treated by a holistic mental health team during the COVID-19 pandemic. The extent of use of mental health team services was explored considering different risk factors, and users and non-users of these services were compared. Methods: Participants had free and optional access to psychology and psychiatry services, outside of the study protocol. Descriptive statistics was used to analyze the frequency of the mental health difficulties. A multivariable logistic regression model has been used to assess associations with using this program. Results: 66 participants were treated by the Mental Health Team from March 1, 2020, to December 31, 2020. Before and after the start of the pandemic, the most common psychological problems were anxiety (36.4% before, 63.6% after) and depression (34.8% before, 37.9% after). 70% of users assisted by psychology and 81.6% of those assisted by psychiatry felt that the services were useful for them. Female sex, depression, and anxiety before the pandemic were positively associated with being assisted by either psychology or psychiatry, while the association with hyperlipidemia was negative. Conclusions: A holistic mental health program, carried out in the context of a study, could mitigate psychopathology during pandemics such as COVID-19. © 2023 – IOS Press. All rights reserved.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

NOMIS Researcher(s)

Published in

August 23, 2023

Autosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors. © 2023, Springer Nature Limited.

Research field(s)
Health Sciences

NOMIS Researcher(s)

June 6, 2023

Plasma tau phosphorylated at threonine 217 (P-tau217) and neurofilament light (NfL) have emerged as markers of Alzheimer’s disease (AD) pathology. Few studies have examined the role of sex in plasma biomarkers in sporadic AD, yielding mixed findings, and none in autosomal dominant AD. METHODS: We examined the effects of sex and age on plasma P-tau217 and NfL, and their association with cognitive performance in a cross-sectional study of 621 Presenilin-1 E280A mutation carriers (PSEN1) and non-carriers. RESULTS: As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. Yet, as disease progresses, female carriers had a greater plasma NfL increase than male carriers. There were no sex differences in the association between age and plasma biomarkers among non-carriers. DISCUSSION: Our findings suggest that, among PSEN1 mutation carriers, females had a greater rate of neurodegeneration than males, yet it did not predict cognitive performance. HIGHLIGHTS: We examined sex differences in plasma P-tau217 and NfL in Presenilin-1 E280A (PSEN1) mutation carriers and non-carriers. Female carriers had a greater plasma NfL increase, but not P-tau217, than male carriers. As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. The interaction effect of sex by plasma NfL levels did not predict cognition among carriers. © 2023 the Alzheimer’s Association.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

NOMIS Researcher(s)

Published in

April 13, 2023

We calculate reflectivities of dynamically compressed water, water-ethanol mixtures, and ammonia at infrared and optical wavelengths with density functional theory and molecular dynamics simulations. The influence of the exchange-correlation functional on the results is examined in detail. Our findings indicate that the consistent use of the HSE hybrid functional reproduces experimental results much better than the commonly used PBE functional. The HSE functional offers not only a more accurate description of the electronic band gap but also shifts the onset of molecular dissociation in the molecular dynamics simulations to significantly higher pressures. We also highlight the importance of using accurate reference standards in reflectivity experiments and reanalyze infrared and optical reflectivity data from recent experiments. Thus, our combined theoretical and experimental work explains and resolves lingering discrepancies between calculations and measurements for the investigated molecular substances under shock compression. © 2023 American Physical Society.

Research field(s)
Natural Sciences

NOMIS Researcher(s)

December 1, 2022

Objective: The amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly challenged. Here, we aim to refocus the amyloid cascade hypothesis on its original premise that the accumulation of amyloid beta (Aβ) peptide is the primary and earliest event in AD pathogenesis as based on current evidence, initiating several pathological events and ultimately leading to AD dementia. Background: An ongoing debate about the validity of the amyloid cascade hypothesis for AD has been triggered by clinical trials with investigational disease-modifying drugs targeting Aβ that have not demonstrated consistent clinically meaningful benefits. Updated Hypothesis: It is an open question if monotherapy targeting Aβ pathology could be markedly beneficial at a stage when the brain has been irreversibly damaged by a cascade of pathological changes. Interventions in cognitively unimpaired individuals at risk for dementia, during amyloid-only and pre-amyloid stages, are more appropriate for proving or refuting the amyloid hypothesis. Our updated hypothesis states that anti-Aβ investigational therapies are likely to be most efficacious when initiated in the preclinical (asymptomatic) stages of AD and specifically when the disease is driven primarily by amyloid pathology. Given the young age at symptom onset and the deterministic nature of the mutations, autosomal dominant AD (ADAD) mutation carriers represent the ideal population to evaluate the efficacy of putative disease-modifying Aβ therapies. Major Challenges for the Hypothesis: Key challenges of the amyloid hypothesis include the recognition that disrupted Aβ homeostasis alone is insufficient to produce the AD pathophysiologic process, poor correlation of Aβ with cognitive impairment, and inconclusive data regarding clinical efficacy of therapies targeting Aβ. Challenges of conducting ADAD research include the rarity of the disease and uncertainty of the generalizability of ADAD findings for the far more common “sporadic” late-onset AD. Linkage to Other Major Theories: The amyloid cascade hypothesis, modified here to pertain to the preclinical stage of AD, still needs to be integrated with the development and effects of tauopathy and other co-pathologies, including neuroinflammation, vascular insults, synucleinopathy, and many others.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

NOMIS Researcher(s)

November 1, 2022

Introduction: Females may have greater susceptibility to Alzheimer’s disease (AD)-pathology. We examined the effect of sex on pathology, neurodegeneration, and memory in cognitively-unimpaired Presenilin-1 (PSEN1) E280A mutation carriers and non-carriers. Methods: We analyzed baseline data from 167 mutation carriers and 75 non-carriers (ages 30 to 53) from the Alzheimer’s Prevention Initiative Autosomal Dominant AD Trial, including florbetapir- and fludeoxyglucose-PET, MRI based hippocampal volume and cognitive testing. Results: Females exhibited better delayed recall than males, controlling for age, precuneus glucose metabolism, and mutation status, although the effect was not significant among PSEN1 mutation carriers only. APOE ε4 did not modify the effect of sex on AD biomarkers and memory. Discussion: Our findings suggest that, among cognitively-unimpaired individuals at genetic risk for autosomal-dominant AD, females may have greater cognitive resilience to AD pathology and neurodegeneration than males. Further investigation of sex-specific differences in autosomal-dominant AD is key to elucidating mechanisms of AD risk and resilience.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

NOMIS Researcher(s)

August 10, 2022

Clinical trials for Alzheimer’s disease (AD) are slower to enroll study participants, take longer to complete, and are more expensive than trials in most other therapeutic areas. The recruitment and retention of a large number of qualified, diverse volunteers to participate in clinical research studies remain among the key barriers to the successful completion of AD clinical trials. An advisory panel of experts from academia, patient-advocacy organizations, philanthropy, non-profit, government, and industry convened in 2020 to assess the critical challenges facing recruitment in Alzheimer’s clinical trials and develop a set of recommendations to overcome them. This paper briefly reviews existing challenges in AD clinical research and discusses the feasibility and implications of the panel’s recommendations for actionable and inclusive solutions to accelerate the development of novel therapies for AD. © 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

NOMIS Researcher(s)

January 1, 2022

Introduction: The Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease (API ADAD) Trial evaluated the anti-oligomeric amyloid beta (Aβ) antibody therapy crenezumab in cognitively unimpaired members of the Colombian presenilin 1 (PSEN1) E280A kindred. We report availability, methods employed to protect confidentiality and anonymity of participants, and process for requesting and accessing baseline data. Methods: We developed mechanisms to share baseline data from the API ADAD Trial in consultation with experts and other groups sharing data from Alzheimer’s disease (AD) prevention trials, balancing the need to protect anonymity and trial integrity with making data broadly available to accelerate progress in the field. We pressure-tested deliberate and inadvertent potential threats under specific assumptions, employed a system to suppress or mask both direct and indirect identifying variables, limited and firewalled data managers, and put forth specific principles requisite to receive data. Results: Baseline demographic, PSEN1 E280A and apolipoprotein E genotypes, florbetapir and fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, clinical, and cognitive data can now be requested by interested researchers. Discussion: Baseline data are publicly available; treatment data and biological samples, including baseline and treatment-related blood-based biomarker data will become available in accordance with our original trial agreement and subsequently developed Collaboration for Alzheimer’s Prevention principles. Sharing of these data will allow exploration of important questions including the differential effects of initiating an investigational AD prevention therapy both before as well as after measurable Aβ plaque deposition.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

Introduction: Cortical thinning is a marker of neurodegeneration in Alzheimer’s disease (AD). We investigated the age-related trajectory of cortical thickness across the lifespan (9-59 years) in a Colombian kindred with autosomal dominant AD (ADAD). Methods: Two hundred eleven participants (105 presenilin-1 [PSEN1] E280A mutation carriers, 16 with cognitive impairment; 106 non-carriers) underwent magnetic resonance imaging. A piecewise linear regression identified change-points in the age-related trajectory of cortical thickness in carriers and non-carriers. Results: Unimpaired carriers exhibited elevated cortical thickness compared to non-carriers, and thickness more negatively correlated with age and cognition in carriers relative to non-carriers. We found increased cortical thickness in child carriers, after which thickness steadied compared to non-carriers prior to a rapid reduction in the decade leading up to the expected age at cognitive impairment in carriers. Discussion: Findings suggest that cortical thickness may fluctuate across the ADAD lifespan, from early-life increased thickness to atrophy proximal to clinical onset.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

NOMIS Researcher(s)

Published in

September 8, 2020

Objective: To determine whether performance on the Free and Cued Selective Reminding Test (FCSRT) is associated with PET in vivo markers of brain pathology and whether it can distinguish those who will develop dementia later in life due to autosomal-dominant Alzheimer disease (AD) from age-matched controls. Methods:Twenty-four cognitively unimpaired Presenilin-1 E280A carriers (mean age 36 years) and 28 noncarriers (mean age 37 years) underwent Pittsburg compound B-PET (amyloid), flortaucipir-PET (tau), and cognitive testing, including the FCSRT (immediate and delayed free and cued recall scores). Linear regressions were used to examine the relationships among FCSRT scores, age, mean cortical amyloid, and regional tau burden. Results:Free and total recall scores did not differ between cognitively unimpaired mutation carriers and noncarriers. Greater age predicted lower free recall and delayed free and total recall scores in carriers. In cognitively impaired carriers, delayed free recall predicted greater amyloid burden and entorhinal tau, while worse immediate free recall scores predicted greater tau in the inferior temporal and entorhinal cortices. In turn, in all carriers, lower free and total recall scores predicted greater amyloid and regional tau pathology. Conclusions:FCSRT scores were associated with in vivo markers of AD-related pathology in cognitively unimpaired individuals genetically determined to develop dementia. Difficulties on free recall, particularly delayed recall, were evident earlier in the disease trajectory, while difficulties on cued recall were seen only as carriers neared the onset of dementia, consistent with the pathologic progression of the disease. Findings suggest that the FCSRT can be a useful measure to track disease progression in AD.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

NOMIS Researcher(s)

July 1, 2020

Introduction: The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo-controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60-year-old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non-carriers who receive placebo. Methods: Of the 252 enrolled, we present data on a total of 242 mutation carriers and non-carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity. Results: We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non-carriers, 30 to 53 years of age. Carriers were significantly younger than non-carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores. Discussion: Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non-carriers. Their demographic characteristics are representative of the local population.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

NOMIS Researcher(s)

Published in

June 1, 2020

Background: Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer’s disease kindred. Methods: In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer’s disease Colombian kindred aged 8–75 years with no other neurological or health conditions were recruited from the Alzheimer’s Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single molecule array immunoassay and log-transformed data to examine the relationship between plasma NfL concentrations and age, and establish the earliest age at which NfL concentrations begin to diverge between mutation carriers and non-carriers. Findings: We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments; of these participants, longitudinal measures (with a mean follow-up of 6 years) were available for 242 mutation carriers and 262 non-carriers. Plasma NfL measurements increased with age in both groups (p<0·0001), and began to differentiate carriers from non-carriers when aged 22 years (22 years before the estimated median age at mild cognitive impairment onset of 44 years), although the ability of plasma NfL to discriminate between carriers and non-carriers only reached high sensitivity close to the age of clinical onset. Interpretation: Our findings further support the promise of plasma NfL as a biomarker of active neurodegeneration in the detection and tracking of Alzheimer's disease and the evaluation of disease-modifying therapies. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Banner Alzheimer's Foundation, COLCIENCIAS, the Torsten Söderberg Foundation, the Swedish Research Council, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, and the Swedish state under the ALF-agreement.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

NOMIS Researcher(s)

April 1, 2019

Introduction: Recruitment for Alzheimer’s disease (AD) prevention research studies is challenging because of lack of awareness among cognitively healthy adults coupled with the high screen fail rate due to participants not having a genetic risk factor or biomarker evidence of the disease. Participant recruitment registries offer one solution for efficiently and effectively identifying, characterizing, and connecting potential eligible volunteers to studies. Methods: Individuals aged 55-75 years who live in the United States and self-report not having a diagnosis of cognitive impairment such as MCI or dementia are eligible to join GeneMatch. Participants enroll online and are provided a cheek swab kit for DNA extraction and apolipoprotein E (APOE) genotyping. Participants are not told their APOE results, although the results may be used in part to help match participants to AD prevention studies. Results: As of August 2018, 75,351 participants had joined GeneMatch. Nearly 30% of participants have one APOE4 allele, and approximately 3% have two APOE4 alleles. The percentages of APOE4 heterozygotes and homozygotes are inversely associated with age (P <.001). Discussion: GeneMatch, the first trial-independent research enrollment program designed to recruit and refer cognitively healthy adults to AD prevention studies based in part on APOE test results, provides a novel mechanism to accelerate prescreening and enrollment for AD prevention trials.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

Introduction: Alzheimer’s disease (AD) pathology, including the accumulation of amyloid beta (Aβ) species and tau pathology, begins decades before the onset of cognitive impairment. This long preclinical period provides an opportunity for clinical trials designed to prevent or delay the onset of cognitive impairment due to AD. Under the umbrella of the Alzheimer’s Prevention Initiative Generation Program, therapies targeting Aβ, including CNP520 (umibecestat), a β-site-amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitor, and CAD106, an active Aβ immunotherapy, are in clinical development in preclinical AD. Methods: The Alzheimer’s Prevention Initiative Generation Program comprises two pivotal (phase 2/3) studies that assess the efficacy and safety of umibecestat and CAD106 in cognitively unimpaired individuals with high risk for developing symptoms of AD based on their age (60–75 years), APOE4 genotype, and, for heterozygotes (APOE ε2/ε4 or ε3/ε4), elevated brain amyloid. Approximately, 3500 individuals will be enrolled in either Generation Study 1 (randomized to cohort 1 [CAD106 injection or placebo, 5:3] or cohort 2 [oral umibecestat 50 mg or placebo, 3:2]) or Generation Study 2 (randomized to oral umibecestat 50 mg and 15 mg, or placebo [2:1:2]). Participants receive treatment for at least 60 months and up to a maximum of 96 months. Primary outcomes include time to event, with event defined as diagnosis of mild cognitive impairment due to AD and/or dementia due to AD, and the Alzheimer’s Prevention Initiative preclinical composite cognitive test battery. Secondary endpoints include the Clinical Dementia Rating Sum of Boxes, Repeatable Battery for the Assessment of Neuropsychological Status total score, Everyday Cognition Scale, biomarkers, and brain imaging. Discussion: The Generation Program is designed to assess the efficacy, safety, and biomarker effects of the two treatments in individuals at high risk for AD. It may also provide a plausible test of the amyloid hypothesis and further accelerate the evaluation of AD prevention therapies.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

Introduction: Autosomal-dominant Alzheimer’s disease (ADAD) represents a crucial population for identifying prevention strategies that might modify disease course for cognitively unimpaired individuals at high imminent risk for developing symptoms due to Alzheimer’s disease (AD), that is, who have “preclinical” AD. Crenezumab is an antiamyloid monoclonal antibody that binds monomeric and aggregated forms of amyloid β, with highest affinity for oligomers; it is in development for early stages of sporadic AD and for ADAD. Methods: This is a prospective, randomized, double-blind, placebo-controlled phase 2 study of the efficacy of crenezumab versus placebo in asymptomatic PSEN1 E280A mutation carriers from family kindreds with ADAD in Colombia. Participants were randomized to receive either crenezumab or placebo for 260 weeks. The study was designed to enroll a planned total of 300 participants, including 200 preclinical mutation carriers (approximately 100 treatment, 100 placebo) and an additional control group of mutation noncarriers from the same family kindreds included to mask mutation carrier status (100 placebo only). The primary outcome is change in the Alzheimer’s Prevention Initiative ADAD Composite Cognitive Test Score from baseline to week 260. Secondary outcomes include time to progression to mild cognitive impairment due to AD or dementia due to AD; changes in dementia severity, memory, and overall neurocognitive functioning; and changes in amyloid–positron emission tomography, fluorodeoxyglucose–positron emission tomography, magnetic resonance imaging volumes, and cerebrospinal fluid levels of β amyloid, tau, and p-tau. Safety and tolerability are assessed. Results: Two hundred fifty-two participants were enrolled between December 2013 and February 2017. Discussion: We describe the first large-scale, potentially label-enabling clinical trial of a preclinical treatment for ADAD. Results from this trial will inform on the efficacy of crenezumab for delaying onset of, slowing decline in, or preventing cognitive impairment in individuals with preclinical ADAD and will foster an improved understanding of AD biomarkers and their relationship to clinical outcomes.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

Introduction: The Alzheimer’s Prevention Initiative Colombia Trial is a collaborative project involving the Neurosciences Group of Antioquia, Genentech/Roche, and the Banner Alzheimer’s Institute, studying whether crenezumab can delay or prevent the clinical onset of Alzheimer’s disease in cognitively unimpaired individuals who carry the PSEN1 E280A mutation. In an effort to optimize participant compliance and adherence and maintain interest in the trial for its duration, the Neurosciences Group of Antioquia developed an “Adherence/Retention Plan.” This plan identifies potential barriers to trial adherence related to characteristics of the participants and study partners, protocol design, sponsors, investigators, environmental factors, and characteristics of this population in general and identifies potential solutions to these barriers. Methods: Neurosciences Group of Antioquia designed and implemented a number of strategies including a) a prescreening process that emphasized detailed and staged informed consent involving the participant and family and/or friends, b) a schedule of visits and assessments designed to minimize burden while achieving the trial’s aims, c) appointment reminders, d) reimbursement for transportation and missed work, e) meals during study visits, f) birthday cards, g) quarterly newsletters, h) annual in-person feedback meetings, i) a supplemental health plan to participants, and j) a social plan to support family members. All the methods used in this plan were approved by local ethics committees. Results: By the end of the fourth year of the trial, participant retention was 94.0%, with most participants reporting that they felt “very satisfied” with their participation in the trial. Discussion: The Adherence/Retention Plan plays a crucial role in maintaining adherence and compliance needed to achieve the ambitious goals of the Alzheimer’s Prevention Initiative-Colombia Autosomal Dominant Alzheimer’s Disease Trial and may offer guideposts for other prevention trials.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

NOMIS Researcher(s)

November 1, 2014

Background There is growing interest in the evaluation of preclinical Alzheimer’s disease (AD) treatments. As a result, there is a need to identify a cognitive composite that is sensitive to track preclinical AD decline to be used as a primary endpoint in treatment trials. Methods Longitudinal data from initially cognitively normal, 70- to 85-year-old participants in three cohort studies of aging and dementia from the Rush Alzheimer’s Disease Center were examined to empirically define a composite cognitive endpoint that is sensitive to detect and track cognitive decline before the onset of cognitive impairment. The mean-to-standard deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of cognitive tests/subtests drawn from the neuropsychological battery in cognitively normal participants who subsequently progressed to clinical stages of AD during 2- and 5-year periods, using data from those who remained unimpaired during the same period to correct for aging and practice effects. Combinations that performed well were then evaluated for representation of relevant cognitive domains, robustness across individual years before diagnosis, and occurrence of selected items within top performing combinations. Results The optimal composite cognitive test score comprised seven cognitive tests/subtests with an MSDR = 0.964. By comparison, the most sensitive individual test score was Logical Memory Delayed Recall with an MSDR = 0.64. Conclusions We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared with the most sensitive single test item to track preclinical AD decline and evaluate preclinical AD treatments. We are confirming the power of the composite in independent cohorts and with other analytical approaches, which may result in refinements, have designated it as the primary endpoint in the Alzheimer’s Prevention Initiative’s preclinical treatment trials for individuals at high imminent risk for developing symptoms due to late-onset AD.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

NOMIS Researcher(s)

July 1, 2013

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. © 2013 Macmillan Publishers Limited. All rights reserved.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

NOMIS Researcher(s)

Published in

December 1, 2012

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 Aβ1-42, total tau and phospho-tau181 concentrations, and plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 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) e{open}4 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 Aβ1-42 concentrations (p=0·008) and plasma Aβ1-42 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 Aβ1-42 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. © 2012 Elsevier Ltd.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery