Alzheimer's Prevention Initiative Research Articles

SV2A PET shows hippocampal synaptic loss in cognitively unimpaired APOE ε4/ε4 homozygotes.

We investigated hippocampal synaptic density using synaptic vesicle 2A positron emission tomography (PET), and its association with amyloid beta (Aβ) and cognitive performance in healthy apolipoprotein E (APOE) ε4 carriers. Synaptic density was assessed in 46 individuals (APOE ε4/ε4 n=14; APOE ε3/ε4 n=16; APOE ε3/ε3 n=16) with [11C]UCB-J-PET standardized uptake value ratios (SUVRs), by using the centrum semiovale as a reference region. Differences in hippocampal [11C]UCB-J SUVRs were analyzed with analysis of variance (ANOVA) and linear models. Associations among [11C]UCB-J SUVR, Aβ, hippocampal volume, and cognitive variables were analyzed with Spearman correlation. Hippocampal synaptic density was different among the APOE groups (PANOVA=0.016): APOE ε4/ε4 carriers had lower [11C]UCB-J SUVRs compared to APOE ε3/ε3 (p=0.013). Hippocampal synaptic density did not correlate with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score (rho=-0.052, p=0.74), Alzheimer's Prevention Initiative Preclinical Cognitive Composite (APCC) score (rho=0.17, p=0.28), or [11C]PiB uptake (rho=-0.10, p=0.50). Hippocampal synaptic loss emerges early in the AD continuum and is measurable in vivo in cognitively unimpaired high-risk individuals. Synaptic density was studied in vivo in healthy older adults using [11C]UCB-J positron emission tomography. Apolipoprotein E (APOE) ε4/ε4 carriers had lower hippocampal synaptic density compared to APOE ε3/ε3. Synaptic density was not associated with cognitive performance in this population. Hippocampal synaptic alterations occur before clinical symptoms in APOE ε4/ε4 carriers.

Reversibility of cognitive worsening observed with BACE inhibitor umibecestat in the Alzheimer's Prevention Initiative (API) Generation Studies.

The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed. Cognitively unimpaired 60- to 75-year-old apolipoprotein E (APOE)ε4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n=1556) received umibecestat (50 or 15mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout. Compared to placebo, umibecestat-treated participants had small, non-progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating-Sum of Boxes. RBANS differences were no longer significant at the end of follow-up. In people at genetic risk for AD, high-dose beta-site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition. This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention.

Strategies to promote contraception use by female volunteers in Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia trial.

Including women of childbearing age in a clinical trial makes it necessary to consider two factors from a bioethical perspective: first, the lack of knowledge about the potential teratogenic effects of an investigational product, and also, the principle of justice not to exclude any population from the benefits of research. The most common way to address this issue is by requiring volunteers to use contraceptives before, during, and a few weeks after the clinical trial. This work presents all the strategies used to promote contraception use and prevent pregnancy during the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Colombia clinical trial. Two characteristics of this trial make it of special interest for closely monitoring contraception use. One is that the trial lasted more than 7 years, and the other is that participants could be carriers of the E280A PSEN1 mutation, leading to a mild cognitive impairment as early as their late 30s. An individual medical evaluation to select the contraception method that best fits the volunteer was carried out during the screening visit, remitting to the gynecologist when necessary. All non-surgical contraception methods were supplied by the sponsor. Staff were trained on contraception counseling, correctly dispensing contraceptive drugs to volunteers, and identifying, reporting, and following up on pregnancies. Two comprehensive educational campaigns on contraception use were performed, and the intervention included all volunteers. In addition, volunteers were asked on an annual survey to evaluate the dispensing procedure. Finally, the effectiveness of these strategies was retrospectively evaluated, comparing by extrapolation the number of pregnancies presented throughout the trial with the General Fertility Rate in Colombia. A total of 159 female volunteers were recruited. All strategies were implemented as planned, even during the COVID-19 contingency. Ten pregnancies occurred during the evaluation period (2015-2021). Two were planned; the rest were associated with a potential therapeutic failure or incorrect use of contraceptive methods for a contraceptive failure of 0.49% per year. Sixty percent of pregnancies led to an abortion, either miscarriage or therapeutic abortion. However, there was not enough data to associate the pregnancy outcome with the administration of the investigational product. Finally, we observed a lower fertility rate in women participating in the trial compared to the Colombian population. The lower rates of contraceptive failure and the decrease in the incidence of pregnancies in women participating in the trial compared to the Colombian population across the 7 years of evaluation suggest that the strategies used in API ADAD Colombia were adequate and effective in addressing contraception use.

Basal forebrain volume and metabolism in carriers of the Colombian mutation for autosomal dominant Alzheimer's disease.

We aimed to study atrophy and glucose metabolism of the cholinergic basal forebrain in non-demented mutation carriers for autosomal dominant Alzheimer's disease (ADAD). We determined thelevel of evidence for or against atrophy and impaired metabolism of the basal forebrain in 167 non-demented carriers of the Colombian PSEN1 E280A mutation and 75 age- and sex-matched non-mutation carriers of the same kindred using a Bayesian analysis framework. We analyzed baseline MRI, amyloid PET, and FDG-PET scans of the Alzheimer's Prevention Initiative ADAD Colombia Trial. We found moderate evidence against an association of carrier status with basal forebrain volume (Bayes factor (BF10) = 0.182). We found moderate evidence against a difference of basal forebrain metabolism (BF10 = 0.167). There was only inconclusive evidence for an association between basal forebrain volume and delayed memory and attention (BF10 = 0.884 and 0.184, respectively), and between basal forebrain volume and global amyloid load (BF10 = 2.1). Our results distinguish PSEN1 E280A mutation carriers from sporadic AD cases in which cholinergic involvement of the basal forebrain is already detectable in the preclinical and prodromal stages. This indicates an important difference between ADAD and sporadic AD in terms of pathogenesis and potential treatment targets.

Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes.

Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450μg (n=42) or placebo (n=23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aβ positron emission tomography (PET) scans at 18 to 24 months. CAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P<0.001), and three amyloid-related imaging abnormality cases (one symptomatic). Despite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD. This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.

Informed consent process experience in Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease Colombia trial

AbstractBackgroundRecruiting cognitively‐unimpaired volunteers at high genetic risk of developing dementia into the Alzheimer’s Prevention Initiative (API) Colombia trial, and maintaining study adherence for at least 5 years has been a monumental challenge. Major barriers included inclusion criteria, protocol visit schedule, long informed consent form (ICF), low levels of education of participants, misconceptions about participating in a clinical trial, and blinding to genetic status and treatment arm. We explain how our group went out of the conventional and traditional schemes of informed consent while adhering to good clinical practice and developed a novel approach to the consent process for potential candidates.MethodThe identification, community education, and follow‐up of affected PSEN1 E280A families for the past three decades was the initial fundamental step to initiate a proper ICF process for the study. Then the launch of API Colombia Registry in 2010 was the base for appropriate preparation for the prevention trial. The process for API Colombia trial included step by step strategies, such as: a pre‐screening process developed by the team, pre‐consent informational meeting with the principal investigator in small groups of potential candidates, illustrated materials like a booklet titled “What I should know about informed consent and my decision to participate”, and detailed infographics as a complementary material to main study ICF, use of a voluntary pre‐selection survey. The screening visit was divided in parts: discussion with the sub‐investigator about clinical trial participation, review of participant’s questions, and signatures according to regulatory requirements.ResultFrom 623 potentially eligible registrants for pre‐screening, 319 were consented and underwent full eligibility screening and 252 were randomized. After eight years of study duration, 94% of participants completed the protocol, 90.5% completed the trial on treatment. Most participants who dropped out of the study did it due to incompatibility with work, unexpected pregnancy, or the decision to have children.ConclusionWe attribute successful trial adherence to the consent process that led to a well‐informed, voluntary, and responsible decision, and the participant’s understanding of the unique contribution they can make to change the world by participating in clinical research.

Psychological Status of the Participants in Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Colombia.

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. 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. 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. 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. A holistic mental health program, carried out in the context of a study, could mitigate psychopathology during pandemics such as COVID-19.

Outreach, Screening, and Randomization of APOE ε4 Carriers into an Alzheimer’s Prevention Trial: A global Perspective from the API Generation Program

BackgroundAlzheimer’s disease (AD) prevention trials require a large outreach and screening funnel to identify cognitively unimpaired adults who meet the study’s inclusion criteria, such as certain clinical or demographic criteria, genetic risk factors, and/or biomarker evidence of the disease.ObjectivesDescribe tactics and strategies to identify and enroll cognitively unimpaired adults with one (heterozygotes [HT]) or two (homozygotes [HM]) copies of the APOE ε4 allele, a genetic risk factor for dementia due to AD, into the Alzheimer’s Prevention Initiative (API) Generation Program, the largest and only prevention trials for late onset AD using this enrichment technique.Design and SettingThe Generation Program was comprised of two global, randomized, double-blind, placebo-controlled, parallel group adaptive design with variable treatment duration clinical trials. Generation Study 1 randomized participants into one of two cohorts: Cohort 1 which evaluated CAD106 vs. placebo or Cohort 2 which evaluated umibecestat vs placebo. Generation Study 2 randomized participants into two doses of umibecestat vs. placebo. The Generation Program was terminated early in 2019, while enrollment was still occurring.ParticipantsBoth Generation Study 1 and Generation Study 2 enrolled cognitively unimpaired APOE ε4 HMs aged 60–75; Generation Study 2 also enrolled APOE ε4 HTs ages 60–75 with elevated brain amyloid.Methods and MeasurementsDescribe results of the centralized and localized outreach, recruitment, screening strategies and tactics as well as characteristics of sites successful at enrolling genetically eligible participants, with a particular focus on APOE ε4 HMs given the 2–3% prevalence of this genotype.ResultsAt the time the trial program was terminated, 35,333 individuals had consented to the optional prescreening ICF1a/ ICFA and provided a sample of DNA for APOE genotyping, 1,138 APOE ε4 HMs consented to screening for Generation Study 1 (ICF1b), and 1,626 APOE ε4 carriers were randomized into either Generation Study 1 or Generation Study 2. Genetic testing registries, partnerships with genetic testing/counseling companies, and the optional prescreening ICF1a/ICFA were the most successful strategies for identifying genetically eligible participants for screening.ConclusionsIt is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites.

Rationale for the selection of dual primary endpoints in prevention studies of cognitively unimpaired individuals at genetic risk for developing symptoms of Alzheimer’s disease

BackgroundThere is a critical need for novel primary endpoints designed to detect early and subtle changes in cognition in clinical trials targeting the asymptomatic (preclinical) phase of Alzheimer’s disease (AD). The Alzheimer’s Prevention Initiative (API) Generation Program, conducted in cognitively unimpaired individuals at risk of developing AD (e.g., enriched by the apolipoprotein E (APOE) genotype), used a novel dual primary endpoints approach, whereby demonstration of treatment effect in one of the two endpoints is sufficient for trial success. The two primary endpoints were (1) time to event (TTE)—with an event defined as a diagnosis of mild cognitive impairment (MCI) due to AD and/or dementia due to AD—and (2) change from baseline to month 60 in the API Preclinical Composite Cognitive (APCC) test score.MethodsHistorical observational data from three sources were used to fit models to describe the TTE and the longitudinal APCC decline, both in people who do and do not progress to MCI or dementia due to AD. Clinical endpoints were simulated based on the TTE and APCC models to assess the performance of the dual endpoints versus each of the two single endpoints, with the selected treatment effect ranging from a hazard ratio (HR) of 0.60 (40% risk reduction) to 1 (no effect).ResultsA Weibull model was selected for TTE, and power and linear models were selected to describe the APCC score for progressors and non-progressors, respectively. Derived effect sizes in terms of reduction of the APCC change from baseline to year 5 were low (0.186 for HR = 0.67). The power for the APCC alone was consistently lower compared to the power of TTE alone (58% [APCC] vs 84% [TTE] for HR = 0.67). Also, the overall power was higher for the 80%/20% distribution (82%) of the family-wise type 1 error rate (alpha) between TTE and APCC compared to 20%/80% (74%).ConclusionsDual endpoints including TTE and a measure of cognitive decline perform better than the cognitive decline measure as a single primary endpoint in a cognitively unimpaired population at risk of AD (based on the APOE genotype). Clinical trials in this population, however, need to be large, include older age, and have a long follow-up period of at least 5 years to be able to detect treatment effects.

API ADAD Colombia Trial initial findings: a randomized, double‐blind, placebo‐controlled, parallel‐ group study in cognitively unimpaired PSEN1 E280A mutation carriers evaluating efficacy and safety of crenezumab

AbstractThe Alzheimer’s Prevention Initiative (API) ADAD Colombia trial enrolled 252 cognitively unimpaired 30‐ 60‐year‐old Presenilin 1 (PSEN1) E280A mutation carriers and non‐carriers; carriers were randomized 1:1 to crenezumab or placebo, non‐carriers received placebo only. Crenezumab is an anti‐amyloid monoclonal antibody that binds beta‐amyloid (Aβ) oligomers that is hypothesized to prevent the buildup of pathogenic Aβ plaques and modify Alzheimer’s disease (AD) progression with a low risk of amyloid related imaging abnormalities. The presentation will begin with a summary of the partnership between the Neurosciences Group of Antioquia and ADAD kindreds, including those who volunteered for the trial. Next will be a brief summary of the trial design and baseline participant characteristics, including the distribution of Aβ‐positive and ‐negative individuals, followed by the results for the co‐primary endpoints, change in cognitive function (using the API ADAD Cognitive Composite Test Battery) or episodic memory function (using the Free and Cued Selective Reminding Test); secondary efficacy results including time to clinical progression to MCI or dementia due to AD, time to Clinical Dementia Rating (CDR) score &gt;0, and increase in CDR Sum of Boxes; other outcomes including FAST, NPI, MMSE, CERAD word recall and RBANS results; and safety and tolerability. Last will be a presentation of results for changes in Aβ, FDG and tau PET; volumetric brain MRI; CSF biomarkers; a preview of pending plasma biomarker data; and a brief summary of the historical context and strategic aims of API and the trial. There will be an interactive question and answer session.

Clinical Profiles of Persons Who Progress to Cognitive Impairment in the Alzheimer’s Prevention Initiative (API) ADAD Colombia Trial

AbstractBackgroundIn Colombia, 13 pathogenic variants of presenilin 1 (PSEN1) causing Autosomal Dominant Alzheimer’s Disease (ADAD) have been identified. Some cases have atypical presentations, with variability in the age of onset and course of the disease. We characterized clinical profiles of cognitively unimpaired PSEN1 E280A mutation carriers who progress to MCI or dementia in the API ADAD Colombia Trial.MethodThe API ADAD Colombia Trial enrolled 252 cognitively unimpaired 30–60 year‐old participants into a 5‐8‐year double‐blind placebo controlled randomized prevention trial with a common close design. About 1/3 of participants were PSEN1 E280A mutation carriers who were randomized to the investigational anti‐oligomeric amyloid‐β antibody therapy crenezumab, 1/3 were mutation carriers who were randomized to placebo, and 1/3 were non‐carriers from the same kindred who were randomized to placebo. Trial results are pending. We used standardized procedures to blindly assess clinical features of participants who progressed to MCI and/or dementia during the trial, reviewed by an independent progression adjudication committee (PAC), to confirm the first instance of clinical progression.ResultDuring the trial 45 participants had an initial progression to MCI due to AD and 2 to dementia due to AD confirmed by the PAC. Among the 45 adjudicated with MCI due to AD, 32 subsequently progressed to dementia (30 due to AD and 2 due to other causes as determined by the site clinicians by consensus). The mean age onset of MCI was 45 (range 36–60 years) and of dementia was 47 (range 36–62 years). Three participants developed dementia before 40 years and one participant at 62 years. At the time of MCI, 43 participants had a predominantly amnesic profile, one had a predominantly behavioral disinhibition, and one had a Capgras syndrome, severe aggression and myoclonus. One participant developed severe global aphasia two years after the onset of dementia; two of the participant’s first‐degree relatives had language impairment in conjunction with MCI; one developed primary progressive logopenic aphasia.ConclusionSome persons with ADAD have an atypical clinical presentation. Additional studies are needed to clarify the biological changes, genetic/environmental risk factors, clinical course and response to treatment in these individuals.

A public resource of baseline data from the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial.

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. 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. 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. 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.

Psychological status in the participants of the API ADAD Colombia trial assisted by a comprehensive mental health program during COVID 19 pandemic

BackgroundDue to the global SARS‐CoV2 pandemic it has been hard to conduct research, including research related to prevention of neurodegenerative diseases. The Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) Colombia trial is being conducted in participants with family history of early‐onset dementia due to the PSEN1 E280A mutation who are cognitively unimpaired at baseline. Participants are enduring three stressors: 1) fear of developing dementia; 2) logistic changes to the study caused by the public health emergency due to the pandemic; and 3) concern about getting infected by SARS‐CoV2. Objective: To describe the frequency of new or exacerbated psychological disorders among the participants of the API ADAD Colombia trial assisted by a comprehensive mental health team during the COVID‐19 pandemic.MethodParticipants in the API ADAD Colombia trial have free access to psychology and psychiatry services, either in person or through teleassistance, as well as psychoeducational offerings. These mental health services are provided by the site, outside of the study protocol, and are supported by Health and Social plans which were created to support participants’ wellbeing during the trial. Descriptive statistics (mean, standard deviation and percentages) were used to analyze characteristics and frequency of mental health issues in the participants.Result66 participants (53 women, 80.3%) were treated by the Mental Health Team from March 1st, 2020 through December 31st, 2020. Mean age was 44.09 (SD 6.97) y.o. Before and after the pandemic onset, the most common psychological problems were anxiety (before 36.4%, after 63.6%) and depression (before 34.8 %, after 37.9%). From people who received psychological and psychiatric services, 70% vs. 81.6% felt that those services helped them, respectively. Among participants who received psychological vs. psychiatric assistance, 71.4% vs. 86.9% of patients with depression, 70.3% vs 75% of patients with anxiety and 60% vs 76.2% of patients with other disorders, felt the services helped them with these conditions.ConclusionA comprehensive mental health program immersed in a trial to prevent or treat devastating diseases as dementia, could mitigate the psychological effects of the COVID‐19 pandemic in study participants.

Strategies for activity maintenance in patient and family care and clinical trial adherence of GNA social plan in context of COVID‐19 health emergency

BackgroundThe current pandemic COVID‐19 caused by SARS‐CoV2 has become a public health challenge, causing difficulty in patient care and follow up of people with cognitive impairment due to Alzheimer's disease. This situation motivated changes and adjustments to the Group of Neurosciences of Antioquia’s (GNA) Social Plan to guarantee effective continuity in patient care, family follow‐up, community interventions and adherence to the Alzheimer’s Prevention Initiative (API) Colombia clinical trial. This was an opportunity to innovate, create, reinvent and expand forms of care and intervention during confinement and pandemic to promote access through virtual media and the well‐being of beneficiaries.MethodsThe Social Plan program involves free access to basic care supplies for patients, home‐visits, support groups, cognitive stimulation groups and virtual community outreach activities like workshops for caregivers/interested public, Alzheimer's Day Commemoration “Cuidarme – Cuidarte” event (with available recorded resources), symposiums for caregivers, and informative meetings with participants of the API Colombia clinical trial.ResultsIn the period of mandatory preventive confinement, 30 families obtained diapers, 23 families received prescription drugs not provided by health maintenance organizations (HMO) and 48 families received groceries. A total of 32 home‐visits were made: 7 in rural areas and 25 in urban areas. At the end of the mandatory preventive confinement, outpatient medical consults were resumed, no participants withdrew from the trial during this period. Thirty‐six people with MCI or dementia participated in virtual cognitive stimulation activities. Caregiver remote workshops held in the first semester of 2020 had a total attendance of 80 people, and events held in the second semester, such as the Commemoration of Alzheimer's Day and the Symposium for Caregivers, had a total attendance of 1,665 people and 1,000 people respectively.ConclusionGNA’s Social Plan and the amended which includes strategies of social support, knowledge and patient/caregiver empowerment strengthened the interaction between the community and GNA and likely favorably influenced adherence and retention in the API Colombia clinical trial in the face of challenges from the global pandemic.

Trajectory of Unawareness of Memory Decline in Individuals With Autosomal Dominant Alzheimer Disease

Recent studies have suggested that unawareness, or anosognosia, of memory decline is present in predementia stages of Alzheimer disease (AD) and may serve as an early symptomatic indicator of AD. To investigate the evolution of anosognosia of memory decline in individuals who carry the PSEN1 E280A variant for autosomal dominant AD compared with family members who do not carry the variant. This cohort study investigated a total of 2379 members of a Colombian kindred with autosomal dominant AD who were part of the Alzheimer's Prevention Initiative Registry. Assessments were completed at the University of Antioquia, Colombia, with data collected between January 1, 2000, and July 31, 2019. Awareness of memory function was operationalized using the discrepancy between self-report and study partner report on a memory complaint scale. Linear mixed effects models were used to assess memory self-awareness over age separately in variant carriers and noncarriers. This study included 396 variant carriers (mean [SD] age, 32.7 [11.9] years; 200 [50.5%] female), of whom 59 (14.9%) were cognitively impaired, and 1983 cognitively unimpaired noncarriers (mean [SD] age, 33.5 [12.5] years; 1129 [56.9%] female). The variant carriers demonstrated increased awareness until the mean (SD) age of 35.0 (2.0) years and had anosognosia at approximately 43 years of age, approximately 6 years before their estimated median age of dementia onset (49 years; 95% CI, 49-51 years). Cognitively unimpaired noncarriers reported more complaints than their study partners aged 20 and 60 years (10.1 points, P < .001). On the awareness index, a decrease with age (mean [SE] estimate, -0.04 [0.02] discrepant-points per years; t = -2.2; P = .03) in the noncarriers and in the variant carriers (mean [SE] estimate, -0.21 [0.04] discrepant-points per years; t = -5.1; P < .001) was observed. In this cohort study, increased participant complaints were observed in both groups, suggesting that increased awareness of memory function was common and nonspecific to AD in this cohort. In variant carriers, awareness of memory function decreased in the predementia stages, reaching anosognosia close to the age of mild cognitive impairment onset, providing support for the usefulness of awareness of memory decline.

Screening characteristics of PSEN1 E280A mutation carriers and non‐carriers in the API Autosomal Dominant Alzheimer’s Disease Colombia Trial

AbstractBackgroundThe Colombia Alzheimer’s Prevention Initiative (API) Registry was a resource for enrollment into the API Colombia clinical trial. Potentially eligible candidates from the Colombia API Registry went through a prescreening and then in‐person screening process with the goal of enrolling them in the API ADAD Colombia Trial. Analysis of screening data might provide additional information to consider for other AD prevention trials. We present descriptive screening data from the API ADAD Colombia trial in Presenilin 1 (PSEN1) E280A mutation carriers vs non‐carriers.MethodConsent was obtained from 319 potentially eligible participants after prescreening. Screening data from 315, including 210 mutation carriers, were used to compare demographics, medical comorbidities, toxic and reproductive antecedents, selected clinical, functional, and anthropometric measurements, vital signs, and brain MRI and laboratory results in the mutation carrier and non‐carrier groups. Descriptive statistics comparing mutation carriers and non‐carriers were performed using generalized linear regression models using link function according to whether the outcome was categorical or numerical. Results were adjusted for age, sex, level of education, depression or body mass index (BMI) depending upon which measurements were compared.ResultResults of the above characteristics at screening for carriers and non‐carriers will be presented. Briefly, compared to mutation non‐carriers in screening, carriers were younger (mean 40 vs 48 years), had similar educational attainment (mean 8.3 vs 7.5 years), and showed generally lower cognitive performance, especially in memory (e.g., mean (sd) CERAD world list scores were 20.30 (3.82) vs 19.46 (3.68), respectively). There were no differences in other demographic characteristics, medical comorbidities, toxic and reproductive antecedents, anthropometric measurements, vital signs, MRI findings or laboratory results. Mutation non‐carriers compared to carriers showed a non‐significant trend towards more vascular risks according to medical comorbidities (hypertension, dyslipidemia), borderline higher level of triglycerides and cholesterol, microvascular changes in the brain and higher BMI. The higher prevalence of vascular risk factors among non‐carriers may be explained by an 8‐year age difference between non‐carriers vs carriers.ConclusionThe API ADAD Colombia Trial screening data provide insights into demographics as well as clinical, cognitive and non‐cognitive characteristics, and medical comorbidities of a (PSEN1) E280A population.

Sex differences in neurodegeneration and memory performance in preclinical autosomal dominant Alzheimer’s disease: Baseline findings from the API ADAD trial

AbstractBackgroundGrowing evidence suggests that females have greater biological risk for Alzheimer’s disease (AD). As levels of AD pathology increase, females show greater tau accumulation, faster hippocampal volume loss, and faster cognitive decline than males. We sought to investigate sex differences in individuals with preclinical autosomal dominant AD (ADAD), who are destined to develop early‐onset dementia and have minimal age‐related confounds known to vary by sex (e.g., mortality, cardiovascular disease, or menopause). We plan to examine the role of sex in the associations among markers of pathology, neurodegeneration, and cognition leveraging baseline data from the Alzheimer’s Prevention Initiative (API) ADAD Colombia Trial.MethodsWe analyzed baseline data from 242 cognitively unimpaired 30‐53 year‐old prevention trial participants, including 167 PSEN1 E280A mutation carriers and 75 non‐carrier family members. Clinical ratings, CERAD word list delayed recall, hippocampal grey matter volume, florbetapir cortical‐to‐pontine standard‐uptake value ratios (SUVR), and precuneus 18F‐fludeoxyglucose (FDG) positron emission tomography were included in the analyses. T‐tests and multiple regressions models controlling for age, PSEN1 mutation status and amyloid burden were conducted.ResultsAcross groups, females had greater hippocampal volumes (p=.05) and better delayed recall (p=.005) than males. Female carriers were younger than male carriers (p=.04). Females continued to have better delayed recall after adjusting for glucose metabolism in the precuneus (Sex: β=.562, p=.023), and showed a trend towards significance after adjusting for hippocampal volumes (Sex: β=.462, p=.059). In carriers only, as age increased, males had lower hippocampal volumes than females (Slope difference: p ≤ .05), while no differences were found in amyloid levels or metabolism. There was no sex difference in the relationship between amyloid accumulation, hippocampal volumes (Sex: β=.000, p=.094), and metabolism (Sex: β=‐.004, p=.815).ConclusionFindings suggest that cognitively unimpaired female mutation carriers may have greater cognitive resilience to AD‐related neurodegeneration compared to male mutation carriers. Further investigation of sex‐specific differences in AD‐related clinical and pathological markers is key to inform AD detection, prevention, and development of treatments.

Depression and anxiety disorder along life in familial Alzheimer’s disease in the API ADAD Colombia trial

AbstractBackgroundSome late‐onset Alzheimer’s disease studies suggest that affective disorders begin before cognitive impairment and promote decline. Nevertheless, it has been observed that in Autosomal Dominant Alzheimer’s Disease (ADAD), asymptomatic mutation carriers have a lower risk of disorders such as depression compared to non‐carriers. The relationship between affective disorders and Alzheimer’s disease would be clearer if there were more studies in preclinical Alzheimer’s disease. Currently, the biggest population of familial Alzheimer’s disease, caused by the PSEN1 E280A mutation, is located in Colombia. The Alzheimer’s Prevention Initiative (API) ADAD Colombia trial is being conducted with PSEN1 E280A carriers and non‐carriers, cognitively unimpaired at baseline. During screening, investigators asked about antecedents of mental health disorders. We examined whether asymptomatic mutation carriers reported a different rate of affective disorders compared to non‐carriers.ObjectiveTo compare the prevalence of affective disorders between PSEN1 E280A mutation carriers and non‐carriers at the time of API ADAD trial screening.MethodWe performed a retrospective analysis to understand the history of affective disorders (reported by participants), after screening 315 mutation carriers and non‐carriers aged 30 ‐60 years. The comparison between carriers and non‐carriers was made by a generalized linear regression model. Results were adjusted by age, gender, educational level and the Clinical Dementia Rating (CDR) scale. Odds ratios (OR) were used as measure of association, with a 95% confidence interval (95%CI).Result315 candidates underwent screening: 210 carriers and 105 non‐carriers. Of people with antecedent of affective disorders, 65 (30.9%) were mutation carriers and 32 (30.5%) were non‐carriers. Comparing carriers with non‐carriers, the OR for depression was 1.010 (95%CI 0.492 – 2.113) and for anxiety was 1.325 (95%CI 0.485 – 3.938). Results were similar after excluding 15 participants with CDR of 0.5.ConclusionAlthough there were no differences between groups, the prevalence of affective disorders through life was high in carriers and non‐carriers, compared to the adult Colombian population (30.8% vs 6.7%). Possible reasons include: 1) Concern about having a family with an elevated risk of AD; 2) observing the progressive decline of close relatives; 3) living with or caring for persons with dementia.

Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study.

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. 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. 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. 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. 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.

CONNECT 4 APOE: A RANDOMIZED STUDY OF PHONE VERSUS VIDEOCONFERENCE DELIVERY OF APOE GENOTYPE DISCLOSURE IN THE GENERATION STUDY

APOE testing is increasingly important to identify candidates eligible for Alzheimer's trials. How best to provide genetic services for the disclosure of APOE results remains unclear. Both telephone and real-time videoconferencing (RTVC) have been shown to be feasible for remote delivery of genetic services, but outcomes have not been compared in a randomized trial. The Alzheimer's Prevention Initiative Generation Study 1 (NCT02565511) is enrolling cognitively normal APOE e4 homozygotes aged 60–75 years and includes a standardized approach to APOE disclosure. Some study sites do not have genetic providers to provide counseling and test disclosure to participants. CONNECT 4 APOE (NCT02978729) is a multi-site randomized study to evaluate the relative advantages of RTVC disclosure over telephone for disclosure of APOE genotype results in a large clinical trial. Participants are randomized to disclosure of results by phone or RTVC; counselors use standardized counseling checklists, risk estimates and visual aids. Knowledge and psychosocial outcomes are measured at various time points. In a planned interim analysis, 410 participants have been randomized (201 to RTVC, 209 to phone disclosure). Mean participant age is 67 years, 64% are female, 93% white, and >99% have a family history of dementia. 124 (31%) are APOE e4 homozygotes and 157 (39%) are heterozygotes. Participant characteristics and APOE results did not differ significantly between arms. In this early planned analysis, there were no statistically significant differences in change in any measured outcome from baseline to 2–7 days or 6 weeks post-disclosure (Table 1). Those in the telephone arm reported less increase in disease specific-distress, although this was not statistically significant. Satisfaction with services was slightly higher in the telephone disclosure arm post-disclosure (0.8 higher in telephone arm, p=0.07). Further analysis by APOE result (heterozygote v. homozygote v. noncarrier) will be completed to better understand if outcomes are similar by test result.