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Background: Neuropsychiatric symptoms (NPS) are common in early stages of Alzheimer's disease (AD) and may be early markers of cognitive decline and dementia in older individuals. The Mild Behavioral Impairment Checklist (MBI‐C) was developed to capture new‐onset transdiagnostic NPS in individuals at risk of dementia. We sought to determine whether mild behavioral impairment symptoms are elevated in non‐demented Presenilin‐1 (PSEN1) E280A carriers, who are genetically determined to develop dementia by their 50s. We hypothesized that those with higher MBI‐C total scores would have worse memory performance and greater brain pathology. Method: A total of 25 mutation carriers (mean age = 36.3±7.23; 56% females; 18 cognitively‐unimpaired, 7 impaired) and 30 non‐carriers (70% females) from the Colombia‐Boston (COLBOS) Biomarker study were included. All participants completed cognitive testing, the MBI‐C (self‐reported), and florbetapir (amyloid), flortaucipir (tau) PET, and structural magnetic resonance imaging. We used Mann‐Whitney Test to examine group differences, and Spearman's correlation and linear regression to examine associations among MBI‐C total score, Geriatric Depression Scale‐15 (GDS), Mini‐Mental State Examination (MMSE), CERAD word list learning delayed recall, cortical amyloid burden, regional tau, and hippocampal volume. In sensitivity analyses, we restricted carriers to the 18 unimpaired. Result: MBI‐C total scores were similar between carriers and non‐carriers (p = 0.09). Compared to non‐carriers, carriers had greater amyloid burden (r = 0.55; p = 0.004) and lower hippocampal volume (r = ‐0.43; p = 0.034). Among all carriers, higher MBI‐C total scores were associated with lower hippocampal volume (r = ‐0.44; p = 0.034), greater amyloid burden (r = 0.5; p = 0.011), and worst memory performance (r = ‐0.36; p = 0.021). There were no associations with tau pathology (p‐values>0.05). Sensitivity analyses were consistent with previous results except for hippocampal volume (r = ‐0.4; p = 0.08). Conclusion: Findings suggest that NPS captured by MBI‐C are associated with pathology and memory in a Colombian kindred with autosomal dominant AD, years before the median age of dementia onset in this cohort. This underscores the importance of behavioral symptoms in preclinical and prodromal ADAD. Follow‐up analyses with larger samples and longitudinal assessments are needed to characterize neuropsychiatric symptom evolution as an early marker and target for intervention. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) biomarkers have potentially important roles in Alzheimer's disease (AD) treatment and prevention trials. The Alzheimer's Prevention Initiative Autosomal‐Dominant AD (API ADAD) trial protocol (NCT01998841) includes optional CSF biomarker measurements at baseline, 24 months, and 60 months. We determined the adherence to lumbar puncture (LP) procedures and predictors of dropout rates in trial participants who had a baseline LP. Method: Available data from cognitively unimpaired 30–60‐year‐old members of the Presenilin 1 E280A kindred were used to characterize LP participation rates at baseline, LP‐related complications and potential factors associated with adherence to 24‐month follow‐up LPs (age, sex, education, place of residence, puncture site, needle gauge, number of attempts, and traumatic puncture). Logistic regression was used to investigate associations. Result: 130 (51.6%) of 252 trial individuals consented to participate in the CSF biomarkers substudy. Consent was not associated with age, sex, education or location of residence. 43 (33.1%) participants had 49 LP‐related complications at baseline. The most frequent complications were headache in 25 (19.2%) participants and low back pain in 14 (10,8%) participants. Other baseline LP‐related events were dizziness, photopsia, and tremor. Complications at baseline were not associated with puncture site (L3‐L4 or L4‐L5), needle gauge (22 or 24 G), number of attempts or traumatic puncture. Ninety‐eight (75.4%) of the eligible participants consented to have the 24‐month follow‐up LP. Absence of any baseline LP‐related complications was associated with less attrition in this subsequent LP consent (0R = 0.25; 95%CI 0.10‐0.61), after controlling for age, sex, years of schooling, rural home and city of residence. Conclusion: Adherence to 24‐month follow‐up LP in API ADAD trial was 75.4%. This clinical trial is conducted in young people, active at work. Although some participants live far from the city where LP's are performed or in remote areas, this did not affect their willingness to consent to a second LP. However, the presence of any complication did increase the risk of withdrawal for the subsequent procedure since it impacted ability to work. This information could help to inform the design and statistical power of future AD prevention trials using CSF biomarker endpoints. [ABSTRACT FROM AUTHOR]

Background: Some but not all studies have found compromised myocardial function and amyloid deposition, related or unrelated to amyloid‐β pathology itself, in persons with late‐onset Alzheimer's Disease (AD). Other changes in QT interval, heart rate variability, and QRS voltages have been described in the electrocardiogram (ECG), but those are not consistent between studies. We explored differences in several ECG measures in cognitively unimpaired (CU) Presenilin 1 (PSEN1)‐E280A carriers and non‐carriers from the Alzheimer's Prevention Initiative Autosomal Dominant AD (API ADAD) Trial (NCT01998841). Method: The trial enrolled 252 CU 30–60‐year‐old participants. We included participants (144 PSEN1‐E280A mutation carriers and 71 non‐carriers) in these analyses who were enrolled in the trial during their first screening attempt. Baseline cardiovascular data and medical history were obtained by medical assessment and blood sample. Interval durations, QRS voltages of all leads, and the diagnosis were taken from baseline ECG. T‐test, chi‐square, correlation, and effect size were used in the data analysis. The p values in this are exploratory. Result: Mean age (years) for carriers was 36 and 43 for non‐carriers. Years of education, sex, and clinical variables like body mass index, cholesterol, hemoglobin A1c, TSH, and previous cardiovascular disorders were similar between groups. There were no differences in the heart rate, PR, QRS, or corrected QT interval duration. Voltages in AVL and DI leads were lower in carriers than non‐carriers with a low size of effect (0.42 vs. 0.50, p = 0.03; 0.64 vs. 0.71, p = 0.04, respectively), while the other ten leads and low voltage in any of the 12 derivates did not show any difference. There was also a negative and small correlation between voltage and age for DII, V6, and AVR (‐0.146, ‐0.144, ‐0.137; p = 0.03,0.03,0.04; respectively). Conclusion: Our findings suggest no clinically significant difference in ECG parameters between PSEN1‐E280A mutation carriers compared to non‐carriers. Since intramyocardial deposits of amyloid‐β are age‐dependent, it is likely that there are low levels of these deposits in young CU individuals. Longitudinal studies with larger samples that include CU patients might identify ECG‐related changes associated with amyloid‐β cardiac deposits. [ABSTRACT FROM AUTHOR]

Background: In 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. Method: The 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. Result: During 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. Conclusion: Some 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. [ABSTRACT FROM AUTHOR]

Background: Due 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. Method: Participants 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. Result: 66 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. Conclusion: A 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. [ABSTRACT FROM AUTHOR]

Background: The 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. Methods: The 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. Results: In 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. Conclusion: GNA'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. [ABSTRACT FROM AUTHOR]

Background: Some 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. Objective: To compare the prevalence of affective disorders between PSEN1 E280A mutation carriers and non‐carriers at the time of API ADAD trial screening. Method: We 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). Result: 315 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. Conclusion: Although 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. [ABSTRACT FROM AUTHOR]