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This open-label extension study evaluated the long-term safety and tolerability of idalopirdine 60 mg/day as adjunctive therapy in patients with mild-moderate Alzheimer's disease (AD). This extension study was a continuation of Studies 1 and 2 of the Phase III development program for idalopirdine and comprised a 28-week open-label treatment period ("OLEX") and a subsequent 24-week open-label treatment period with memantine ("MEMOLEX") in selected patients. The previous studies had shown no evidence of efficacy with idalopirdine as adjunctive treatment to donepezil but with good tolerability (of 1,791 patients randomized, 1,609 [90%] completed the double-blind studies). Of those, 1,463 patients (91%) entered the open-label extension study. During the 28-week OLEX period, the percentage of patients having treatment-emergent adverse events (TEAEs) ranged between 51% and 59% across the treatment groups originating from the lead-in studies. During the subsequent 24-week MEMOLEX period, 51% of the patients had TEAEs. Increases in liver enzymes (occurring in 1-3% of trial participants) were transient and no new safety signals were observed with longer term exposure. No consistent effects demonstrating benefits with idalopirdine were observed on efficacy parameters when patients transitioned to 60 mg in the extension study. Overall, idalopirdine was safe and well tolerated when added to donepezil, and when memantine was added to a prior combination of idalopirdine and donepezil. There were no new safety signals observed with up to 18 months of exposure at the described doses to idalopirdine. [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: The impact of sex steroid hormones on Alzheimer's disease (AD) remains to be further clarified. Research suggests that shorter reproductive span, late menarcheal age, early menopause, oophorectomies and hysterectomies, are associated with increased dementia risk. We examined reproductive health and its associations with brain imaging and cognitive measurements in unimpaired female Presenilin 1 (PSEN1) E280A mutation carriers and non‐carriers from the Alzheimer's Prevention Initiative Autosomal Dominant AD (API ADAD) Trial (NCT01998841). Method: A total of 151 cognitively unimpaired 30‐53 year‐old females (101 PSEN1 mutation carriers and 50 non‐carriers) were included. Reproductive health data (i.e., menarcheal age, number of pregnancies, deliveries, miscarriages, and living children) from all participants were examined, as well as the extent to which menarcheal age was related to age‐adjusted baseline 1) cortical amyloid plaque burden (florbetapir PET), 2) Precuneus cerebral glucose metabolism (fluorodeoxyglucose PET), 3) hippocampal volume (3TMRI), and 4) the API ADAD preclinical cognitive composite score, which includes the MMSE Orientation score, CERAD Word List Delayed Recall and Constructional Praxis, Multilingual Naming Test and Raven's Progressive Matrices subset. We examined associations with the cognitive and brain imaging measures corrected for multiple comparisons (Bonferroni). Result: Carrier and non‐carrier females did not differ on number of pregnancies, deliveries, miscarriages, or living children. Female carriers had a significantly younger menarcheal age than non‐carriers (12.8 ±1.5 versus 13.7±1.6 years, p = 0.007, Bonferroni). Among carrier females, older menarcheal age was associated with lower scores on the Raven's test (Bonferroni: r = ‒0.28,p =0.035). Menarcheal age was not associated with scores on the cognitive composite or other individual subtests, or with brain imaging measures. Conclusion: Our findings suggest reproductive health data did not differ between carrier and non‐carrier females, except for a slightly younger menarcheal age compared to non‐carriers, and that menarcheal age may have a very limited impact on brain pathology and function at preclinical stages of ADAD. Longitudinal studies with larger samples are needed to clarify the extent to which earlier menarcheal age may be related to changes in cognitive function in mutation carrier females transitioning from preclinical to clinical stages. [ABSTRACT FROM AUTHOR]

Background: With the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer's Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals.Methods and Findings: We included cognitively unimpaired individuals aged 60-75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer's Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60-64, 65-69, 70-75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60-64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65-69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70-75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80-85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%-38.45% at age 60-64 y, 30.76%-40.26% at 65-69 y, and 33.3%-35.17% at 70-75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables.Conclusions: Estimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies-with implications for informed consent and design for clinical trials targeting high-risk individuals. [ABSTRACT FROM AUTHOR]