UNASSIGNED: In randomized clinical trials (RCTs), monitoring adverse events (AEs) and serious AEs (SAEs) is critical. All Alzheimer\'s disease (AD) RCTs require participants to enroll with a study partner.
UNASSIGNED: We examined AE reporting rates in mild-to-moderate AD trials and their associations with study partner type.
UNASSIGNED: We estimated AE reporting rates using placebo data from seven independent RCTs conducted by the Alzheimer\'s Disease Cooperative Study. We assessed the heterogeneity of reporting rates as a function of visits using generalized estimating equations. In the primary analysis, we tested the hypotheses that the rates of reporting differed by study partner type and time they spent with the participant weekly using Poisson regression with robust variance estimation. In all regression models, log-transformed total patient years was included.
UNASSIGNED: The estimated reporting rates were 2.83 (95% CI: 2.66, 3.02), 1.18 (95% CI: 1.09, 1.28), 0.23 (95% CI: 0.19, 0.27), and 0.28 (95% CI: 0.24, 0.33) events per participant year for grade 1-3 AEs and SAEs, respectively. We estimated that greater number of visits per year was associated with increased reporting for grade 1-2 AEs and SAEs. We did not find evidence to suggest that AE reporting differed by study partner type or by time the study partner spent with the participant.
UNASSIGNED: Study partner type and time the study partner spent with the participant did not appear to impact AE reporting. Estimated reporting rates may be useful to evaluate safety in future studies, particularly those with no control arm and similar visit frequencies.

BACKGROUND: Alzheimer\'s disease (AD) trials require enrollment with an informant.
METHODS: We assessed relationships between informant replacement and Alzheimer\'s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores across four AD trials. Using generalized estimating equations, we examined associations between replacement and change in ADCS-ADL between successive visits. We used analysis of covariance to estimate the association between replacement and 18-month change from baseline, and an F-test to compare the variance of this change.
RESULTS: Among 1336 participants, 63 (≈5%) experienced replacement. Between-visit mean change in ADCS-ADL was 2.44 points lower comparing replacement to stable informants (95% confidence interval [CI]: -3.91, -0.98). The difference in between-visit mean absolute change was 2.38 points (95% CI: 1.24, 3.52). Replacement was not significantly associated with an 18-month change from baseline. The ratio of variances (replacement/stable) was 1.80 (95% CI: 1.19, 2.99).
CONCLUSIONS: Informant replacement is associated with bias and increased variability between visits and increased variance for overall ADCS-ADL.

UNASSIGNED: The role of subjective cognitive concerns (SCC) as a diagnostic criterion for MCI remains uncertain and limits the development of a universally (or widely)-accepted MCI definition. The optimal MCI definition should define an at-risk state and accurately predict the development of incident dementia. Questions remain about operationalization of definitions of self- and informant-reported SCCs and their individual and joint associations with incident dementia.
UNASSIGNED: The present study included Einstein Aging Study participants who were non-Hispanic White or Black, free of dementia at enrollment, had follow-up, and completed neuropsychological tests and self-reported SCC at enrollment to determine MCI status. Informant-reported SCC at baseline were assessed via the CERAD clinical history questionnaire. Self-reported SCC were measured using the CERAD, items from the EAS Health Self-Assessment, and the single memory item from the Geriatric Depression Scale. Cox proportional hazards models examined the association of different operationalizations of SCC with Petersen and Jak/Bondi MCI definitions on the risk of dementia, further controlling for age, sex, education, and race/ethnicity. Time-dependent sensitivity and specificity at specific time points for each definition, and Youden\'s index were calculated as an accuracy measure. Cox proportional hazards models were also used to evaluate the associations of combinations of self- and informant-reported SCC with the risk of incident dementia.
UNASSIGNED: 91% of the sample endorsed at least one SCC. Youden\'s index showed that not including SCC in either Jak/Bondi or Petersen classifications had the best balance between sensitivity and specificity across follow-up. A subset of individuals with informants, on average, had a lower proportion of non-Hispanic Blacks and 94% endorsed at least one self-reported SCC. Both informant-reported and self-reported SCC were significantly associated with incident dementia.
UNASSIGNED: Our findings suggest that the SCC criterion may not improve the predictive validity for dementia when included in widely-employed definitions of MCI. Consistent with some prior research, informant-reported SCC was more related to risk of incident dementia than self-reported SCC. Given that requiring informant report as a diagnostic criterion may unintentionally exclude health disparate groups, additional consideration is needed to determine how best to utilize informant-report in MCI diagnosis.

Alzheimer\'s disease (AD) clinical research depends on engaging and enrolling appropriate research participants to address specific scientific questions. Investigators, however, are beginning to recognize the importance of participant study partners who contribute to AD research in multiple ways, including their contributions to the diagnostic process through observations of participant cognition and daily functioning. These contributions justify increased efforts to understand factors that impede or facilitate their willingness to remain in this role in longitudinal studies and clinical trials. Study partners, including those from diverse, underrepresented communities, are stakeholders significantly invested in AD research that benefits all living with the disease.

UNASSIGNED: Subjective cognitive decline (SCD) has been associated with elevated amyloid levels and increased risk of future cognitive decline, as well as modifiable variables, including depression, anxiety, and physical inactivity. Participants generally endorse greater and earlier concerns than their close family and friends (study partners [SPs]), which may reflect subtle changes at the earliest stages of disease among participants with underlying neurodegenerative processes. However, many individuals with subjective concerns are not at risk of Alzheimer\'s disease (AD) pathology, suggesting that additional factors, such as lifestyle habits, may be contributory.
UNASSIGNED: We examined the relation between SCD, amyloid status, lifestyle habits (exercise, sleep), mood/anxiety, and demographic variables among 4481 cognitively unimpaired older adults who are being screened for a multi-site secondary prevention trial (A4 screen data; mean ±SD: age = 71.3 ±4.7, education = 16.6 ±2.8, 59% women, 96% non-Hispanic or Latino, 92% White].
UNASSIGNED: On the Cognitive Function Index (CFI) participants endorsed higher concerns compared to SPs. Participant concerns were associated with older age, positive amyloid status, worse mood/anxiety, lower education, and lower exercise, whereas SP concerns were associated with older participant age, male gender of participant, positive amyloid status of participant, and worse participant-reported mood/anxiety.
UNASSIGNED: Findings suggest that modifiable/lifestyle factors (e.g., exercise, education) may be associated with participant concerns among cognitively unimpaired individuals and highlight the importance of further examining how modifiable factors impact participant- and SP-reported concerns, which may inform trial recruitment and clinical interventions.

UNASSIGNED: Individuals with subjective cognitive complaints (SCCs) are at an increased risk of dementia. Questions remain about participant-reported versus informant-reported SCCs as indicators of future dementia and about longitudinal changes in participant-and informant-reported SCCs and risk of incident dementia.
UNASSIGNED: Participants were 873 older adults (M = 78.65-years; 55% female) and 849 informants from the Sydney Memory and Ageing Study. Comprehensive assessments occurred biennially, and clinical diagnoses were made by expert consensus for 10-years. SCCs were participants\' and informants\' responses to a single binary question concerning their/the participant\'s memory decline (Yes/No) over the first 6-years. Categorical latent growth curve analyses, using the logit transformation, were used to model SCC change over time. Associations of initial propensity to report SCCs at baseline, and change in propensity to report SCCs over time, with dementia risk were examined using Cox regression.
UNASSIGNED: 70% of participants reported SCCs at baseline, with a proportional increase in the odds of reporting by 11% for each additional year in the study. In contrast, 22% of informants reported SCCs at baseline, with a proportional increase by 30% in the odds of reporting per year. Participants\' initial level of (p = 0.007), but not change in SCC reporting (p = 0.179), was associated with risk of dementia controlling for all covariates. Both informants\' initial level of (p < 0.001), and change in (p < 0.001), SCCs significantly predicted incident dementia. When modelled together, informants\' initial level of, and change in, SCCs were still independently associated with increased dementia risk (p\'s < 0.001).
UNASSIGNED: These data suggest that informants\' initial impressions, and increased reporting, of SCCs appear to be uniquely prognostic of future dementia compared to participants\', even based on a single SCC question.

Although subjective cognitive decline (SCD) may be an early risk marker of Alzheimer\'s Disease (AD), research on SCD among Hispanics/Latinos/as/x (henceforth Latinos/as) living in the U.S. is lacking. We investigated if the cross-sectional relationship of self-reported SCD with objective cognition varies as a function of ethnic background (Latinos/as versus Non-Hispanic Whites [NHWs]). Secondary analyses conducted solely within the Latino/a group investigated if informant reported SCD is associated with objective cognition and whether self-reported SCD is related to markers of brain health in a sub-sample of Latinos/as with available MRI data.
Eighty-three participants (≥60 years of age) without dementia (35 Latinos/as; 48 NHWs) completed the Mattis Dementia Rating Scale (MDRS) and the Subjective Cognitive Decline-Questionnaire (SCD-Q). Additionally, 22 Latino/a informants completed the informant-version of the SCD-Q. Hierarchical regression models investigated if ethnicity moderates the association of MDRS and SCD-Q scores after adjusting for demographics and depressive symptoms. Correlational analyses within the Latino/a group investigated self- and informant-reported associations of SCD-Q scores with objective cognition, and associations of self-reported SCD-Q scores with medial temporal lobe volume and thickness.
Latinos/as had lower education and MDRS scores than NHWs. Higher SCD-Q scores were associated with lower MDRS scores only in Latinos/as. Within the Latino/a group, self, but not informant reported SCD was related to objective cognition. Medium to large effect sizes were found whereby higher self-reported SCD was associated with lower entorhinal cortex thickness and left hippocampal volume in Latinos/as.
The association of SCD and concurrent objectively measured global cognition varied by ethnic background and was only significant in Latinos/as. Self-reported SCD may be an indicator of cognitive and brain health in Latinos/as without dementia, prompting clinicians to monitor cognition. Future studies should explore if SCD predicts objective cognitive decline in diverse groups of Latinos/as living in the U.S.

Early study exit is detrimental to statistical power and increases the risk for bias in Alzheimer\'s disease clinical trials. Previous analyses in early phase academic trials demonstrated associations between rates of trial incompletion and participants\' study partner type, with participants enrolling with non-spouse study partners being at greater risk.
We conducted secondary analyses of two multinational phase III trials of semagacestat, an oral gamma secretase inhibitor, for mild-to-moderate AD dementia. Cox\'s proportional hazards regression model was used to estimate the relationship between study partner type and the risk of early exit from the trial after adjustment for a priori identified potential confounding factors. Additionally, we used a random forest model to identify top predictors of dropout.
Among participants with spousal, adult child, and other study partners, respectively, 35%, 38%, and 36% dropped out or died prior to protocol-defined study completion, respectively. In unadjusted models, the risk of trial incompletion differed by study partner type (unadjusted p value = 0.027 for test of differences by partner type), but in models adjusting for potential confounding factors, the differences were not statistically significant (p value = 0.928). In exploratory modeling, participant age was identified as the primary characteristic to explain the relationship between study partner type and the risk of failing to complete the trial. Participant age was also the strongest predictor of trial incompletion in the random forest model.
After adjustment for age, no differences in the risk of incompletion were observed when comparing participants with different study partner types in these trials. Differences between our findings and the findings of previous studies may be explained by differences in trial phase, size, geographic regions, or the composition of academic and non-academic sites.

Assessment of functional status is associated with risk of cognitive decline and diagnosis of dementia, and can be assessed by participants and study partners (SPs).
In 770 older adults enrolled in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study and the online Brain Health Registry (BHR), we estimated associations between online assessments and clinical variables related to Alzheimer\'s disease (AD) risk.
Worse online learning scores and SP-reported functional decline were associated with higher probability of AD dementia diagnosis and poor in-clinic cognitive assessment, and with higher odds of amyloid beta (Aβ) positivity when combined with participants\' report of less decline. SP report of functional decline conferred predictive value independent of online cognitive assessments. Participants underreported decline compared to SPs.
The results support the validity of online assessments and their greater utilization in healthcare and research settings. Online SP-reported functional decline is an indicator of dementia and AD risk.

BACKGROUND: Cognitive dysfunction is common in Parkinson\'s disease (PD) and associated with reduced functional abilities and increased dependence. To date, however, little is known about the relationship between performance of instrumental activities of daily living (IADLs) and cognitive stages in PD, and there are conflicting reports as to whether declines in specific cognitive domains predict IADL impairment.
METHODS: Participants with PD were drawn from the Pacific Udall Center and included in the study if both participant and study partner IADL ratings and cognitive tests were completed (n = 192). Logistic regression analyses were performed to determine whether participant and/or study partner rating predicted mild cognitive impairment or dementia. Correlations are reported for the relationship between participant/study partner IADL reports as well as for specific cognitive tests.
RESULTS: Although both participant and study partner ratings of IADL performance were associated with a diagnosis of PD with dementia, only participant self-rating of functional ability was significantly associated with a diagnosis of PD with mild cognitive impairment. Functional ability correlated most strongly with measures of processing speed, auditory working memory, and immediate verbal recall for both the participant and study partner ratings.
CONCLUSIONS: For participants with PD in the early stages of cognitive decline, self-rating may be more sensitive to the impact of cognitive changes on IADL function than ratings made by a knowledgeable study partner. Changes in executive function, processing speed, and learning may indicate a higher likelihood of IADL impairment. Careful assessment of cognition and IADL performance is recommended to permit individualized interventions prior to significant disability.