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AbstractBackgroundPartners of persons with mild cognitive impairment (pwMCI) show increased rates of depression and other mental health problems compared to the general population. While dyadic behavioral interventions such as cognitive rehabilitation have shown beneficial effects in reducing caregiver burden, research to date lacks consistent outcome measures and rarely focuses on distressed partners. Therefore, this study explored the longitudinal effect of the Healthy Action to Benefit Independence & Thinking® (HABIT) program on partners with relatively low initial adjustment level. We hypothesized that the HABIT program would improve partner adjustment in those who were distressed.MethodData from 322 pwMCI and partners were utilized from the HABIT IRB research registry. Among them, 240 completed HABIT while 82 served as an untreated control group. Consistent with our previous exploratory factor analysis, a composite partner adjustment score was calculated using the Center for Epidemiologic Studies Depression scale (CES‐D), the REACH Anxiety Inventory Form, and the Quality of Life scale for adults with Alzheimer’s Disease (QOL‐AD). We included partners with an adjustment score below the median of each group to focus on partners with low levels of baseline adjustment. Latent growth curve models were conducted at baseline, 3‐month, 6‐month, and 1‐year follow‐ups to investigate the trajectories of partner adjustment level.ResultIn the low adjustment subsample, no between group difference was found at baseline. An overall improvement in partner adjustment scores was observed only in the treatment group (b = 5.00, p<.001). The slope of change was larger (b = 3.75, p = .016) in the treatment group, indicating a faster improvement in adjustment level in HABIT partners with marginally lower baseline and higher follow‐up scores. This difference in the improvement rates was most evident at the 3‐month follow‐up (t(1, 94) = ‐2.63, p = .010) and gradually reduced in subsequent visits.ConclusionIn partners of those with MCI who have low levels of emotional adjustment, behavioral interventions like HABIT can be beneficial in accelerating improvement in their overall adjustment level and facilitate adaptation to their loved ones’ MCI symptoms compared to untreated controls. Techniques taught in dyadic interventions may serve as protective factors for mental health problems in primary caregivers of pwMCI.

AbstractINTRODUCTIONResting‐state functional magnetic resonance imaging (fMRI) graph theory may help detect subtle functional connectivity changes affecting memory prior to impairment.METHODSCognitively normal apolipoprotein E (APOE) ε4 carriers/noncarriers underwent longitudinal cognitive assessment and one‐time MRI. The relationship of left/right hippocampal connectivity and memory trajectory were compared between carriers/noncarriers.RESULTSSteepness of verbal memory decline correlated with decreased connectivity in the left hippocampus, only among APOE ε4 carriers. Right hippocampal metrics were not correlated with memory and there were no significant correlations in the noncarriers. Verbal memory decline correlated with left hippocampal volume loss for both carriers and noncarriers, with no other significant volumetric findings.DISCUSSIONFindings support early hippocampal dysfunction in intact carriers, the AD disconnection hypothesis, and left hippocampal dysfunction earlier than the right. Combining lateralized graph theoretical metrics with a sensitive measure of memory trajectory allowed for detection of early‐stage changes in APOE ε4 carriers before symptoms of mild cognitive impairment are present.Highlights Graph theory connectivity detects preclinical hippocampal changes in APOE ε4 carriers. The AD disconnection hypothesis was supported in unimpaired APOE ε4 carriers. Hippocampal dysfunction starts asymmetrically on the left.

AbstractBackgroundThe syndrome of mild cognitive impairment (MCI) is classified into different subtypes– amnestic MCI (aMCI) and non‐amnestic MCI based on cognitive domains impacted, while different underlying disease etiologies cause the impairments. The Memory Support System (MSS), a memory‐support tool which utilizes a calendar/planner, has been shown to have positive impact on daily functioning in MCI (Chandler et al., 2017). We have previously shown that cognitive impairment severity and personality traits are associated with MSS learning (De Wit et al., 2021; Khayoun et al., 2021). In this study, we hypothesized that 1) participants with single domain aMCI (SD‐aMCI) will have higher MSS learning scores than multi‐domain aMCI (MD‐aMCI), and 2) participants with suspected Alzheimer’s disease (AD) etiology will have lower MSS learning scores than other etiologies.MethodParticipants (mean age = 75.2) underwent daily MSS training between 2017 and 2021 as part of the 10‐day Mayo Clinic HABIT program. The MSS learning success score (LSS) was determined by how far participants progressed in three learning phases of increasing difficulty: Acquisition (0‐2 points), Application (3‐4 points), and Adaptation (5‐6 points; Greenway et al., 2008). Ordinal logistic regression analysis was used to predict MSS learning scores between SD‐aMCI (n = 142) versus MD‐aMCI (n = 119), and AD etiology (n = 213) versus other neurodegenerative etiologies (n = 57). Dementia Rating Scale‐2 scores (Jurica, 2001) were included to control for cognitive severity.ResultCompared to participants with SD‐aMCI, those with MD‐aMCI had 54.1% lower odds of having higher LSS at training end (p = .004), after controlling for cognitive impairment severity. AD versus other etiology’s impact on LSS was nonsignificant.ConclusionParticipants with MD‐aMCI showed poorer MSS learning efficiency than participants with SD‐aMCI. Etiology did not impact MSS learning. Results suggest having more than just memory impairment (e.g., additional language or executive dysfunction) reduces MSS learning, regardless of overall impairment level. Additional MSS training may be needed to facilitate learning for these individuals.

Background: Older age is a major risk factor for severe COVID-19 disease which has been associated with a variety of neurologic complications, both acutely and chronically. Objective: We sought to determine whether milder COVID-19 disease in older vulnerable individuals is also associated with cognitive and behavioral sequelae. Methods: Neuropsychological, behavioral, and clinical outcomes before and after contracting COVID-19 disease, were compared in members of two ongoing longitudinal studies, the Arizona APOE Cohort and the national Alzheimer’s Disease Research Center (ADRC). Results: 152 APOE and 852 ADRC cohort members, mean age overall roughly 70 years, responded to a survey that indicated 21 APOE and 57 ADRC members had contracted COVID-19 before their ensuing (post-COVID) study visit. The mean interval between test sessions that preceded and followed COVID was 2.2 years and 1.2 years respectively for the APOE and ADRC cohorts. The magnitude of change between the pre and post COVID test sessions did not differ on any neuropsychological measure in either cohort. There was, however, a greater increase in informant (but not self) reported cognitive change in the APOE cohort (p = 0.018), but this became nonsignificant after correcting for multiple comparisons. Conclusion: Overall members of both cohorts recovered well despite their greater age-related vulnerability to more severe disease.

AbstractBackgroundBehavioral interventions are often recommended for persons with mild cognitive impairment (MCI). The Healthy Action to Benefit Independence & Thinking® Program (HABIT) has been shown to benefit activities of daily living (ADL) and self‐efficacy in patients at 6‐ and 12‐months post intervention. However, to date, the findings have been limited by comparison to a relatively small, untreated control group. This study attempted to explore HABIT ADL outcomes compared to a large, presumably untreated Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort.MethodA total of 767 participants with MCI were selected from the ADNI database, whereas 478 participants with MCI were recruited from the HABIT IRB approved research registry. Functional outcomes were assessed with informant‐based measures ‐ Functional Activities Questionnaire (FAQ) and Everyday Cognition scale (ECOG) memory and total scores – at both 6‐month‐ and 12‐month‐follow‐ups. After near‐neighbor propensity score matching with a caliper of 0.2, 288 participants from each group were matched for the FAQ, and 333 were matched for the ECOG scores. Latent growth curve models were used to test the hypothesis that the HABIT program might delay functional decline in patients with MCI.ResultAfter matching HABIT group continued to show higher initial scores on FAQ (b=.849, p=.013), and ECOG memory (b=.200, p=.004) and total scores (b=1.115, p<.001) compared to the ADNI group. Although an increase in scores was observed in both groups for each functional outcome, the slopes were steeper for the HABIT group for FAQ (b=1.194, p<.001), ECOG memory (b=.073, p=.019) and ECOG total (b=.383, p=.007).ConclusionContrary to our hypothesis, in this non‐randomized study, partners of HABIT participants with MCI reported more rapid functional decline compared to those in an imaging study. This discrepancy could be due to the HABIT group’s higher baseline impairment level even after matching. Furthermore, patients with perceived more rapid decline may be more likely to seek interventions relative to those who elect to participate in a non‐interventional imaging study. In addition, the intervention sessions could prime the partners to be more scrupulous and aware when rating functional assessments. Additional randomized research may help add clarity to these findings.

Although recent studies have explored the potential of multidomain brain health programs, there is a dearth of literature on operationalizing this research to create a clinical treatment program specifically for subjective cognitive decline (SCD). Patients seen by geriatricians in primary care and by behavioral neurology services at our institution presenting with SCD were recruited via a patient-appropriate flyer. After all participants had a 1-h brain health consultation with a neuropsychologist and were provided with program materials, they were randomized to attend a 10-week intervention designed to support program implementation (N = 10) or the control group of implementing the program on their own (N = 11). The program included (1) a calendar-based executive and memory support system for compensatory training and (2) training in healthy lifestyle. There were no significant differences between groups for any outcomes. Participants across both groups showed significant improvements with moderate effect sizes in compensatory strategy use, anxiety symptoms, and daily functioning, which were sustained through 6-month follow-up. They also increased physical activity by the end of the intervention period but did not sustain this through 6-month follow-up. Our pilot study demonstrates preliminary feasibility of a cognitive compensatory and lifestyle-based brain health program. Additional research is recommended to further develop two potentially scalable implementation strategies—coaching and self-implementation after brief consultation.

Background: In Alzheimer’s disease and related disorders (ADRD) research, common outcome measures include cognitive and functional impairment, as well as persons with mild cognitive impairment (pwMCI) and care partner self-reported mood and quality of life. Studies commonly analyze these measures separately, which potentially leads to issues of multiple comparisons and/or multicollinearity among measures while ignoring the latent constructs they may be measuring. Objective: This study sought to examine the latent factor structure of a battery of 12-13 measures of domains mentioned above, used in a multicomponent behavioral intervention (The HABIT® program) for pwMCI and their partners. Methods: Exploratory factor analysis (EFA) involved 214 pwMCI-partner pairs. Subsequent Confirmatory factor analyses (CFA) used 730 pairs in both pre- and post-intervention conditions. Results: EFA generated a three-factor model. Factors could be characterized as partner adjustment (29.9%), pwMCI adjustment (18.1%), and pwMCI impairment (12.8%). The subsequent CFA confirmed our findings, and the goodness-of-fit for this model was adequate in both the pre- (CFI = 0.937; RMSEA = 0.057, p = 0.089) and post-intervention (CFI = 0.942; RMSEA = 0.051, p = 0.430) groups. Conclusion: Results demonstrated a stable factor structure across cohorts and intervention conditions suggesting that three broad factors may provide a straightforward and meaningful model to assess intervention outcome, at least during the MCI phase of ADRD.

There is currently limited and mixed evidence for the cognitive benefits of Computerized Cognitive Training (CCT) and yoga in persons with Mild Cognitive Impairment (pwMCI). The objective of this study was to investigate the benefit of computerized cognitive training (CCT) vs. physical (yoga) intervention on cognitive abilities. Participants in this study were part of the larger Mayo Clinic’s Healthy Action to Benefit Independence and Thinking (HABIT) program comparative effectiveness trial. The HABIT program is designed for pwMCI and their care partner and consists of five behavioral interventions: CCT, Memory Support System-Calendar (MSS-Calendar), wellness education, support groups, and yoga. The subtractive study design randomly withheld one of the interventions for a total of five study arms. Longitudinal mixed-effects regression models were used to investigate the hypothesis that CCT and yoga has a greater positive impact on psychomotor and basic attention abilities at 12 months post-intervention as compared to the other HABIT interventions. Findings showed CCT had a positive impact compared to yoga on the Cogstate psychomotor/attention composite at 12 months post-intervention (ES = 0.54; unadjusted p value = 0.007, adjusted p value = 0.021). The impact of yoga or combining CCT with yoga did not show statistically significant improvement. Continued CCT practice at home showed further benefit on psychomotor/attention at 12 months post-intervention. There was no significant benefit of CCT or yoga on Cogstate learning/working memory composite.

Background: Besides their other roles, brain imaging and other biomarkers of Alzheimer’s disease (AD) have the potential to inform a cognitively unimpaired (CU) person’s likelihood of progression to mild cognitive impairment (MCI) and benefit subject selection when evaluating promising prevention therapies. We previously described that among baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD, hippocampal volume was the best predictor of incident MCI within 2 years (79%sensitivity/78%specificity), using standard automated MRI volumetric algorithmic programs, binary logistic regression, and leave-one-out procedures. Objective: To improve the same prediction by using different hippocampal features and machine learning methods, cross-validated via two independent and prospective cohorts (Arizona and ADNI). Methods: Patch-based sparse coding algorithms were applied to hippocampal surface features of baseline TI-MRIs from 78 CU adults who subsequently progressed to amnestic MCI in approximately 2 years (“progressors”) and 80 matched adults who remained CU for at least 4 years (“nonprogressors”). Nonprogressors and progressors were matched for age, sex, education, and apolipoprotein E4 allele dose. We did not include amyloid or tau biomarkers in defining MCI. Results: We achieved 92%prediction accuracy in the Arizona cohort, 92%prediction accuracy in the ADNI cohort, and 90%prediction accuracy when combining the two demographically distinct cohorts, as compared to 79%(Arizona) and 72%(ADNI) prediction accuracy using hippocampal volume. Conclusion: Surface multivariate morphometry and sparse coding, applied to individual MRIs, may accurately predict imminent progression to MCI even in the absence of other AD biomarkers.