Psychometric and adherence considerations for high-frequency, smartphone-based cognitive screening protocols in older adults.

OBJECTIVE: The psychometric rigor of unsupervised, smartphone-based assessments and factors that impact remote protocol engagement is critical to evaluate prior to the use of such methods in clinical contexts. We evaluated the validity of a high-frequency, smartphone-based cognitive assessment protocol, including examining convergence and divergence with standard cognitive tests, and investigating factors that may impact adherence and performance (i.e., time of day and anticipated receipt of feedback vs. no feedback). METHODS: Cognitively unimpaired participants (N = 120, Mage = 68.8, 68.3% female, 87% White, Meducation = 16.5 years) completed 8 consecutive days of the Mobile Monitoring of Cognitive Change (M2C2), a mobile app-based testing platform, with brief morning, afternoon, and evening sessions. Tasks included measures of working memory, processing speed, and episodic memory. Traditional neuropsychological assessments included measures from the Preclinical Alzheimer's Cognitive Composite battery. RESULTS: Findings showed overall high compliance (89.3%) across M2C2 sessions. Average compliance by time of day ranged from 90.2% for morning sessions, to 77.9% for afternoon sessions, and 84.4% for evening sessions. There was evidence of faster reaction time and among participants who expected to receive performance feedback. We observed excellent convergent and divergent validity in our comparison of M2C2 tasks and traditional neuropsychological assessments. CONCLUSIONS: This study supports the validity and reliability of self-administered, high-frequency cognitive assessment via smartphones in older adults. Insights into factors affecting adherence, performance, and protocol implementation are discussed.

Compensatory strategy use in diverse older adults with subjective cognitive complaints.

OBJECTIVES: The current study aimed to evaluate the relationship between subjective cognitive complaints (SCC) and compensatory strategy (CS) use in a diverse sample of non-Latinx White (NLW), Black, and Latinx American older adults. METHOD: 807 older adults (Mage = 65.38, 62.7% female) were recruited through Amazon's Mechanical Turk (MTurk) and Qualtrics Panel to complete questionnaires on SCC and CS use. Kruskall-Wallis tests were used to evaluate differences in SCC across groups given non-normal distributions. Analysis of variance (ANOVA) was used to evaluate group differences in CS use. The PROCESS macro for SPSS was used to examine whether demographic factors moderated the relationship between SCC and CS use. RESULTS: NLWs reported higher levels of SCC and greater overall use of CS in comparison to Latinx and Black individuals. Several demographic and psychosocial factors including age, ethno-racial group, education, and anxiety level were found to be associated with CS use. Education was found to moderate the association between SCC and CS use. CONCLUSION: Inconsistent with prior studies, our study found that NLWs reported the highest levels of SCC. CS were used across all racial/ethnic groups, but the frequency of CS use may be impacted by education level. While all education groups increased their CS in response to higher levels of SCC, this increase was more substantial for those with lower levels of education. Future work should consider individuals' cultural and educational background when examining SCC and/or developing CS-based intervention for the aging population.

Utility of cerebrovascular imaging biomarkers to detect cerebral amyloidosis.

INTRODUCTION: The relationship between cerebrovascular disease (CVD) and amyloid beta (Aß) in Alzheimer's disease (AD) is understudied. We hypothesized that magnetic resonance imaging (MRI)-based CVD biomarkers-including cerebral microbleeds (CMBs), lacunar infarction, and white matter hyperintensities (WMHs)-would correlate with Aß positivity on positron emission tomography (Aß-PET). METHODS: We cross-sectionally analyzed data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 1352). Logistic regression was used to calculate odds ratios (ORs), with Aß-PET positivity as the standard-of-truth. RESULTS: Following adjustment, WMHs (OR = 1.25) and superficial CMBs (OR = 1.45) remained positively associated with Aß-PET positivity (p < 0.001). Deep CMBs and lacunes exhibited a varied relationship with Aß-PET in cognitive subgroups. The combined diagnostic model, which included CVD biomarkers and other accessible measures, significantly predicted Aß-PET (pseudo-R2 = 0.41). DISCUSSION: The study highlights the translational value of CVD biomarkers in diagnosing AD, and underscores the need for more research on their inclusion in diagnostic criteria. CLINICALTRIALS: gov: ADNI-2 (NCT01231971), ADNI-3 (NCT02854033). HIGHLIGHTS: Cerebrovascular biomarkers linked to amyloid beta (Aß) in Alzheimer's disease (AD). White matter hyperintensities and cerebral microbleeds reliably predict Aß-PET positivity. Relationships with Aß-PET vary by cognitive stage. Novel accessible model predicts Aß-PET status. Study supports multimodal diagnostic approaches.

Dissociating Statistically Determined Normal Cognitive Abilities and Mild Cognitive Impairment Subtypes with DCTclock.

OBJECTIVE: To determine whether the DCTclock can detect differences across groups of patients seen in the memory clinic for suspected dementia. METHOD: Patients (n = 123) were classified into the following groups: cognitively normal (CN), subtle cognitive impairment (SbCI), amnestic cognitive impairment (aMCI), and mixed/dysexecutive cognitive impairment (mx/dysMCI). Nine outcome variables included a combined command/copy total score and four command and four copy indices measuring drawing efficiency, simple/complex motor operations, information processing speed, and spatial reasoning. RESULTS: Total combined command/copy score distinguished between groups in all comparisons with medium to large effects. The mx/dysMCI group had the lowest total combined command/copy scores out of all groups. The mx/dysMCI group scored lower than the CN group on all command indices (p < .050, all analyses); and lower than the SbCI group on drawing efficiency (p = .011). The aMCI group scored lower than the CN group on spatial reasoning (p = .019). Smaller effect sizes were obtained for the four copy indices. CONCLUSIONS: These results suggest that DCTclock command/copy parameters can dissociate CN, SbCI, and MCI subtypes. The larger effect sizes for command clock indices suggest these metrics are sensitive in detecting early cognitive decline. Additional research with a larger sample is warranted.

Machine Learning Analysis of Digital Clock Drawing Test Performance for Differential Classification of Mild Cognitive Impairment Subtypes Versus Alzheimer's Disease.

OBJECTIVE: To determine how well machine learning algorithms can classify mild cognitive impairment (MCI) subtypes and Alzheimer's disease (AD) using features obtained from the digital Clock Drawing Test (dCDT). METHODS: dCDT protocols were administered to 163 patients diagnosed with AD(n = 59), amnestic MCI (aMCI; n = 26), combined mixed/dysexecutive MCI (mixed/dys MCI; n = 43), and patients without MCI (non-MCI; n = 35) using standard clock drawing command and copy procedures, that is, draw the face of the clock, put in all of the numbers, and set the hands for "10 after 11." A digital pen and custom software recorded patient's drawings. Three hundred and fifty features were evaluated for maximum information/minimum redundancy. The best subset of features was used to train classification models to determine diagnostic accuracy. RESULTS: Neural network employing information theoretic feature selection approaches achieved the best 2-group classification results with 10-fold cross validation accuracies at or above 83%, that is, AD versus non-MCI = 91.42%; AD versus aMCI = 91.49%; AD versus mixed/dys MCI = 84.05%; aMCI versus mixed/dys MCI = 84.11%; aMCI versus non-MCI = 83.44%; and mixed/dys MCI versus non-MCI = 85.42%. A follow-up two-group non-MCI versus all MCI patients analysis yielded comparable results (83.69%). Two-group classification analyses were achieved with 25-125 dCDT features depending on group classification. Three- and four-group analyses yielded lower but still promising levels of classification accuracy. CONCLUSION: Early identification of emergent neurodegenerative illness is criterial for better disease management. Applying machine learning to standard neuropsychological tests promises to be an effective first line screening method for classification of non-MCI and MCI subtypes.

Visual versus Verbal Working Memory in Statistically Determined Patients with Mild Cognitive Impairment: On behalf of the Consortium for Clinical and Epidemiological Neuropsychological Data Analysis (CENDA).

OBJECTIVE: Previous research in mild cognitive impairment (MCI) suggests that visual episodic memory impairment may emerge before analogous verbal episodic memory impairment. The current study examined working memory (WM) test performance in MCI to assess whether patients present with greater visual versus verbal WM impairment. WM performance was also assessed in relation to hippocampal occupancy (HO), a ratio of hippocampal volume to ventricular dilation adjusted for demographic variables and intracranial volume. METHODS: Jak et al. (2009) (The American Journal of Geriatric Psychiatry, 17, 368-375) and Edmonds, Delano-Wood, Galasko, Salmon, & Bondi (2015) (Journal of Alzheimer's Disease, 47(1), 231-242) criteria classify patients into four groups: little to no cognitive impairment (non-MCI); subtle cognitive impairment (SCI); amnestic MCI (aMCI); and a combined mixed/dysexecutive MCI (mixed/dys MCI). WM was assessed using co-normed Wechsler Adult Intelligence Scale-IV (WAIS-IV) Digit Span Backwards and Wechsler Memory Scale-IV (WMS-IV) Symbol Span Z-scores. RESULTS: Between-group analyses found worse WMS-IV Symbol Span and WAIS-IV Digit Span Backwards performance for mixed/dys MCI compared to non-MCI patients. Within-group analyses found no differences for non-MCI patients; however, all other groups scored lower on WMS-IV Symbol Span than WAIS-IV Digit Span Backwards. Regression analysis with HO as the dependent variable was statistically significant for WMS-IV Symbol Span performance. WAIS-IV Digit Span Backwards performance failed to reach statistical significance. CONCLUSIONS: Worse WMS-IV Symbol Span performance was observed in patient groups with measurable neuropsychological impairment and better WMS-IV Symbol Span performance was associated with higher HO ratios. These results suggest that visual WM may be particularly sensitive to emergent illness compared to analogous verbal WM tests.

Medication management error types: Associations with mild cognitive impairment subtype.

Objective: Medication management errors are suspected to be prevalent among older adults with mild cognitive impairment (MCI). This study examined types of simulated medication-taking errors in cognitively normal older adults (CN; n = 131), single domain amnestic MCI (sdMCI, n = 91), and multi-domain MCI (mdMCI, n = 44). Errors were measured using the medication management ability assessment (MMAA). Methods: 266 participants seen for neuropsychological evaluation (94.4% White, 57.9% female, average age = 72, average education = 14 years) completed the MMAA (version 4.1), a performance-based task of medication management. Group differences in MMAA total scores, accuracy, and error types were evaluated using Kruskall-Wallis H tests. This study was the first to explore a newly operationalized error, perseverations, caused by taking a specific dose ≥2 times during the simulation. Results: CN and sdMCI groups had higher MMAA total scores than individuals with mdMCI, indicating better overall performance. The mdMCI group made a higher number of omission errors (missed pills) than other groups, but no differences were found for commission errors (extra pills). The sdMCI group made more perseverative errors compared to the CN group. Conclusions: Individuals with mdMCI made more simulated medication management errors than CN and sdMCI groups, indicating that they may be most vulnerable to difficulties in medication management. In contrast, sdMCI individuals were more likely to make perseverative errors, which may reflect a tendency towards overcompensation of memory loss. Future studies should assess whether MMAA performance is associated with patterns of real-world medication-taking in more diverse samples of older adults.

Utility of cerebrovascular imaging biomarkers to detect cerebral amyloidosis.

INTRODUCTION: The relationship between cerebrovascular disease (CVD) and amyloid-ß (Aß) in Alzheimer disease (AD) is understudied. We hypothesized that magnetic resonance imaging (MRI)-based CVD biomarkers, including cerebral microbleeds (CMBs), ischemic infarction, and white matter hyperintensities (WMH), would correlate with Aß positivity on positron emission tomography (Aß-PET). METHODS: We cross-sectionally analyzed data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, N=1,352). Logistic regression was used to calculate odds ratios (ORs), with Aß-PET positivity as the standard-of-truth. RESULTS: Following adjustment, WMH (OR=1.25) and superficial CMBs (OR=1.45) remained positively associated with Aß-PET positivity (p<.001). Deep CMBs and infarcts exhibited a varied relationship with Aß-PET in cognitive subgroups. The combined diagnostic model, which included CVD biomarkers and other accessible measures, significantly predicted Aß-PET (pseudo-R 2 =.41). DISCUSSION: The study highlights the translational value of CVD biomarkers in diagnosing AD, and underscores the need for more research on their inclusion in diagnostic criteria. ClinicalTrials.gov: ADNI-2 ( NCT01231971 ), ADNI-3 ( NCT02854033 ).

Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer's disease.

Background: With the approval of disease-modifying treatments (DMTs) for early Alzheimer's disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-ß (Aß) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). Methods: In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific training data and BioFINDER-2, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aß-PET/CSF testing as the standard of truth. Results: Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aß-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aß positivity in potential DMT candidates (AUC = 0.97 [0.92-1]), with diagnostic accuracy ranging from 0.88 (0.76-0.95, p = 0.028) to 0.96 (0.86-1, p < .001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required from confirmatory testing. Conclusions: This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aß-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations.

Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer's disease.

BACKGROUND: With the approval of disease-modifying treatments (DMTs) for early Alzheimer's disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-ß (Aß) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). METHODS: In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific and BioFINDER-2 training data, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aß-PET/CSF testing as the standard of truth. RESULTS: Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aß-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aß positivity in potential DMT candidates (AUC = 0.97 [0.92-1]), with diagnostic accuracy ranging from 0.88 (0.76-0.95, p = 0.028) to 0.96 (0.86-1, p < .001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required confirmatory testing. CONCLUSIONS: This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aß-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations.

Time to Dementia Diagnosis Among Veterans with Comorbid Insomnia and Depressive Episodes.

Background: Older adults with heart failure are at elevated risk of Alzheimer's disease and related dementias (AD/ADRD). Research suggests that insomnia and depressive episodes contribute somewhat dissociable impacts on risk for AD/ADRD in this patient population, although the temporal ordering of effects is unknown. Objective: This study examined time to dementia diagnosis among patients with comorbid insomnia and/or depressive episodes in an epidemiological sample. Methods: Secondary data analyses were conducted using a cohort study of 203,819 Veterans with a primary admission diagnosis of heart failure in 129 VA Medical Centers. Results: Patients with diagnoses of both insomnia and depressive episodes had the shortest time to a dementia diagnosis at both 1-year (Hazard ratio = 1.43, 95% CI [1.36, 1.51]) and 3-year follow-up time points (Hazard ratio = 1.40, 95% CI [1.34, 1.47]) versus patients with one or neither comorbidity. Conclusions: Individuals with both comorbidities had the shortest time to dementia onset. Screening for these comorbidities may help to identify patients at elevated risk of dementia who could benefit from enhanced monitoring or early intervention strategies for more rapid detection and management of dementia symptoms.

Neurocognitive Operations Underlying Working Memory Abilities: An Analysis of Latency and Time-Based Parameters.

BACKGROUND: The theory of executive attention (Fuster, 2015) suggests considerable plasticity regarding when specific neurocognitive operations are recruited to bring executive tasks to fruition. OBJECTIVE: We tested the hypothesis that differing neurocognitive operations are recruited upon the initiation of a response, but that other distinct neurocognitive operations are recruited towards the middle or end of a response. METHODS: The Backward Digit Span Test (BDST) was administered to 58 memory clinic patients (MCI, n = 22; no-MCI, n = 36). Latency to generate all correct 5-span responses was obtained. Statistical analyses found that optimal group classification was achieved using the first and third digit backward. First and third response latencies were analyzed in relation to verbal working memory (WM), visual WM, processing speed, visuospatial operations, naming/lexical access, and verbal episodic memory tests. RESULTS: For the first response, slower latencies were associated with better performance in relation to verbal WM and visuospatial test performance. For the third response, faster latencies were associated with better processing speed and visuospatial test performance. CONCLUSION: Consistent with the theory of executive attention, these data show that the neurocognitive operations underlying successful executive test performance are not monolithic but can be quite nuanced with differing neurocognitive operations associated with specific time epochs. Results support the efficacy of obtaining time-based latency parameters to help disambiguate successful executive neurocognitive operations in memory clinic patients.

Early Detection of Alzheimer's Disease-Related Pathology Using a Multi-Disease Diagnostic Platform Employing Autoantibodies as Blood-Based Biomarkers.

BACKGROUND: Evidence for the universal presence of IgG autoantibodies in blood and their potential utility for the diagnosis of Alzheimer's disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. The fact that AD-related neuropathological changes in the brain can begin more than a decade before tell-tale symptoms emerge has made it difficult to develop diagnostic tests useful for detecting the earliest stages of AD pathogenesis. OBJECTIVE: To determine the utility of a panel of autoantibodies for detecting the presence of AD-related pathology along the early AD continuum, including at pre-symptomatic [an average of 4 years before the transition to mild cognitive impairment (MCI)/AD)], prodromal AD (MCI), and mild-moderate AD stages. METHODS: A total of 328 serum samples from multiple cohorts, including ADNI subjects with confirmed pre-symptomatic, prodromal, and mild-moderate AD, were screened using Luminex xMAP® technology to predict the probability of the presence of AD-related pathology. A panel of eight autoantibodies with age as a covariate was evaluated using randomForest and receiver operating characteristic (ROC) curves. RESULTS: Autoantibody biomarkers alone predicted the probability of the presence of AD-related pathology with 81.0% accuracy and an area under the curve (AUC) of 0.84 (95% CI = 0.78-0.91). Inclusion of age as a parameter to the model improved the AUC (0.96; 95% CI = 0.93-0.99) and overall accuracy (93.0%). CONCLUSION: Blood-based autoantibodies can be used as an accurate, non-invasive, inexpensive, and widely accessible diagnostic screener for detecting AD-related pathology at pre-symptomatic and prodromal AD stages that could aid clinicians in diagnosing AD.

Instrumental activities of daily living and mild cognitive impairment.

BACKGROUND: Functional impairments are a necessary requirement for the diagnosis of a dementia along with observed cognitive impairment. Comparatively, functional abilities are often relatively intact in those with mild cognitive impairment (MCI). OBJECTIVE: The current research examined the associations between memory clinic participants classified as cognitively intact, amnestic MCI, and mixed/dysexecutive MCI, using Jak-Bondi criteria, and Instrumental Activities of Daily Living - Compensation Scale (IADL-C) abilities, an informant-based questionnaire that quantifies functional abilities. The associations between functional abilities as assessed with the IADL-C and performance on neuropsychological tests were also investigated. METHODS: IADLC scores were obtained along with a comprehensive neuropsychological protocol on memory clinic participants (n = 100) classified as cognitively normal (CN), amnestic MCI (aMCI), or a combined mixed/dysexecutive (mixed/dys) MCI. Regression analyses were employed to determine how the IADLC related to neuropsychological test performance. RESULTS: On the IADLC, greater functional impairment was commonly observed in the mixed/dys MCI group compared to CN participants. Furthermore, the mixed/dys MCI group had lower scores on activities such as Money and Self-Management, Travel and Event Memory subscales compared to the CN group. Linear regression analyses found greater functional impairment in relation to lower scores on executive and episodic memory tests. CONCLUSIONS: Greater functional impairment as assessed with the IADL-C appears to be disproportionately associated with dysexecutive difficulty, and to a lesser degree, episodic memory.

Remote and in-clinic digital cognitive screening tools outperform the MoCA to distinguish cerebral amyloid status among cognitively healthy older adults.

INTRODUCTION: We evaluated the accuracy of remote and in-person digital tests to distinguish between older adults with and without AD pathological change and used the Montreal Cognitive Assessment (MoCA) as a comparison test. METHODS: Participants were 69 cognitively normal older adults with known beta-amyloid (Aß) PET status. Participants completed smartphone-based assessments 3×/day for 8 days, followed by TabCAT tasks, DCTclock™, and MoCA at an in-person study visit. We calculated the area under the curve (AUC) to compare task accuracies to distinguish Aß status. RESULTS: Average performance on the episodic memory (Prices) smartphone task showed the highest accuracy (AUC = 0.77) to distinguish Aß status. On in-person measures, accuracy to distinguish Aß status was greatest for the TabCAT Favorites task (AUC = 0.76), relative to the DCTclockTM (AUC = 0.73) and MoCA (AUC = 0.74). DISCUSSION: Although further validation is needed, our results suggest that several digital assessments may be suitable for more widespread cognitive screening application.

Comparing Lookback Periods to Ascertain Alzheimer's Disease and Related Dementias.

Claims data are a valuable resource for studying Alzheimer's disease and related dementias (ADRD). Alzheimer's disease and related dementias is often identified using a list of claims codes and a fixed lookback period of 3 years of data. However, a 1-year lookback or an approach using all-available lookback data could be beneficial based on different research questions. Thus, the purpose of this study was to compare 1-year and all-available lookback approaches to ascertaining ADRD compared to the standard 3-year approach. Using a cohort of Veterans hospitalized for heart failure (N = 373, 897), our results suggested high agreement (93% or greater) between the lookback periods. The 1-year lookback period had lower sensitivity (60%) and underestimated the prevalence of ADRD. These results suggest that 1-year and all-available lookback periods are viable approaches when using claims data.

Latent Profile Analysis of Cognition in a Non-Demented Diverse Cohort: A Focus on Modifiable Cardiovascular and Lifestyle Factors.

BACKGROUND: Cognitively-defined subgroups are well-documented within neurodegeneration. OBJECTIVE: We examined such profiles in diverse non-demented older adults and considered how resulting subgroups relate to modifiable factors associated with neurodegeneration. METHODS: 121 non-demented (MMSE = 28.62) diverse (46%non-Latino Black, 40%non-Latino White, 15%Latino) community-dwelling adults (age = 67.7 years) completed cognitive, cardiovascular, physical activity, and diet evaluations. Latent profile analyses (LPA) employed six cognitive scores (letter fluency, letter-number sequencing, confrontational naming, 'animal' fluency, list-learning delayed recall, and recognition discriminability) to characterize cognitively-defined subgroups. Differences between resulting subgroups on cardiovascular (composite scores of overall health; specific health components including fasting blood levels) and lifestyle (sedentary behavior; moderate-to-vigorous physical activity; Mediterranean diet consumption) factors were examined using ANCOVAs adjusting for relevant confounders. RESULTS: Based on sample means across cognitive scores, LPA resulted in the following cognitive subgroups: 1) high-average cognition, 55%non-Latino White and 64%female participants; 2) average cognition, 58%non-Latino Black and 68%male participants; 3) lower memory, 58%non-Latino Black participants; and 4) lower executive functioning, 70%Latinos. The high-average subgroup reported significantly higher Mediterranean diet consumption than the average subgroup (p = 0.001). The lower executive functioning group had higher fasting glucose and hemoglobin A1c than all other subgroups (p-values<0.001). CONCLUSION: LPA revealed two average subgroups reflecting level differences in cognition previously reported between non-Latino White and Black adults, and two lower cognition subgroups in domains similar to those documented in neurodegeneration. These subgroups, and their differences, suggest the importance of considering social determinants of health in cognitive aging and modifiable risk.

Neurocognitive Constructs Underlying Executive Control in Statistically-Determined Mild Cognitive Impairment.

BACKGROUND: The model of executive attention proposes that temporal organization, i.e., the time necessary to bring novel tasks to fruition is an important construct that modulates executive control. Subordinate to temporal organization are the constructs of working memory, preparatory set, and inhibitory control. OBJECTIVE: The current research operationally-defined the constructs underlying the theory of executive attention using intra-component latencies (i.e., reaction times) from a 5-span backward digit test from patients with suspected mild cognitive impairment (MCI). METHODS: An iPad-version of the Backward Digit Span Test (BDT) was administered to memory clinic patients. Patients with (n = 22) and without (n = 36) MCI were classified. Outcome variables included intra-component latencies for all correct 5-span serial order responses. RESULTS: Average total time did not differ. A significant 2-group by 5-serial order latency interaction revealed the existence of distinct time epochs. Non-MCI patients produced slower latencies on initial (position 2-working memory/preparatory set) and latter (position 4-inhibitory control) correct serial order responses. By contrast, patients with MCI produced a slower latency for middle serial order responses (i.e., position 3-preparatory set). No group differences were obtained for incorrect 5-span test trials. CONCLUSION: The analysis of 5-span BDT serial order latencies found distinct epochs regarding how time was allocated in the context of successful test performance. Intra-component latencies obtained from tests assessing mental re-ordering may constitute useful neurocognitive biomarkers for emergent neurodegenerative illness.

APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer's disease: a systematic review.

Possession of the ε4 allele of apolipoprotein E (APOE) is the primary genetic risk factor for the sporadic form of Alzheimer's disease (AD). While researchers have extensively characterized the impact that APOE ε4 (APOE4) has on the susceptibility of AD, far fewer studies have investigated the phenotypic differences of patients with AD who are APOE4 carriers vs. those who are non-carriers. In order to understand these differences, we performed a qualitative systematic literature review of the reported cognitive and pathological differences between APOE4-positive (APOE4+) vs. APOE4-negative (APOE4-) AD patients. The studies performed on this topic to date suggest that APOE4 is not only an important mediator of AD susceptibility, but that it likely confers specific phenotypic heterogeneity in AD presentation, as well. Specifically, APOE4+ AD patients appear to possess more tau accumulation and brain atrophy in the medial temporal lobe, resulting in greater memory impairment, compared to APOE4- AD patients. On the other hand, APOE4- AD patients appear to possess more tau accumulation and brain atrophy in the frontal and parietal lobes, resulting in greater impairment in executive function, visuospatial abilities, and language, compared to APOE4+ AD patients. Although more work is necessary to validate and interrogate these findings, these initial observations of pathological and cognitive heterogeneity between APOE4+ vs. APOE4- AD patients suggest that there is a fundamental divergence in AD manifestation related to APOE genotype, which may have important implications in regard to the therapeutic treatment of these two patient populations.

Alzheimer's/Vascular Spectrum Dementia: Classification in Addition to Diagnosis.

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common types of dementia. Although the combination of these disorders, called 'mixed' dementia, is recognized, the prevailing clinical and research perspective continues to consider AD and VaD as independent disorders. A review of recent neuropathological and neuropsychological literature reveals that these two disorders frequently co-occur and so-called 'pure' AD or VaD is comparatively rare. In addition, recent research shows that vascular dysfunction not only potentiates AD pathology, but that pathological changes in AD may subsequently induce vascular disorders. On the basis of these data, we propose that the neurobiological underpinnings underlying AD/VaD dementia and their neuropsychological phenotypes are best understood as existing along a clinical/pathological continuum or spectrum. We further propose that in conjunction with current diagnostic criteria, statistical modeling techniques using neuropsychological test performance should be leveraged to construct a system to classify AD/VaD spectrum dementia in order to test hypotheses regarding how mechanisms related to AD and VaD pathology interact and influence each other.