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Background: Misidentification of dementia in Medicare claims is quite common., Objective: We examined potential race/ethnic disparities in misidentification of dementia in Medicare claims in a diverse cohort of older adults who underwent careful clinical assessment., Methods: Participants were enrolled in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, population-based, prospective study of cognitive aging in which dementia status was assessed using a rigorous clinical protocol. ICD-9-CM and ICD-10-CM diagnosis codes in all available Medicare claims (1999-2019) were compared to clinical dementia diagnosis and categorized into three mutually exclusive groups: 1) congruent-, 2) over-, and 3) under- identification during the study period. Multinomial logistic regression model was used to examine the relationship between race (White, African American/Black, other) and ethnicity (Hispanic/Latinx, non-Hispanic/Latinx) and congruency of dementia identification after controlling for clinical (cognition, function, comorbidities) and demographic characteristics (age, sex, education), and inpatient and outpatient utilization., Results: Across all person-years, 88.4% had congruent identification of dementia compared to clinical diagnosis, in 4.1% of the times participants were over-identified with dementia, and 7.5% of the times the participants were under-identified. Rates of misidentification was higher in minority participants than in White, non-Hispanic participants. Multivariable estimation results showed that the probability of over-identification with dementia was 2.2% higher for African American/Black than White (p = 0.05) and 2.7% higher for Hispanic participants than non-Hispanics (p = 0.03) participants. Differences in under-identification by race/ethnicity were not statistically significant., Conclusions: African American/Black and Hispanic participants were more likely over-identified with dementia in Medicare claims.

Background: Little is known regarding healthcare expenditures for patients with dementia with Lewy bodies (DLB) during the end of life., Objective: This study estimated Medicare expenditures during the last 5 years of life in a decedent sample of patients who were clinically diagnosed with Alzheimer's disease (AD) or DLB and had autopsy confirmed diagnosis., Methods: The study included 58 participants clinically diagnosed with mild dementia at study entry (AD: n = 44, DLB: n = 14) and also had autopsy-confirmed diagnoses of pure AD (n = 32), mixed AD+Lewy body (LB) (n = 5), or pure LB (n = 11). Total Medicare expenditures were compared by clinical and pathology confirmed diagnosis, adjusting for sex, age at death, and patient's cognition, function, comorbidities, and psychiatric and extrapyramidal symptoms., Results: When pathology diagnoses were not considered, predicted annualized total Medicare expenditures during the last 5 years of life were similar between clinically diagnosed AD ($7,465±1,098) and DLB ($7,783±1,803). When clinical diagnoses were not considered, predicted expenditures were substantially higher in patients with pathology confirmed mixed AD+LB ($12,005±2,455) than either pure AD ($6,173±941) or pure LB ($4,629±1,968) cases. Considering clinical and pathology diagnosis together, expenditures for patients with clinical DLB and pathology mixed AD+LB ($23,592±3,679) dwarfed other groups., Conclusion: Medicare expenditures during the last 5 years of life were substantially higher in patients with mixed AD+LB pathology compared to those with pure-AD and pure-LB pathologies, particularly in those clinically diagnosed with DLB. Results highlight the importance of having both clinical and pathology diagnoses in examining healthcare costs.

Background: The major aims of the three Predictors Studies have been to further our understanding of Alzheimer's disease (AD) progression sufficiently to predict the length of time from disease onset to major disease outcomes in individual patients with AD., Objectives: To validate a longitudinal Grade of Membership (L-GoM) prediction algorithm developed using clinic-based, mainly white patients from the Predictors 2 Study in a statistically representative community-based sample of Hispanic (N = 211) and non-Hispanic (N = 62) older adults (with 60 males and 213 females) from the Predictors 3 Study and extend the algorithm to mild cognitive impairment (MCI)., Methods: The L-GoM model was applied to data collected at the initial Predictors 3 visit for 150 subjects with AD and 123 with MCI. Participants were followed annually for up to seven years. Observed rates of survival and need for full-time care (FTC) were compared to those predicted by the algorithm., Results: Initial MCI/AD severity in Predictors 3 was substantially higher than among clinic-based AD patients enrolled at the specialized Alzheimer's centers in Predictors 2. The observed survival and need for FTC followed the L-GoM model trajectories in individuals with MCI or AD, except for N = 32 subjects who were initially diagnosed with AD but reverted to a non-AD diagnosis on follow-up., Conclusion: These findings indicate that the L-GoM model is applicable to community-dwelling, multiethnic older adults with AD. They extend the use of the model to the prediction of outcomes for MCI. They also justify release of our L-GoM calculator at this time.

Background: Impaired awareness of ability is common in dementia and has important clinical implications. Evidence from different clinical groups has shown that awareness can vary according to whether evaluation refers to self or other performance., Objective: The present study aimed to investigate awareness for self- and other-performance in Alzheimer's disease (AD) patients, exploring if results vary according to cognitive domain of the tasks. It was hypothesized that, particularly for memory tasks, AD patients would be inaccurate in relation to self-but not other-performance., Methods: Twenty-two mild to moderate AD patients and twenty-two healthy older adults participated. Two tasks, with reaction time and working memory tasks, were carried out, and each had a success and a failure condition. Participants were asked to estimate their own performance, as well as the performance of another person they observed. Awareness of performance was measured comparing participant estimations of performance with actual performance., Results: For both the reaction time and working memory tasks, results indicate that participants from both groups overestimated the performance in the failure condition and underestimated the performance in the success condition. They tended to overestimate more the performance of the other person compared to themselves. Additionally, for the working memory task, AD patients tended to overestimate more performances compared to controls., Conclusion: Findings suggest that the AD and control groups present the same pattern, with attribution of better performance to another person. For the AD group, the pattern of response was different for memory tasks, which may suggest domain-specific limited awareness.

Neuropsychological assessment using the Boston Process Approach (BPA) suggests that an analysis of the strategy or the process by which tasks and neuropsychological tests are completed, and the errors made during test completion convey much information regarding underlying brain and cognition and are as important as overall summary scores. Research over the last several decades employing an analysis of process and errors has been able to dissociate between dementia patients diagnosed with Alzheimer's disease, vascular dementia associated with MRI-determined white matter alterations, and Parkinson's disease; and between mild cognitive impairment subtypes. Nonetheless, BPA methods can be labor intensive to deploy. However, the recent availability of digital platforms for neuropsychological test administration and scoring now enables reliable, rapid, and objective data collection. Further, digital technology can quantify highly nuanced data previously unobtainable to define neurocognitive constructs with high accuracy. In this paper, a brief review of the BPA is provided. Studies that demonstrate how digital technology translates BPA into specific neurocognitive constructs using the Clock Drawing Test, Backward Digit Span Test, and a Digital Pointing Span Test are described. Implications for using data driven artificial intelligence-supported analytic approaches enabling the creation of more sensitive and specific detection/diagnostic algorithms for putative neurodegenerative illness are also discussed.

Background: The utility of subjective cognitive decline (SCD) as an indicator of preclinical AD is overshadowed by its inconsistent association with objective cognition., Objective: This study examines if manipulations of SCD measurement affect its association with early cognitive dysfunction characteristic of preclinical AD., Methods: Cognitively healthy older adults (n = 110) completed SCD questionnaires that elicited complaints in general, compared to 5 years ago (retrospective SCD) and compared to their peers (age-anchored SCD) in binary and Likert scales. Outcome cognitive tasks included an associative memory task (Face-Name Test), a visual short-term memory binding task (STMB test), and a clinical neuropsychological list learning test (Selective Reminder Test)., Results: SCD complaints, when compared to age-matched peers (age-anchored SCD) were endorsed less frequently than complaints compared to 5 years ago (retrospective SCD) (p < 0.01). In demographically adjusted regressions, age-anchored ordinal-rated SCD was associated with short term memory binding (β= -0.22, p = 0.040, CI = -0.45, -0.01), associative memory (β= -0.26, p = 0.018, CI = -0.45, -0.06), and list learning (β= -0.31, p = 0.002, CI = -0.51, -0.12). Retrospective and general ordinal-rated SCD was associated with associative memory (β= -0.25, p = 0.012, CI = -0.44, -0.06; β= -0.29, p = 0.003, CI = -0.47, -0.10) and list learning only (β= -0.25, p = 0.014, CI = -0.45, -0.05; β= -0.28, p = 0.004, CI = -0.48, -0.09)., Conclusion: Ordinal age-anchored SCD appears better suited than other SCD measurements to detect early cognitive dysfunction characteristic of preclinical AD.

Background: The E4 allele of the APOE gene is known to be associated with cognitive impairment. However, a limited number of studies have examined the association between the E2 allele and longitudinal changes of cognitive function., Objective: To determine whether rates of cognitive change differ in carriers of the APOE E2 allele compared to other genotypes., Methods: We conducted a secondary analysis of data from two ongoing longitudinal cohort studies, the Long Life Family Study (LLFS) and New England Centenarian Study (NECS). We included participants who had APOE genotyping data, data from longitudinal administrations of the Telephone Interview for Cognitive Status (TICS), and age, sex, and education available. We assessed whether cognitive change as measured by rate of decline in TICS score differed among people with different APOE genotypes. We used a hierarchical mixed effect model with APOE genotypes, their interactions with age, and potential confounders., Results: After adjusting for sex and education, in carriers of the common E3/E3 genotype, TICS score decreased by 0.15 points per year of age. In those with the E2/E2 genotype, TICS score decreased by 0.05 points per year of age, a significantly slower rate of decline (p = 0.017). We observed no protective effect of the E2/E3 genotype on cognitive decline., Conclusion: These results suggest a protective effect of the E2/E2 genotype on a measure of global cognitive function.

Background: Psychotic symptoms are an important and increasingly recognized aspect of Alzheimer's disease (AD). They have been shown to contribute to faster disease progression in clinic-based, demographically homogenous samples with high educational attainment., Objective: We studied the association between baseline psychotic symptoms and disease progression among individuals with incident AD or 'at risk' of developing AD, from a demographically heterogenous, community-based cohort with minimal educational attainment., Methods: 212 participants received the Columbia University Scale of Psychopathology in Alzheimer's Disease scale. Participants had psychotic symptoms with any of: visual illusions, delusions, hallucinations, or agitation/aggression. Disease progression was measured yearly and defined by meeting cognitive (≤10 on the Folstein MMSE) or functional endpoints (≥10 on the Blessed Dementia Rating Scale or ≥4 on the Dependence Scale)., Results: The mean age was 85 years old. The cohort was 78.3% female, 75.9% Hispanic, and had a mean 6.96 years of education. Within the follow-up period (mean: 3.69 years), 24 met the cognitive endpoint, 59 met the functional endpoint, and 132 met the cutoff for dependence. The presence of at least one psychotic symptom was initially associated with an increased risk of reaching the functional endpoint (HR 3.12, 95% CI 1.67-5.86, p < 0.001) and the endpoint of dependence (HR = 1.498, 95% CI 1.05-2.13, p = 0.03). However, these associations were attenuated and non-significant when adjusted for baseline functional status. Psychotic symptoms were not associated with the cognitive endpoint., Conclusion: Psychotic symptoms may predict functional decline in patients of non-Caucasian ethnicity and with lower educational attainment.

Background: Coupling digital technology with traditional neuropsychological test performance allows collection of high-precision metrics that can clarify and/or define underlying constructs related to brain and cognition., Objective: To identify graphomotor and information processing trajectories using a digitally administered version of the Digit Symbol Substitution Test (DSST)., Methods: A subset of Long Life Family Study participants (n = 1,594) completed the DSST. Total time to draw each symbol was divided into 'writing' and non-writing or 'thinking' time. Bayesian clustering grouped participants by change in median time over intervals of eight consecutively drawn symbols across the 90 s test. Clusters were characterized based on sociodemographic characteristics, health and physical function data, APOE genotype, and neuropsychological test scores., Results: Clustering revealed four 'thinking' time trajectories, with two clusters showing significant changes within the test. Participants in these clusters obtained lower episodic memory scores but were similar in other health and functional characteristics. Clustering of 'writing' time also revealed four performance trajectories where one cluster of participants showed progressively slower writing time. These participants had weaker grip strength, slower gait speed, and greater perceived physical fatigability, but no differences in cognitive test scores., Conclusion: Digital data identified previously unrecognized patterns of 'writing' and 'thinking' time that cannot be detected without digital technology. These patterns of performance were differentially associated with measures of cognitive and physical function and may constitute specific neurocognitive biomarkers signaling the presence of subtle to mild dysfunction. Such information could inform the selection and timing of in-depth neuropsychological assessments and help target interventions.

Background: Changes in sexual behaviors in frontotemporal dementia (FTD) are common and multifaceted, but not well characterized., Objective: To characterize changes in sexual behaviors and intimacy in FTD compared to corticobasal syndrome (CBS) and normal controls (NC), and to evaluate the neuroanatomical associations of these changes., Methods: Spouses of 30 FTD patients, 20 CBS patients, and 35 NC completed the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), which captures changes in sexual interest, inappropriate sexual behaviors, and prosocial sexual behaviors. 25 patients with FTD and 14 patients with CBS also received 18-flouorodeoxyglucose positron-emission topography (18FDG-PET) scans to determine the metabolic changes associated with these symptoms., Results: FTD patients showed a greater increase in inappropriate sexual behaviors than CBS patients [p = 0.009] and NC [p < 0.001] and a greater decrease in prosocial sexual behaviors than CBS patients [p = 0.026] and NC [p < 0.001]. Groups did not differ in change in sexual interest. Among both patient groups, the most common change was decreased prosocial sexual behaviors p < 0.01. Hypometabolism in Brodmann's Area 10 (BA10), within the right frontal pole, correlated with decreased prosocial sexual behaviors [p(FWE-corr) <0.05, k = 44]. No anatomical associations were found with other sexual changes., Conclusion: Decreased prosocial sexual behavior was associated with hypometabolism in BA 10, an area tied to social knowledge and theory of mind, supporting the idea that changes reflect social-cognitive deficits due to frontal dysfunction.

Background: Frontotemporal dementia (FTD) is the second most common cause of early-onset neurodegenerative dementia. Several studies have focused on early imaging changes in FTD patients, but once subjects meet full criteria for FTD diagnosis, structural changes are generally widespread., Objective: This study aims to determine the earliest structural brain changes in asymptomatic MAPT MUTATION carriers., Methods: This is a cross-sectional multicenter study comparing global and regional brain volume and white matter integrity in a group of MAPT mutation preclinical carriers and controls. Participants belong to multiple generations of six families with five MAPT mutations. All participants underwent a medical examination, neuropsychological tests, genetic analysis, and a magnetic resonance scan (3T, scout, T1-weighted image followed by EPI (BOLD), MPRAGE, DTI, FLAIR, and ASL sequences)., Results: Volumes of five cortical and subcortical areas were strongly correlated with mutation status: temporal lobe (left amygdala, left temporal pole), cingulate cortex (left rostral anterior cingulate gyrus, right posterior cingulate), and the lingual gyrus in the occipital lobe. We did not find significant differences in whole brain volume, white matter hyperintensities volume, and white matter integrity using DTI analysis., Conclusion: Temporal lobe, cingulate cortex and the lingual gyrus seem to be early targets of the disease and may serve as biomarkers for FTD prior to overt symptom onset.

Subjective impairment in memory is a frequently defining feature of subjective cognitive decline (SCD), a state hypothesized to precede objectively apparent cognitive symptoms of Alzheimer's disease (AD) and to hold promise as a non-invasive, inexpensive, preclinical indicator of AD. However, a full model of the factors that contribute to subjective memory (SM), and therefore to SCD, has yet to be articulated. While SM impairment is widely known to be associated with negative affect, the extent to which SM functioning may also reflect other factors, particularly subjective beliefs or perceptions about one's health, is not known. To examine the extent to which SM is associated with subjective perceptions of health more broadly, the current study investigated the link between SM and subjective physical functioning (independent of depressive affect, and objective cognitive and physical function) in an ethnically diverse sample of 471 older adults enrolled in the population-based Northern Manhattan Aging Project. 199 (42%) participants endorsed no difficulty on a 5-point SM index while 272 (58%) endorsed some degree of difficulty. As hypothesized, SM correlated with both depression and subjective physical function, but not with age, education, global cognition, or objective physical function. When objective and subjective physical function were entered in two separate, adjusted linear regressions predicting SM, only subjective physical function and depressive affect independently predicted SM. Subjective perceptions of memory appear to reflect individuals' broader health perceptions in part. Articulating the various correlates of SM will improve identification of SCD specific to preclinical AD.

Background: Few studies have examined how dementia and comorbidities may interact to affect healthcare expenditures., Objective: To examine whether effects of dementia severity on Medicare expenditures differed for individuals with different levels of comorbidities., Methods: Data are drawn from the Washington Heights-Inwood Columbia Aging Project (WHICAP). Comprehensive clinical assessments of dementia severity were systematically carried out at ∼18 month intervals. Dementia severity was measured by Clinical Dementia Rating (CDR). Comorbidities were measured by a modified Elixhauser comorbidities index. Generalized linear models examined effects of dementia severity, comorbidities, and their interactions on Medicare expenditures (1999-2010)., Results: At baseline, 1,280 subjects were dementia free (CDR = 0, 66.4%), 490 had very mild dementia (CDR = 0.5, 25.4%), 108 had mild dementia (CDR = 1, 5.6%), and 49 had moderate/severe dementia (CDR = 2/3, 2.5%). Average annual Medicare expenditures for individuals with moderate/severe dementia were more than twice as high as those who were dementia free (CDR = 0: $9,108, CDR = 0.5/1: $11,664, CDR≥2: $19,604, p < 0.01). Expenditures were approximately 10 times higher among those with≥3 comorbidities than among those with no comorbidities ($2,612 for those with no comorbidities, to $6,109 for those with 1, $10,656 for those with 2, and $30,244 for those with≥3 comorbidities, p < 0.001). Dementia severity was associated with higher expenditures, but comorbidities were the most important predictor of expenditures. We did not find strong interaction effects between number of comorbidities and dementia severity., Conclusions: Increasing dementia severity and higher comorbidities are associated with higher Medicare expenditures. Care of individuals with dementia should focus on management of comorbidities.

Background: Subjective cognitive decline (SCD) is increasingly considered promising to detect preclinical Alzheimer's disease. How SCD is ascertained is critical for determining its potential utility in identifying at-risk individuals, yet SCD measures differ along several dimensions., Objective: We aimed to examine the extent to which reports of SCD in healthy elderly may be influenced by the characteristics of the SCD measures. We investigated variations in rates of SCD endorsement across different measures, including an open-ended question. We also examined the association of responses across measures, and the degree to which specific SCD items were associated with objective memory performance., Methods: 99 healthy elderly completed a series of questionnaires from which 10 items examining SCD for memory and other aspects of cognition were drawn. We applied Cochran's Q tests to assess differences in rates of SCD, correlation analyses to examine association of SCD responses, and regression models to determine the association between SCD items and delayed verbal memory., Results: Rates of SCD varied as a function of the assessment format, ranging from 1 to 7% for memory and 5 to 20% for concentration. SCD was lower for memory versus non-memory domains. SCD items were associated both within and across domains. The most accurate predictor of memory was memory-related SCD in comparison to others the same age., Conclusion: Characteristics of SCD items influence rates of endorsement. Querying SCD using an "age-anchored" question may provide the most accurate reflection of actual cognitive performance.

The study's objective was to compare demographics, APOE genotypes, and rate of rise over time in functional impairment in neuropsychologically defined language, typical, and memory subgroups of clinical Alzheimer's disease (AD). 1,368 participants from the National Alzheimer's Coordinating Center database with a diagnosis of probable AD (CDR 0.5-1.0) were included. A language subgroup (n = 229) was defined as having language performance >1 SD worse than memory performance. A memory subgroup (n = 213) was defined as having memory performance >1 SD worse than language performance. A typical subgroup (n = 926) was defined as having a difference in language and memory performance of <1 SD. Compared with the memory subgroup, the language subgroup was 3.7 years older and more frequently self-identified as African American (OR = 3.69). Under a dominant genetic model, the language subgroup had smaller odds of carrying at least one APOEε4 allele relative to the memory subgroup. While this difference was present for all ages, it was more striking at a younger age (OR = 0.19 for youngest tertile; OR = 0.52 for oldest tertile). Compared with the memory subgroup, the language subgroup rose 35% faster on the Functional Assessment Questionnaire and 44% faster on CDR sum of boxes over time. Among a subset of participants who underwent autopsy (n = 98), the language, memory, and typical subgroups were equally likely to have an AD pathologic diagnosis, suggesting that variation in non-AD pathologies across subtypes did not lead to the observed differences. The study demonstrates that a language subgroup of AD has different demographics, genetic profile, and disease course in addition to cognitive phenotype.