National Alzheimer's Coordinating Center Research Articles

The Association between Metformin Use and Risk of Developing Severe Dementia among AD Patients with Type 2 Diabetes.

This study explores the potential impact of metformin on the development of severe dementia in individuals with Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). With an emerging interest in the role of the APOE genotype in mediating metformin's effects on cognitive decline in AD patients, we sought to investigate whether metformin usage is associated with a reduced risk of severe dementia. Using data from the National Alzheimer's Coordinating Center (NACC) database (2005-2021), we identified 1306 participants with both AD and T2DM on diabetes medications. These individuals were categorized based on metformin usage, and a propensity score-matched cohort of 1042 participants was analyzed. Over an average follow-up of 3.6 years, 93 cases of severe dementia were observed. A Kaplan-Meier analysis revealed that metformin users and non-users had similar probabilities of remaining severe dementia-free (log-rank p = 0.56). Cox proportional hazards models adjusted for covariates showed no significant association between metformin usage and a lower risk of severe dementia (HR, 0.96; 95% CI, 0.63-1.46; p = 0.85). A subgroup analysis based on APOE ε4 carrier status demonstrated consistent results, with metformin use not correlating with a reduced severe dementia risk. In conclusion, our findings from a substantial cohort of AD and T2DM patients suggest that metformin usage is not significantly associated with a decreased risk of severe dementia. This observation persists across APOE ε4 carriers and non-carriers, indicating a lack of genotype-mediated effect.

Type 2 Diabetes Comorbidity and Cognitive Decline in Patients with Alzheimer's Disease.

Although insulin dysregulation and resistance likely participate in Alzheimer's disease (AD) etiologies, little is known about the correlation between type 2 diabetes mellitus (T2DM) and the progression of cognitive decline in patients with AD. To determine whether AD patients with T2DM experience more rapid cognitive decline than those without T2DM. All cognitive performance data and the presence or absence of T2DM comorbidity in patients with AD were derived from the US National Alzheimer's Coordinating Center's (NACC) Uniform Data Set (UDS). A search of the UDS identified 3,055 participants with AD who had more than one epoch completed. The data set culled clinically diagnosed AD dementia patients who were assessed for diabetes type identified during at least 1 visit. These patients were divided into 2 groups based on whether they had a diagnosis of T2DM. The data from these groups were then analyzed for differences in cognitive decline based on neuropsychological test battery scores and a Clinician Dementia Rating using a general linear model. Comparisons of the mean scores for 16 selected tests from the neuropsychological test battery showed no significant differences in baseline scores and scores at subsequent visits between the T2DM and nondiabetic groups. The results revealed no differences in cognitive decline metrics over the course of 5 visits in either study group. These data indicate that the presence of T2DM does not increase the rate of cognitive decline in AD. This finding contradicts expected disease burden and will need to be explored further.

A - 48 Neuropsychiatric Symptom Severity Predicts Rate of Executive Function Decline.

Neuropsychiatric symptoms (NPS) are considered diagnostic and prognostic indicators of dementia and are attributable to neurodegenerative processes. NPS are distressing for patients and caregivers and are associated with accelerated functional decline, hospitalization, and institutionalization. Evaluation of NPS effects on disease course may reduce patient and caregiver distress and support development of personalized treatments. We examined whether baseline NPS predicted the rate of executive function (EF) decline among older adults with cognitive impairment. Older adults (n = 1155) with cognitive impairment and four years of data were selected from the National Alzheimer's Coordinating Center database v3-v3.2. Overall EF was estimated with a latent factor indicated by scores on Number Span Backward, Letter Fluency, and Trail Making-Part B. Strict temporal invariance was established. A curve of factors (CUFF) latent growth curve model was estimated to examine rate of change. Baseline NPS severity was entered as a predictor to examine its influence on the rate of change in EF over time. The predicted CUFF model exhibited good fit (χ2[69] = 201.46, p < 0.001; CFI = 0.98, RMSEA = 0.04). EF significantly declined over four waves (slope = -0.53). NPS severity at baseline predicted decline in EF (β= 0.164, p = 0.001), such that those with greater NPS severity demonstrated a more rapid decrease in EF performance over time. Increased NPS severity at baseline predicts more rapid decline in EF over four years. Findings highlight the prognostic value of NPS on cognitive decline and underscore the importance of targeting NPS at early disease stages. Future research will examine influence of individual NPS on rate of cognitive decline.

A - 19 Cognitive Test Score Dispersion VS. Traditional Memory Composite Scores: Predicting Mild Cognitive Impairment (MCI) & Dementia among Cognitively Impaired, Not MCI Patients.

To compare mild cognitive impairment (MCI) and dementia conversion rates between global neuropsychological dispersion (GD) and traditional memory neuropsychological composite score (MComp) in participants with baseline evidence of cognitive decline but no diagnosis of MCI or dementia. Data from the National Alzheimer's Coordinating Center (NACC) for 364 participants with a CDR of 0.5, no initial diagnosis of MCI or dementia, and five visits were analyzed. GD was the intraindividual standard deviation across baseline normative (NACC norms) neuropsychological performance. MComp was the mean of the four verbal and visual memory normed scores. Multinomial logistic regression models fit statistics compared GD and MComp as predictors of conversion to MCI/dementia, adjusting for age, sex, race, ethnicity, ApoE4 status, and stratified by suspected etiology (Alzheimer's disease [ad] or no-ad). Lower Akaike Information Criteria (AIC) values indicate better model fit and predictions. 37% progressed to MCI, and 47% to dementia by visit 5. 53% of these were suspected to have ad etiology, and 47% non-ad. MComp showed a better fit with significant predictions of MCI and dementia progression in both suspected ad (AIC: 351.77, p < 0.001) or non-ad etiology (AIC: 215.02, p < 0.004), versus GD was only significant for non-ad etiology (AIC: 385.74, p < 0.003). Better memory performance predicted a lower likelihood of conversion to non-ad MCI (B = -0.65, p = 0.003) and non-ad dementia (B = -1.33, p < 0.001). GD predicted eventual progression to non-ad dementia (B = 2.311, p = 0.004), but not non-ad MCI. Traditional memory composite score may be a better predictor of MCI and dementia conversion than cognitive dispersion in individuals with early cognitive decline who do not yet meet MCI criteria.

B - 25 Examining Mini-Mental State Examination (MMSE) Performance by Primary and Testing Language.

Previous research has identified that MMSE scores vary by education raising concern that examinees with lower educational level may be inaccurately identified as cognitively impaired. Most studies, however, used the English MMSE and may not generalize to Spanish speakers. We compared MMSE scores in primary Spanish-speakers tested in English (S-E) with primary Spanish-speakers tested in Spanish (S-S). This project involved secondary analysis of de-identified National Alzheimer's Coordinating Center data. Cases with visit one MMSE data and demographics were included if the primary language was Spanish yielding a sample of S-S (n = 1514) and S-E (n = 346) participants. Coarsened exact matching derived a subset of S-E and S-S participants matched on age, education, and Clinical Dementia Rating global score (n = 630). In the overall sample, groups were not different in age, but education was lower in S-S (M = 9.2; SD = 5.1) than S-E (M = 12.9; SD = 5.1; p < 0.001) participants. MMSE scores were lower in S-S (M = 22.4, SD = 7.1) than S-E participants (M = 23.7, SD = 6.2; p = 0.002). More S-S participants (45%) had an abnormal (< 24) MMSE compared to S-E participants (38%; p = 0.02). In the matched sample, MMSE scores were not significantly different between S-S (M = 24.4; SD = 6.0) and S-E (M = 23.9; SD = 6.1; p = 0.30) participants, and rates of abnormal MMSE scores were not significantly different between S-S (32%) and S-E (37%; p = 0.16) participants. Overall sample MMSE scores differed by test administration language groups, but group differences were not observed in the matched subset. Consistent with other research, educational level is associated with MMSE scores in Spanish-speakers regardless of test administration language.

B - 26 Examining Montreal Cognitive Assessment (MoCA) Performance by Primary and Testing Language.

The MoCA has been translated into almost 100 languages including a Spanish version used in multiple validation studies. Research considering primary language and language of test administration is limited. We compared MoCA scores of primary Spanish speakers tested in English (S-E) with those of primary Spanish speakers tested in Spanish (S-S). This project involved secondary analysis of deidentified National Alzheimer's Coordinating Center data. Cases with first visit MoCA data, demographics, and primary language of Spanish were included resulting in a final sample (N = 395) of S-S (n = 265) and S-E (n = 130) participants. Coarsened exact matching was used to derive a sample subset matched on age, education, and Clinical Dementia Rating global score (n = 160). Participants were compared on demographics and MoCA. In the final sample, S-S and S-E participants were not different in age, but educational level was lower in S-S (M = 10.0; SD = 5.3) than S-E (M = 14.6; SD = 3.9; p < 0.001) participants. MoCA scores were lower in S-S (M = 19.1, SD = 6.2) than S-E participants (M = 21.2, SD = 6.1; p = 0.002). A larger proportion of the S-S group (79%) had an abnormal MoCA compared to the S-E group (67%; p = 0.021). In the matched sample, MoCA scores were not significantly different between S-S (M = 21.2; SD = 4.8) and S-E (M = 21.2; SD = 5.3; p = 0.95) participants; rates of abnormal MoCA scores were not significantly different between S-S (73%) and S-E (66%; p = 0.39) participants. Relationships between primary language, test administration language, and MoCA score were reduced in groups matched on education. Future research should explore additional education and language interactions among bilingual older adults.

A - 62 Caregiver Relationship Type Significantly Moderates Association among NPI-Q Symptoms: a Moderated Network Analysis.

We investigated the influence of caregiver type (CT; ex. spouse, child, etc.) on the association among neuropsychiatric symptoms using the caregiver-endorsed Neuropsychiatric Inventory Questionnaire (NPI-Q) and a sample from the National Alzheimer's Coordinating Center database. The selected sample (n = 12,337) includes those aged 50+ with complete baseline data for the NPI-Q and caregiver relationship. Included participants had ≥1 NPI-Q symptom(s) endorsed and a diagnosis of mild cognitive impairment or dementia with Alzheimer's disease as the primary or contributing cause. A Moderated Network Model approach estimated whether associations among NPI-Q items depend on CT (moderator variable). Spouse was used as the reference group for all comparisons. CT significantly moderated the NPI-Q. Interaction effects were found between 3 moderated node pairs: agitation/aggression and disinhibition (edgeweight = 0.02), hallucinations and nighttime behaviors (edgeweight = 0.01), and depression/dysphoria and appetite/eating problems (edgeweight = 0.01). The edgeweights for these node pairs were reduced in the final model due to variance being accounted for by the addition of CT. The association between agitation/aggression and disinhibition was smaller for spouses than children, and larger for spouses than friends and paid caregivers. The association between hallucinations and nighttime behaviors was smaller for spouses than children, and larger for spouses than friends and paid caregivers. The association between depression/dysphoria and appetite/eating problems was smaller for spouses than siblings and friends. The pairwise dependency between neuropsychiatric symptoms differs as a function of CT. Future research is needed to identify factors that influence symptom reporting, including interpersonal dynamics, amount of time spent together, and overall burden of symptoms.

A - 32 Impact of Demographic Factors in African American (AA) Older Adults in Relation to Confrontational Naming Deficits on an Object Naming Task.

Dysnomia, or complaints of word-finding difficulties for names, places, and objects is common in patients with Alzheimer's Disease (ad). This common characteristic makes confrontational naming a fundamental component of neuropsychological assessment in aging populations. The Multilingual Naming Test (MINT) detects naming impairments at various stages of cognitive decline. However, our understanding of how performance varies based on education, is sparse. Authors evaluated the sensitivity of the MINT in predicting naming impairments in AA in relation to education levels. 842 cognitively unimpaired (CU) and 413 mild cognitive impairment (MCI) AA elders were administered the MINT as part of the National Alzheimer's Coordinating Center neuropsychological battery. The MINT consists of 32 items of ascending difficulty that participants must name spontaneously. Semantic and phonemic cues are given in the absence of immediate responses. A 5-number MEANS analysis was used to measure differences among CU and MCI stratifying by education level. Overall naming scores were consistently lower in cohorts with lower education across diagnosis. Unsurprisingly CU participants outperformed MCI counterparts. More sensitive tools are needed to detect cognitive functioning changes in individuals with lower education levels. The MINT offers a novel approach in detecting confrontational naming deficits in those at risk of developing ad, but norms accounting for scholastic attainment are necessary to accurately diagnose minority populations with varying education levels. Further research is required to validate the MINT in participants with diverse backgrounds, low literacy levels and other factors that could affect quality of formative education.

A - 12 Traumatic Brain Injury Characteristics Are Not Related to Neurocognitive Decline in Older Adults: a Nationwide Longitudinal Cohort Study.

Evaluate if traumatic brain injury (TBI) characteristics, age of injury, or recency of injury is related to course of neurocognitive decline in aging and/or increases conversion rates to mild cognitive impairment (MCI) or all-cause dementia later in life. Data were obtained from the National Alzheimer's Coordinating Center for participants 50-85years old with 3 to 5 visits from 2015-2022. Groups were stratified by: 1) self-reported TBI history (No TBI [n = 2382], Single TBI without loss of consciousness [LOC; n = 102], Single TBI w/LOC [n = 228], Multiple TBI without LOC [n = 36], and Multiple TBI w/LOC [n = 115]), 2) age of most recent TBI (No TBI [n = 2382], TBI = 65years old [n = 76]), and 3) recency of TBI (no TBI [n = 2382], 15years ago [n = 301]). Mixed linear models compared normed neuropsychological composite trajectories (executive functioning/attention/speed, language, memory, and overall), co-varying for age, gender, education, apolipoprotein E4 status, and baseline diagnosis (normal aging n = 1720, MCI n = 749, or dementia n = 417). Logistic binary regression examined MCI/dementia conversion rates. Longitudinal neurocognitive trajectories in composite measures were similar among TBI groups (example figure below). Specific TBI history, age of injury, or recency of injury did not impact neurocognitive trajectories or conversion rates to MCI or dementia (all p's > 0.01). TBI history, regardless of injury characteristics, age, or recency, did not worsen neurocognitive decline or MCI/dementia conversion. The mechanism and factors that increase dementia risk after TBI are unclear. Additional longitudinal research in carefully designed longitudinal cohorts is needed.

Reliability of remote National Alzheimer's Coordinating Center Uniform Data Set data.

The National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) neuropsychological battery is being used to track cognition in participants across the country, but it is unknown if scores obtained through remote administration can be combined with data obtained in person. The remote UDS battery includes the blind version of the Montreal Cognitive Assessment (MoCA), Number Span, Semantic and Phonemic Fluency, and Craft Story. For these tests, we assessed intraclass correlation coefficients (ICCs) between in-person and remote scores in 3838 participants with both in-person and remote UDS assessments, and we compared annual score changes between modalities in a subset that had two remote assessments. All tests exhibited moderate to good reliability between modalities (ICCs=0.590-0.787). Annual score changes were also comparable between modalities except for Craft Story Immediate Recall, Semantic Fluency, and Phonemic Fluency. Our findings generally support combining remote and in-person scores for the majority of UDS tests.

Temporal associations between treated and untreated hearing loss and mild behavioral impairment in older adults without dementia.

Hearing loss (HL) and mild behavioral impairment (MBI) are non-cognitive markers of dementia. This study investigated the relationship between hearing and MBI and explored the influence of hearing aid use on the treatment of hearing loss, both cross-sectionally and longitudinally. Data were analyzed from National Alzheimer's Coordinating Center participants, age ≥50, dementia-free at baseline, collected between 2005 and 2022. Three self-report questions were used to generate a three-level categorical hearing variable: No-HL, Untreated-HL, and Treated-HL. MBI status was derived from the informant-rated Neuropsychiatric Inventory Questionnaire (NPI-Q) using a published algorithm. At baseline (n = 7080), logistic regression was used to examine the association between hearing status (predictor) and the presence of global and domain-specific MBI (outcome), adjusting for age, sex, cognitive diagnosis, and apolipoprotein E4 (APOE4). Cox proportional hazard models with time-dependent covariates were used to examine the effect of (1) hearing status as exposure on the rate of incident MBI (n = 5889); and (2) MBI as exposure on the rate of incident HL in those with no HL at baseline (n = 6252). Cross-sectionally, participants with Untreated-HL were more likely to exhibit global MBI (adjusted odds ratio (aOR) = 1.66, 95% CI: 1.24-2.21) and individual MBI domains of social inappropriateness (aOR = 1.95, 95% CI: 1.06-3.39), affective dysregulation (aOR = 1.71, 95% CI: 1.21-2.38), and impulse dyscontrol (aOR = 1.71, 95% CI: 1.21-2.38), compared to those with No-HL. Participants with Treated-HL (i.e., hearing aid use) did not differ from No-HL for odds of global or most MBI domains, except for impulse dyscontrol (aOR = 1.38, 95% CI: 1.05-1.81). Longitudinally, we found relationships between Treated-HL and incident MBI (adjusted hazard ratio (aHR) = 1.29, 95% CI: 1.01-1.63) and between MBI and incident Untreated-HL (aHR = 1.51, 95% CI: 1.19-1.94). Our cross-sectional results support that hearing aid use is associated with lower odds of concurrent global MBI in dementia-free participants. Longitudinally, relationships were found between MBI and HL. The severity of HL was not assessed, however, and may require further exploration. Hearing Loss (HL) and mild behavioral impairment (MBI) are markers of dementiaCross-sectionally: Untreated-HL was associated with global MBI burden, butHL treated with hearing aids was notWe found associations between MBI and incident Untreated-HL.

Persistence of neuropsychiatric symptoms and dementia prognostication: A comparison of three operational case definitions of mild behavioral impairment.

We compared three operational case definitions of mild behavioral impairment (MBI) in the context of MBI prevalence estimates and dementia risk modeling. Participants were dementia-free older adults (n=13701) from the National Alzheimer's Coordinating Center. Operational case definitions of MBI were generated based on neuropsychiatric symptoms at one (OV), two-consecutive (TCV), or more than two-thirds (TTV) of dementia-free study visits. Definitions were compared in prevalence and in Cox regressions using MBI to predict incident dementia. OV MBI was the most prevalent (54.4%), followed by TCV (32.3%) and TTV (26.7%) MBI. However, OV MBI had the lowest rate of incident dementia (hazard ratio [HR]=2.54, 95% confidence interval [CI]: 2.33-2.78) and generated poorer model metrics than TCV MBI (HR=4.06, 95% CI: 3.74-4.40) and TTV MBI (HR=5.77, 95% CI: 5.32-6.26). Case ascertainment with longer timeframe MBI operational case definitions may more accurately define groups at risk of dementia in datasets lacking tools designed to detect MBI.Highlights: Mild behavioral impairment (MBI) can identify older adults at risk of dementia.Neuropsychiatric symptom (NPS) assessment tools can be proxy measures for MBI.Hazard for dementia was highest for MBI defined by NPS presence at more than two-thirds of visits.

Clinical characteristics of pathological confirmed prodromal dementia with Lewy bodies

IntroductionMisdiagnosis rate of Dementia with Lewy Bodies (DLB) remains high despite being second most common cause of neurodegenerative dementia. To date, understanding of clinical profile of pathologically confirmed prodromal DLB remains limited. The main objective of this study was to describe and compare it with pathologically confirmed Alzheimer's disease (AD). MethodsWe accessed the National Alzheimer's Coordinating Center database from 2005 to December 2022 data freeze and included 111 and 501 prodromal DLB and AD patients respectively. First visit data was analyzed. ResultsClinician-determined memory impairment is common in prodromal DLB (>70%) but associated with higher risk for AD diagnosis (OR 0.355, p = 0.0003). DLB had a higher proportion of non-amnestic mild cognitive impairment (MCI) diagnoses but statistically insignificance in differentiating the two. Inattention (OR 2.273, p = 0.0015), and neuropsychiatric features, such as visual hallucinations (OR 11.98, p < 0.0001), depressed mood (OR1.709, p = 0.0292), apathy (1.824, p = 0.0345), and night/REM sleep behaviors, are associated with DLB diagnosis. Hallucinations are infrequent (7–11%). Motor symptoms, particularly gait disorders (OR 4.570, p < 0.001), falls (OR3.939, p = 0.0003), tremors (OR2.237, p = 0.0154), slowness (OR3.573, p < 0.0001), and parkinsonism signs (OR2.443, p < 0.0001), are common. 32% showed no parkinsonism during initial presentation. Neuropsychological examination revealed less impaired memory and language but impaired executive function in DLB. ConclusionIn clinical practice, it is important to note that memory symptoms although being higher risk associated with AD diagnosis, are prominent in prodromal DLB. Psychosis is infrequent, and non-amnestic MCI is not necessarily associated with higher risk of DLB diagnosis. A careful clinical approach is key to improve the diagnosis of prodromal DLB.

Predicting Progression to Clinical Alzheimer's Disease Dementia Using the Random Survival Forest.

Assessing the risk of developing clinical Alzheimer's disease (AD) dementia, by machine learning survival analysis approaches, among participants registered in Alzheimer's Disease Centers is important for AD dementia management. To construct a prediction model for the onset time of clinical AD dementia using the National Alzheimer Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) registered cohorts. A model was constructed using the Random Survival Forest (RSF) approach and internally and externally validated on the NACC cohort and the ADNI cohort. An R package and a Shiny app were provided for accessing the model. We built a predictive model having the six predictors: delayed logical memory score (story recall), CDR® Dementia Staging Instrument - Sum of Boxes, general orientation in CDR®, ability to remember dates and ability to pay bills in the Functional Activities Questionnaire, and patient age. The C indices of the model were 90.82% (SE = 0.71%) and 86.51% (SE = 0.75%) in NACC and ADNI respectively. The time-dependent AUC and accuracy at 48 months were 92.48% (SE = 1.12%) and 88.66% (SE = 1.00%) respectively in NACC, and 90.16% (SE = 1.12%) and 85.00% (SE = 1.14%) respectively in ADNI. The model showed good prediction performance and the six predictors were easy to obtain, cost-effective, and non-invasive. The model could be used to inform clinicians and patients on the probability of developing clinical AD dementia in 4 years with high accuracy.

APOE-ε4 and BIN1 increase risk of Alzheimer’s disease pathology but not specifically of Lewy body pathology

Lewy body (LB) pathology commonly occurs in individuals with Alzheimer’s disease (AD) pathology. However, it remains unclear which genetic risk factors underlie AD pathology, LB pathology, or AD-LB co-pathology. Notably, whether APOE-ε4 affects risk of LB pathology independently from AD pathology is controversial. We adapted criteria from the literature to classify 4,985 subjects from the National Alzheimer’s Coordinating Center (NACC) and the Rush University Medical Center as AD-LB co-pathology (AD+LB+), sole AD pathology (AD+LB–), sole LB pathology (AD–LB+), or no pathology (AD–LB–). We performed a meta-analysis of a genome-wide association study (GWAS) per subpopulation (NACC/Rush) for each disease phenotype compared to the control group (AD–LB–), and compared the AD+LB+ to AD+LB– groups. APOE-ε4 was significantly associated with risk of AD+LB– and AD+LB+ compared to AD–LB–. However, APOE-ε4 was not associated with risk of AD–LB+ compared to AD–LB– or risk of AD+LB+ compared to AD+LB–. Associations at the BIN1 locus exhibited qualitatively similar results. These results suggest that APOE-ε4 is a risk factor for AD pathology, but not for LB pathology when decoupled from AD pathology. The same holds for BIN1 risk variants. These findings, in the largest AD-LB neuropathology GWAS to date, distinguish the genetic risk factors for sole and dual AD-LB pathology phenotypes. Our GWAS meta-analysis summary statistics, derived from phenotypes based on postmortem pathologic evaluation, may provide more accurate disease-specific polygenic risk scores compared to GWAS based on clinical diagnoses, which are likely confounded by undetected dual pathology and clinical misdiagnoses of dementia type.

Racial Differences in Clinical Presentation in Individuals Diagnosed With Frontotemporal Dementia

Prior research suggests there are racial disparities in the presentation of dementia, but this has not been investigated in the context of frontotemporal dementia (FTD). To explore racial disparities in dementia severity, functional impairment, and neuropsychiatric symptoms in individuals with a diagnosis of FTD. This exploratory cross-sectional study of National Alzheimer's Coordinating Center (NACC) data collected between June 2005 to August 2021 evaluated Asian, Black, and White individuals with a diagnosis of FTD (behavioral variant FTD or primary progressive aphasia). Excluded were races with limited data, including American Indian or Alaska Native (n = 4), Native Hawaiian or other Pacific Islander (n = 3), other (n = 13), and unknown (n = 24), and participants with symptom duration more than 4 SDs above the mean. Racial differences at initial NACC visit were examined on Clinical Dementia Rating Dementia Staging Instrument plus NACC Frontotemporal Lobar Degeneration Behavior & Language Domains (FTLD-CDR), Functional Assessment Scale, and Neuropsychiatric Inventory using regression models. Matching was also performed to address the imbalance between racial groups. The final sample comprised 2478 individuals, of which 59 (2.4%) were Asian, 63 (2.5%) were Black, and 2356 (95.1%) were White. The mean (SD) age at initial visit was 65.3 (9.4) years and symptom duration at initial visit was 67.5 (35.6) months. Asian and Black individuals were considerably underrepresented, comprising a small percent of the sample. Black individuals had a higher degree of dementia severity on FTLD-CDR (β = 0.64; SE = 0.24; P = .006) and FTLD-CDR sum of boxes (β = 1.21; SE = 0.57; P = .03) and greater functional impairment (β = 3.83; SE = 1.49; P = .01). There were no differences on FTLD-CDR and Functional Assessment Scale between Asian and White individuals. Black individuals were found to exhibit a higher frequency of delusions, agitation, and depression (delusions: odds ratio [OR], 2.18; 95% CI, 1.15-3.93; P = .01; agitation: OR, 1.73; 95% CI, 1.03-2.93; P = .04; depression: OR, 1.75; 95% CI, 1.05-2.92; P = .03). Asian individuals were found to exhibit a higher frequency of apathy (OR, 1.89; 95% CI, 1.09-3.78; P = .03), nighttime behaviors (OR, 1.72; 95% CI, 1.01-2.91; P = .04), and appetite/eating (OR, 1.99; 95% CI, 1.17-3.47; P = .01) compared to White individuals. This exploratory study suggests there are racial disparities in dementia severity, functional impairment, and neuropsychiatric symptoms. Future work must address racial disparities and their underlying determinants as well as the lack of representation of racially minoritized individuals in nationally representative dementia registries.

BAYESIAN INFERENCE AND DYNAMIC PREDICTION FOR MULTIVARIATE LONGITUDINAL AND SURVIVAL DATA.

Alzheimer's disease (AD) is a complex neurological disorder impairing multiple domains such as cognition and daily functions. To better understand the disease and its progression, many AD research studies collect multiple longitudinal outcomes that are strongly predictive of the onset of AD dementia. We propose a joint model based on a multivariate functional mixed model framework (referred to as MFMM-JM) that simultaneously models the multiple longitudinal outcomes and the time to dementia onset. We develop six functional forms to fully investigate the complex association between longitudinal outcomes and dementia onset. Moreover, we use the Bayesian methods for statistical inference and develop a dynamic prediction framework that provides accurate personalized predictions of disease progressions based on new subject-specific data. We apply the proposed MFMM-JM to two large ongoing AD studies: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Alzheimer's Coordinating Center (NACC), and identify the functional forms with the best predictive performance. our method is also validated by extensive simulation studies with five settings.

Different cohort, disparate results: Selection bias is a key factor in autopsy cohorts.

Research-oriented autopsy cohorts provide critical insights into dementia pathobiology. However, different studies sometimes report disparate findings, partially because each study has its own recruitment biases. We hypothesized that a straightforward metric, related to the percentage of research volunteers cognitively normal at recruitment, would predict other inter-cohort differences. The National Alzheimer's Coordinating Center (NACC) provided data on N=7178 autopsied participants from 28 individual research centers. Research cohorts were grouped based on the proportion of participants with normal cognition at initial clinical visit. Cohorts with more participants who were cognitively normal at recruitment contained more individuals who were older, female, had lower frequencies of apolipoprotein E ε4, Lewy body disease, and frontotemporal dementia, but higher rates of cerebrovascular disease. Alzheimer's disease (AD) pathology was little different between groups. The percentage of participants recruited while cognitively normal predicted differences in findings in autopsy research cohorts. Most differences were in non-AD pathologies. Systematic differences exist between autopsy cohorts that serve dementia research. We propose a metric to use for gauging a research-oriented autopsy cohort. It is essential to consider the characteristics of autopsy cohorts.

Associations between dementia staging, neuropsychiatric behavioral symptoms, and divorce or separation in late life: A case control study.

Dementia can be difficult for married couples for many reasons, including the introduction of caregiving burden, loss of intimacy, and financial strain. In this study, we investigated the impact of dementia staging and neuropsychiatric behavioral symptoms on the likelihood of divorce or separation for older adult married couples. For this case-control study, we used data from the National Alzheimer's Coordinating Center (NACC) Uniform dataset (UDS) versions 2 and 3. This dataset was from 2007 to 2021 and contains standardized clinical information submitted by NIA/NIH Alzheimer's Disease Research Centers (ADRCs) across the United States (US). This data was from 37 ADRCs. We selected participants who were married or living as married/domestic partners at their initial visit. Cases were defined by a first divorce/separation occurring during the follow-up period, resulting in 291 participants. We selected 5 controls for each married/living as married case and matched on age. Conditional logistic regression estimated the association between overall Neuro Psychiatric Inventory (NPI) score and severity of individual symptoms of the NPI with case/control status, adjusted for education, the CDR® Dementia Staging Instrument score, living situation, symptom informant, sex, and race. Separate analyses were conducted for each symptom. Multiple comparisons were accounted for with the Hochberg method. Later stage of dementia was negatively associated with divorce/separation with an adjusted odds ratio (AOR) = 0.68 (95%CI = 0.50 to 0.93). A higher overall NPI score was positively associated with divorce/separation AOR = 1.08 (95% CI = 1.03 to 1.12,). More severe ratings of agitation/aggression, depression/dysphoria, disinhibition, and elation/euphoria were associated with greater odds of divorce/separation. Among older adults in the US, a later stage of dementia is associated with a lower likelihood of divorce or separation, while having more severe neuropsychiatric behavioral symptoms of agitation/aggression, depression/dysphoria, disinhibition, and elation/euphoria are associated with a higher likelihood of divorce or separation.

Disease severity and mortality in Alzheimer's disease: an analysis using the U.S. National Alzheimer’s Coordinating Center Uniform Data Set

BackgroundEvidence on the relative risk of death across all stages of Alzheimer’s disease (AD) is lacking but greatly needed for the evaluation of new interventions. We used data from the Uniform Data Set (UDS) of the National Alzheimer’s Coordinating Center (NACC) to assess the expected survival of a person progressing to a particular stage of AD and the relative risk of death for a person in a particular stage of AD compared with cognitively normal (CN) people.MethodsThis was a retrospective observational cohort study of mortality and its determinants in participants with incident mild cognitive impairment (MCI) due to AD or AD dementia compared with CN participants. Overall survival and hazard ratios of all-cause mortality in participants ≥ 50 years of age with clinically assessed or diagnosed MCI due to AD, or mild, moderate, or severe AD dementia, confirmed by Clinical Dementia Rating scores, versus CN participants were estimated, using NACC UDS data. Participants were followed until death, censoring, or until information to determine disease stage was missing.ResultsAged between 50 and 104 years, 12,414 participants met the eligibility criteria for the study. Participants progressing to MCI due to AD or AD dementia survived a median of 3–12 years, with higher mortality observed in more severe stages. Risk of death increased with the severity of AD dementia, with the increase significantly higher at younger ages. Participants with MCI due to AD and CN participants had a similar risk of death after controlling for confounding factors.ConclusionsRelative all-cause mortality risk increases with AD severity, more so at younger ages. Mortality does not seem to be higher for those remaining in MCI due to AD. Findings might imply potential benefit of lower mortality if preventing or delaying the progression of AD is successful, and importantly, this potential benefit might be greater in relatively younger people. Future research should replicate our study in other samples more representative of the general US population as well as other populations around the world.