NACC’s Uniform Data Set (UDS), collected since 2005, is widely regarded as the gold standard by the field. This longitudinal, multi-domain neurocognitive and phenotypic dataset includes robust, criteria-based diagnoses, providing a valuable foundation for grounding other studies. UDS data collection instruments are trusted benchmarks in Alzheimer’s disease and related dementias (AD/ADRD) clinical phenotypic assessments globally.

National Alzheimer’s Coordinating Center (NACC) uniform dataset characteristics of cases and controls.

The Oregon Alzheimer Disease Center is the core program of the Layton Aging & Alzheimer's Disease Center (LAADC), supported by the National Institute on Aging (NIA, NIH). We promote interactive, multidisciplinary research among the scientific community. Our primary emphasis is on studies of preclinical dementia, as well as early dementia. Well-characterized patients, clinical, MRI and genetic data, as well as biological specimens are made available to investigators and research groups worldwide.

ObjectiveTo compare the rate of cognitive and functional decline in dysexecutive, typical and amnestic subgroups of Alzheimer’s disease.Methods943 participants from the National Alzheimer’s Coordinating Center (NACC) database who had a diagnosis of probable AD were followed for a mean of 2.3 years. A dysexecutive subgroup (n = 165) was defined as having executive performance >1.5 SD worse than memory performance, an amnestic subgroup (n = 157) was defined as having memory performance >1.5 SD worse than executive performance and a typical subgroup (n = 621) was defined as having a difference in executive and memory performance of

(The increment parameters are defined as: , ; ; ; ).

Objective: To compare the proportion of APOEε4 genotype carriers in aphasic versus amnestic variants of Alzheimer's disease (AD). Method: The proportion of APOEε4 carriers was compared among 3 groups. 1) Forty-two patients with primary progressive aphasia (PPA) and AD pathology (PPA/AD) enrolled in the Northwestern Alzheimer Disease Center Clinical Core. 2) 1,418 patients with autopsy confirmed AD and amnestic dementia of the Alzheimer-type (DAT/AD); 3) 2,608 cognitively normal controls (NC). The latter two groups were compiled from the National Alzheimer Coordinating Center (NACC) database. Logistic regression models analyzed the relationship between groups and APOEε4 carrier status, adjusting for age of onset and sex as needed. Results: Using NC as the reference and adjusting for sex and age, the DAT/AD group was 3.97 times more likely to be APOEε4 carriers. Adjusting for sex and age at symptom onset, the DAT/AD group was 2.46 times as likely to be carriers compared to PPA/AD. There was no significant difference in the proportion of APOEε4 carriers for PPA/AD compared to NC. PPA subtypes included 24 logopenic, 10 agrammatic nonfluent, and eight either mixed (n=5) or too severe (n=3) to subtype. The proportion of carriers and non carriers was similar for logopenic and agrammatic subtypes, both having fewer carriers. Conclusion: The proportion of APOEε4 carriers was elevated in amnestic but not aphasic manifestations of AD. These results suggest that APOEε4 is an anatomically selective risk factor that preferentially increases the vulnerability to AD pathology of memory-related medial temporal areas rather that language-related neocortices.

NIAGADS is a national genetics data repository that archives and distributes genetics and genomics data for Alzheimer’s disease and related dementias to qualified researchers. It serves as the data coordinating center for the  Alzheimer’s Disease Sequencing Project (ADSP), and is responsible for collecting phenotypes and consent information from participating cohorts as well as sharing data with the research community. *Some subjects in NIAGADS are also part of other GAAIN Data Partners.

APOE4 PPA Supplementary Materials 04-08-19This file contains information about additional data analysis that was completed in response to reviewer's comments but not necessary to include in the manuscript. There are tables reporting the age makeup of the samples and also an analysis using a matched sample technique that showed no differences from the original analysis in which the samples were not matched and sample numbers were uneven.

Objective Large systolic blood pressure (SBP) variability has been proposed as a novel risk factor for dementia above and beyond SBP levels, but the underlying neuropathology is largely unknown. We investigated the relationship among visit-to-visit SBP variability, cognitive deterioration and underlying neuropathological changes.

Methods We used longitudinal data (between 2005 and 2019) from the National Alzheimer’s Coordinating Center. 13,284 dementia-free participants aged≥50 years were followed over a median of 5.0 (interquartile range: 3.1-7.6) years. Neuropathology data were available in 1,400 autopsied participants. Visit-to-visit SBP variability was quantified from repeated annual SBP measurements. Cognitive deterioration was defined as conversion from normal cognition to mild cognitive impairment (MCI) or dementia, or from MCI to dementia.

Results Larger visit-to-visit SBP variability was associated with cognitive deterioration (adjusted odds ratio comparing extreme quintiles:...

Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) concentrations identify asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.

Methods: Baseline plasma NfL concentrations were measured with Simoa in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN and MAPT mutation carriers and non-carriers from the same families were classified by disease severity [asymptomatic, prodromal and full phenotype] using the CDR^® Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR^®+NACC-FTLD). Linear mixed effect models related NfL to clinical variables.

Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or subsequent disease progression compared to non-progressors (original: 11.4 ± 7 pg/mL vs. 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs. 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR^®+NACC-FTLD sum of boxes scores, neuropsychological function and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.

Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression, and is a potential tool to select participants for prevention clinical trials.

Classification of evidence: This study provides Class I evidence that in familial FTLD, elevation of plasma NfL predicts short-term risk of clinical progression.

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.

Probabilities of disease-stage transition, according to National Alzheimer’s Coordinating Centre data [24].

We used an untargeted mass spectrometric approach, tandem mass tag (TMT) proteomics, for the identification of biomarker signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the GENetic FTD Initiative (GENFI) were analysed, including 107 presymptomatic (44 C9orf72, 38 GRN, 25 MAPT) and 55 symptomatic (27 C9orf72, 17 GRN, 11 MAPT) mutation carriers as well as 76 mutation-negative controls (‘non-carriers’). We found both shared and specific proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared to non-carriers, we found that YWHAZ, YWHAG, UCHL1, NPTXR, NPTX2 and FABP3 were changed across all three genetic forms, as well as in patients with Alzheimer’s disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in MAPT carriers. Further, we identified mu..., Participants and sample collection Participants were recruited from the GENFI study, which includes individuals with a diagnosis of FTD due to a pathogenic mutation in MAPT, GRN, or C9orf72 (symptomatic mutation carriers), at-risk first-degree relatives (presymptomatic mutation carriers), and non-carriers (mutation-negative first-degree relatives from the same families). Demographics of the cohort are described in Table 1. Participants were assessed using a standardised history and examination and were classified as symptomatic if they met consensus diagnostic criteria (51, 52). The CDR Dementia Staging Instrument with National Alzheimer Coordinating Centre Frontotemporal Lobar Degeneration component (CDR® plus NACC FTLD) was used to assess disease severity, and the CDR® plus NACC FTLD sum of boxes (SOB) was used for quantitative analyses in this paper. Participants underwent Volumetric T1-weighted MRI scans. More details on clinical evaluation and imaging can be found in Supplementary ..., , # Raw data proteomic study in genetic frontotemporal dementia (GENFI study)

https://doi.org/10.5061/dryad.r7sqv9snk

Description of the data and file structure

The data corresponds to the normalised relative abundances of proteins in cerebrospinal samples of genetic frontotemporal dementia participants and controls. The data was obtain by Tandem Mass Tag LC-MS.

CSF was collected in polypropylene tubes through a lumbar puncture and centrifuged to remove insoluble material and cells. Supernatants were aliquoted and stored at -80 °C within 2 hours after collection. CSF samples (25 µL) were reduced by the addition of Tris(2)-carboxyethylphosphine (TCEP) in sodium deoxycholate (DOC), and triethylammonium bicarbonate (TEAB) to a final concentration of 5 mM TCEP (1% DOC, 100 mM TEAB). Following incubation at 55 °C for one hour, samples were equilibrated to room temperature (RT). Carbamidomethylation was performed by adding iodoacetamide to a con...

Demographic and clinical characteristics of participants in our samples from the National Alzheimer’s Coordinating Center, the Rotterdam Study, the Framingham Heart Study, and the Sacramento Area Latino Study on Aging.

ObjectiveValidation and widespread use of markers indicating decline in serial neuropsychological exams has remained elusive despite potential value in prognostic and treatment decision-making. This study aimed to operationalize neuropsychological decline, termed “neuropsychological (NP) decline,” in older adults followed over 12 months in order to aid in the stratification of dementia risk along the cognitively unimpaired-to-mild cognitive impairment (MCI) spectrum.MethodsA prospective cohort study utilized 6,794 older adults from the National Alzheimer’s Coordinating Center (NACC) database with a baseline diagnosis of normal cognition, impaired without MCI or with MCI. Operationalization of NP decline over 12-month follow-up used regression-based norms developed in a robustly normal reference sample. The extent to which each participant’s 12-month follow-up score deviated from norm-referenced expectations was quantified and standardized to an NP decline z-score. Cox regression evaluated whether the NP decline metric predicted future dementia.ResultsParticipant’s NP decline scores predicted future all-cause dementia in the total sample, χ2 = 110.71, hazard ratio (HR) = 1.989, p < 0.001, and in the subset diagnosed with normal cognition, χ2 = 40.84, HR = 2.006, p < 0.001, impaired without MCI diagnosis, χ2 = 14.89, HR = 2.465, p < 0.001, and impaired with MCI diagnosis, χ2 = 55.78, HR = 1.916, p < 0.001.ConclusionOperationalizing NP decline over 12 months with a regression-based norming method allows for further stratification of dementia risk along the cognitively unimpaired-to-MCI spectrum. The use of NP decline as an adjunctive marker of risk beyond standard cognitive diagnostic practices may aid in prognosis and clinical decision-making.

IntroductionDementia is characterized by significant declines in cognitive, physical, social, and behavioral functioning, and includes multiple subtypes that differ in etiology. There is limited evidence of the influence of psychiatric and substance use history on the risk of dementia subtypes among older underrepresented racial/ethnic minorities in the United States. Our study explored the role of psychiatric and substance use history on the risk of etiology-specific dementias: Alzheimer’s disease (AD) and vascular dementia (VaD), in the context of a racially and ethnically diverse sample based on national data.MethodsWe conducted secondary data analyses based on the National Alzheimer’s Coordinating Center Uniform Data Set (N = 17,592) which is comprised a large, racially, and ethnically diverse cohort of adult research participants in the network of US Alzheimer Disease Research Centers (ADRCs). From 2005 to 2019, participants were assessed for history of five psychiatric and substance use disorders (depression, traumatic brain injury, other psychiatric disorders, alcohol use, and other substance use). Cox proportional hazard models were used to examine the influence of psychiatric and substance use history on the risk of AD and VaD subtypes, and the interactions between psychiatric and substance use history and race/ethnicity with adjustment for demographic and health-related factors.ResultsIn addition to other substance use, having any one type of psychiatric and substance use history increased the risk of developing AD by 22–51% and VaD by 22–53%. The risk of other psychiatric disorders on AD and VaD risk varied by race/ethnicity. For non-Hispanic White people, history of other psychiatric disorders increased AD risk by 27%, and VaD risk by 116%. For African Americans, AD risk increased by 28% and VaD risk increased by 108% when other psychiatric disorder history was present.ConclusionThe findings indicate that having psychiatric and substance use history increases the risk of developing AD and VaD in later life. Preventing the onset and recurrence of such disorders may prevent or delay the onset of AD and VaD dementia subtypes. Prevention efforts should pay particular attention to non-Hispanic White and African American older adults who have history of other psychiatric disorders.Future research should address diagnostic shortcomings in the measurement of such disorders in ADRCs, especially with regard to diverse racial and ethnic groups.

Background: Gabapentin is increasingly prescribed to older adults, which raises concerns about its potential to cause neurocognitive changes. Therefore, we aimed to examine the association of gabapentin use with neurocognitive changes (i.e., cognitive decline, functional status decline, and motor function change) in older adults.Methods: We conducted a retrospective cohort study using the National Alzheimer’s Coordinating Center Uniform Data Set (UDS; September 2005-March 2021 data freeze). From the eligible sample (≥age 65 years), we identified cognitively normal new-users of gabapentin and the visit they initiated gabapentin (i.e., index visit). Initiators were matched to randomly selected nonusers on year of UDS enrollment and visit number from enrollment to index. Cognitive decline was defined as any increase in the Clinical Dementia Rating global score (CDRGLOB) and as a 1-point increase in CDR sum of boxes (CDR-SB). Functional status decline was defined as a 3-point increase in the sum of the Functional Activities Questionnaire (FAQ) and as 0.3-point increase in mean FAQ. Decline in motor function was defined as new clinician reports of gait disorder, falls, and slowness. To mitigate confounding and selection bias, we used joint stabilized inverse probability of treatment weights and stabilized inverse probability of censoring weights. All analyses were conducted comparing index to index+1 and index+2 visits.Results: From the eligible UDS participants (N = 23,059), we included 480 initiators (mean age [SD]: 78.7 [6.9]; male 34.4%); 4,320 nonusers (78.3 [7.0]; 34.4%). Gabapentin initiation was significantly associated with cognitive/functional status decline: worsening CDRGLOB at index+1 visit (odds ratio [95% confidence interval]: 1.55 [1.07, 2.25]); CDR-SB at index+1 visit (1.94 [1.22, 3.09]); and mean of FAQ at index+2 visit (1.78 [1.12, 2.83]). After excluding initiators with extant motor dysfunction (n = 21), we identified 459 initiators (78.7 [6.9]; 34.0%) and 4,131 nonusers (78.2 [6.9]; 34.7%); in this sample, gabapentin initiation was associated with increased falls at the index+2 visit (2.51 [1.19, 5.31]).Conclusion: Gabapentin initiation was significantly associated with deleterious neurocognitive changes among older adults with initially normal cognition. Further studies are needed to examine the risk/benefit of prescribing gabapentin in older adults.

Objective: Although mild cognitive impairment (MCI) is generally considered a risk state for dementia, its prevalence and association with dementia are impacted by the number of tests and cut-points used to assess cognition and define “impairment,” and sources of norms. Here, we investigate how these methodological variations impact estimates of incident dementia in adults with bipolar disorder (BD), a vulnerable population with pre-existing cognitive deficits and increased dementia risk. Method: Neuropsychological data from 148 adults with BD and 13,610 healthy controls (HC) were drawn from the National Alzheimer’s Coordinating Center. BD participants’ scores were standardized against published norms and again using regression-based norms generated from HC within the same catchment area as individual BD patients (“site-specific norms”), varying the number of within-domain tests (one vs. two) and the cut-points (−1 vs. −1.5 SD) used to operationalize MCI. Results: Site-specific norms were more sensitive to incident dementia (88.6%–94.3%) than published norms (74.3%–88.6%), but only when using a “single test” definition of impairment. Specificity (22.1%–74.3%), accuracy (37.8%–68.9%), and positive predictive values (26.1%–38.3%) were overall poor. Applying a “single test” definition of impairment resulted in better negative predictive values using site-specific (92.3%–93.3%) than published norms (83.6%–86.2%), and a substantial increase in relative risk of incident dementia relative to published norms. Conclusions: Neuropsychologists should define “impairment” as scores below −1.0 or −1.5 SD on at least two within-domain measures when using published norms to interpret cognitive performance in adults with BD.