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This cohort study investigates the risk of mild cognitive impairment, Alzheimer disease, and all-cause dementia associated with subjective cognitive decline using the subjective cognitive decline–plus criteria among cognitively normal adults in the community. Key Points: Question: Among cognitively normal adults in the community, what is the risk from subjective cognitive decline (SCD), using SCD-plus (SCD+) criteria and assessed longitudinally, associated with mild cognitive impairment (MCI), Alzheimer disease (AD), and all-cause dementia? Findings: In this cohort study using longitudinal data from the Framingham Heart Study including 3585 participants, SCD+ was significantly associated with survival time to MCI, AD, and all-cause dementia. Associations were independent of APOE status and an AD polygenic risk score. Meaning: In a community setting, SCD+ was associated with an increased risk of future MCI, AD, and all-cause dementia with similar hazards estimated in clinic-based settings. Importance: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer disease (AD) cognitive continuum. The SCD Initiative International Working Group recently proposed SCD-plus (SCD+) features that increase risk for future objective cognitive decline but that have not been assessed in a large community-based setting. Objective: To assess SCD risk for mild cognitive impairment (MCI), AD, and all-cause dementia, using SCD+ criteria among cognitively normal adults. Design, Setting, and Participants: The Framingham Heart Study, a community-based prospective cohort study, assessed SCD between 2005 and 2019, with up to 12 years of follow-up. Participants 60 years and older with normal cognition at analytic baseline were included. Cox proportional hazards (CPH) models were adjusted for baseline age, sex, education, APOE ε4 status, and tertiles of AD polygenic risk score (PRS), excluding the APOE region. Data were analyzed from May 2021 to November 2023. Exposure: SCD was assessed longitudinally using a single question and considered present if endorsed at the last cognitively normal visit. It was treated as a time-varying variable, beginning at the first of consecutive, cognitively normal visits, including the last, at which it was endorsed. Main Outcomes and Measures: Consensus-diagnosed MCI, AD, and all-cause dementia. Results: This study included 3585 participants (mean [SD] baseline age, 68.0 [7.7] years; 1975 female [55.1%]). A total of 1596 participants (44.5%) had SCD, and 770 (21.5%) were carriers of APOE ε4. APOE ε4 and tertiles of AD PRS status did not significantly differ between the SCD and non-SCD groups. MCI, AD, and all-cause dementia were diagnosed in 236 participants (6.6%), 73 participants (2.0%), and 89 participants (2.5%), respectively, during follow-up. On average, SCD preceded MCI by 4.4 years, AD by 6.8 years, and all-cause dementia by 6.9 years. SCD was significantly associated with survival time to MCI (hazard ratio [HR], 1.57; 95% CI, 1.22-2.03; P <.001), AD (HR, 2.98; 95% CI, 1.89-4.70; P <.001), and all-cause dementia (HR, 2.14; 95% CI, 1.44-3.18; P <.001). After adjustment for APOE and AD PRS, the hazards of SCD were largely unchanged. Conclusions and Relevance: Results of this cohort study suggest that in a community setting, SCD reflecting SCD+ features was associated with an increased risk of future MCI, AD, and all-cause dementia with similar hazards estimated in clinic-based settings. SCD may be an independent risk factor for AD and other dementias beyond the risk incurred by APOE ε4 and AD PRS. [ABSTRACT FROM AUTHOR]

ObjectiveTwo main approaches to the interpretation of cognitive test performance have been utilized for the characterization of disease: evaluating shared variance across tests, as with measures of severity, and evaluating the unique variance across tests, as with pattern and error analysis. Both methods provide necessary information, but the unique contributions of each are rarely considered. This study compares the 2 approaches on their ability to differentially diagnose with accuracy, while controlling for the influence of other relevant demographic and risk variables.MethodArchival data requested from the NACC provided clinical diagnostic groups that were paired to 1 another through a genetic matching procedure. For each diagnostic pairing, 2 separate logistic regression models predicting clinical diagnosis were performed and compared on their predictive ability. The shared variance approach was represented through the latent phenotype δ, which served as the lone predictor in 1 set of models. The unique variance approach was represented through raw score values for the 12 neuropsychological test variables comprising δ, which served as the set of predictors in the second group of models.ResultsExamining the unique patterns of neuropsychological test performance across a battery of tests was the superior method of differentiating between competing diagnoses, and it accounted for 16-30% of the variance in diagnostic decision making.ConclusionImplications for clinical practice are discussed, including test selection and interpretation. (PsycINFO Database Record

Two of the most commonly used methods to assess memory functioning in studies of cognitive aging and dementia are story memory and list learning tests. We hypothesized that the most commonly used story memory test, Wechsler's Logical Memory, would generate more pronounced practice effects than a well validated but less common list learning test, the Neuropsychological Assessment Battery (NAB) List Learning test. Two hundred eighty-seven older adults, ages 51 to 100 at baseline, completed both tests as part of a larger neuropsychological test battery on an annual basis. Up to five years of recall scores from participants who were diagnosed as cognitively normal (n = 96) or with mild cognitive impairment (MCI; n = 72) or Alzheimer's disease (AD; n = 121) at their most recent visit were analyzed with linear mixed effects regression to examine the interaction between the type of test and the number of times exposed to the test. Other variables, including age at baseline, sex, education, race, time (years) since baseline, and clinical diagnosis were also entered as fixed effects predictor variables. The results indicated that both tests produced significant practice effects in controls and MCI participants; in contrast, participants with AD declined or remained stable. However, for the delayed-but not the immediate-recall condition, Logical Memory generated more pronounced practice effects than NAB List Learning (b = 0.16, p < .01 for controls). These differential practice effects were moderated by clinical diagnosis, such that controls and MCI participants-but not participants with AD-improved more on Logical Memory delayed recall than on delayed NAB List Learning delayed recall over five annual assessments. Because the Logical Memory test is ubiquitous in cognitive aging and neurodegenerative disease research, its tendency to produce marked practice effects-especially on the delayed recall condition-suggests a threat to its validity as a measure of new learning, an essential construct for dementia diagnosis.

BackgroundDementia severity can be modeled as the construct δ, representing the "cognitive correlates of functional status."ObjectiveWe recently validated a model for estimating δ in the National Alzheimer's Coordinating Center's Uniform Data Set; however, the association of δ with neuropathology remains untested.MethodsWe used data from 727 decedents evaluated at Alzheimer's Disease (AD) Centers nationwide. Participants spoke English, had no genetic abnormalities, and were pathologically diagnosed with AD as a primary or contributing etiology. Clinical data from participants' last visit prior to death were used to estimate dementia severity (δ).ResultsA structural equation model using age, education, race, and apolipoprotein E (APOE) genotype (number of ɛ2 and ɛ4 alleles) as predictors and latent AD pathology and cerebrovascular disease (CVD) pathology as mediators fit the data well (RMSEA = 0.031; CFI = 0.957). AD pathology mediated the effects of age and APOE genotype on dementia severity. An older age at death and more ɛ2 alleles were associated with less AD pathology and, in turn, with less severe dementia. In contrast, more ɛ4 alleles were associated with more pathology and more severe dementia. Although age and race contributed to differences in CVD pathology, CVD pathology was not related to dementia severity in this sample of decedents with pathologically-confirmed AD.ConclusionsUsing δ as an estimate of dementia severity fits well within a structural model in which AD pathology directly affects dementia severity and mediates the relationship between age and APOE genotype on dementia severity.

Longitudinal normative data obtained from a robust elderly sample (i.e., believed to be free from neurodegenerative disease) are sparse. The purpose of the present study was to develop reliable change indices (RCIs) that can assist with interpretation of test score changes relative to a healthy sample of older adults (ages 50+). Participants were 4217 individuals who completed at least three annual evaluations at one of 34 past and present Alzheimer's Disease Centers throughout the United States. All participants were diagnosed as cognitively normal at every study visit, which ranged from three to nine approximately annual evaluations. One-year RCIs were calculated for 11 neuropsychological variables in the Uniform Data Set by regressing follow-up test scores onto baseline test scores, age, education, visit number, post-baseline assessment interval, race, and sex in a linear mixed effects regression framework. In addition, the cumulative frequency distributions of raw score changes were examined to describe the base rates of test score changes. Baseline test score, age, education, and race were robust predictors of follow-up test scores across most tests. The effects of maturation (aging) were more pronounced on tests related to attention and executive functioning, whereas practice effects were more pronounced on tests of episodic and semantic memory. Interpretation of longitudinal changes on 11 cognitive test variables can be facilitated through the use of reliable change intervals and base rates of score changes in this robust sample of older adults. A Web-based calculator is provided to assist neuropsychologists with interpretation of longitudinal change.

ObjectiveRoyall and colleagues identified a latent dementia phenotype, "δ", reflecting the "cognitive correlates of functional status." We sought to cross-validate and extend these findings in a large clinical case series of adults with and without dementia.MethodA confirmatory factor analysis (CFA) model for δ was fit to National Alzheimer's Coordinating Center data (n = 26,068). Factor scores derived from δ were compared with the Clinical Dementia Rating Sum of Boxes (CDR-SB) and to clinically diagnosed dementia. A longitudinal parallel-process growth model compared changes in δ with changes in CDR-SB over 6 annual evaluations.ResultsThe CFA model fit well; CFI = 0.971, RMSEA = 0.070. Factor scores derived from δ discriminated between demented and nondemented participants with an area under the curve of .96. The growth model also fit well, CFI = 0.969, RMSEA = 0.032.ConclusionsThe δ construct represents a novel approach to measuring dementia-related changes and has potential to improve cognitive assessment of neurodegenerative diseases.

Background: There is growing evidence that epigenetic age acceleration may predict late life cognitive decline and dementia, but it is unknown whether this is due to accelerated neurodegeneration or reduction in cognitive resilience. We examined the relationship between epigenetic clocks and domain specific neuropsychological (NP) factor scores, mild cognitive impairment (MCI), Alzheimer's Disease (AD), and all‐cause dementia, before and after accounting for plasma total tau (t‐tau), a marker of neurodegeneration. Method: DNA methylation and plasma t‐tau (Simoa assay; Quanterix) data from 2091 Framingham Heart Study Offspring cohort participants were generated from blood at the same Exam 8 visit (2005‐2008). Three epigenetic clock measures: DunedinPACE, PC PhenoAge, and PC GrimAge were estimated from the DNA methylation data. Longitudinal NP factor scores were previously derived for memory, language, and executive function using confirmatory factor analysis. We tested the association of epigenetic age acceleration with cognitive trajectories using linear mixed effects models and with time to MCI, all‐cause dementia and AD using Cox‐proportional hazard models. Models were run with and without adjustment for plasma t‐tau. All models included APOE ε4‐carrier status, education, smoking, age, and sex as covariates. Epigenetic measures were standardized in all models. Result: At Exam 8, the sample was, on average, 66.3 (SD = 9.0) years of age, 54.8% female, and had 16.4 (SD = 2.7) years of education. DundeinPACE was significantly associated with faster decline in executive function (βtimeXepi_age = ‐0.005, 95% CI:[‐0.009,‐0.002], p = 0.0020), but not with baseline executive function. Older PhenoAge (βepi_age = ‐0.041, 95% CI:[‐0.067,‐0.014], p = 0.0028) and GrimAge (βepi_age = ‐0.042, 95% CI:[‐0.073,‐0.011], p = 0.0084) were significantly associated with worse baseline executive function, but not with rate of decline. Older PhenoAge also was significantly associated with worse baseline memory (βepi_age = ‐0.037, 95% CI:[‐0.061,‐0.012], p = 0.0036). DunedinPACE was significantly associated with time to MCI (HR = 1.20, 95% CI:[1.06,1.35], p = 0.0034), AD (HR = 1.30, 95% CI:[1.07,1.57], p = 0.0068) and all‐cause dementia (HR = 1.30, 95% CI:[1.10,1.53], p = 0.0017). Results remained similar after adjustment for plasma t‐tau. Conclusion: Epigenetic age acceleration may be a marker of cognitive resilience, particularly in executive function. Of the three epigenetic clocks examined, DundedinPACE showed the most robust associations with cognitive resilience, with lower DunedinPACE associated with greater cognitive resilience. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer's disease (AD) cognitive continuum. An international working group known as the SCD‐initiative recently proposed "SCD plus" features, including report of memory problems, recent SCD relative to conversion, SCD over age 60, and consistent SCD over time, that increase the risk for future objective cognitive decline. These have not been fully assessed in a large community‐based setting. Method: Participants from all cohorts of the Framingham Heart Study who were ≥ 60 years with normal cognition at analytic baseline were included. SCD was assessed longitudinally using a single question. We treated SCD as a time‐varying variable and considered SCD to be present if it was endorsed at the last cognitively normal visit. If SCD was endorsed during two or more consecutive visits, including the last valid visit, it was considered to begin at the first of the consecutive visits. Outcomes included consensus‐diagnosed mild cognitive impairment (MCI), AD, and all‐cause dementia. Survival analyses were performed on time‐to‐event data obtained between 2005 and 2019 with up to 12 years of follow‐up. Models were adjusted for baseline age, sex, education, APOE ε4 status, and tertiles of AD polygenic risk score (PRS) excluding the APOE region. Result: 3,735 participants (mean baseline age: 68.0 years, women: 55.1%, non‐Hispanic Whites: 91.6%, SCD: 44.5%, APOEε4 carriers: 21.5%) were included. On average, SCD preceded MCI by 4.4 years, AD by 6.8 years, and all‐cause dementia by 6.9 years. APOEε4 and tertiles of AD PRS status did not significantly differ between SCD and non‐SCD groups. SCD was significantly associated with survival time to MCI (HR = 1.57; 95% CI = 1.22−2.03; P = 4.79×10−4), AD (HR = 2.98; 95% CI = 1.89−4.70; P = 2.80×10−6), and all‐cause dementia (HR = 2.14; 95% CI = 1.44−3.18; P = 1.82×10−4). After adjustment for APOE and AD PRS, the effects of SCD were largely unchanged. Conclusion: In a community setting, SCD reflecting "SCD plus" features increased the risk of future MCI, AD, and all‐cause dementia with about the same HR estimated in clinic‐based settings. SCD may be an independent clinically expressed risk factor for preclinical AD and other dementias beyond the risk incurred by APOEε4 and AD PRS. [ABSTRACT FROM AUTHOR]

Background: The long‐term neurological impact of the SARS‐CoV‐2 virus is unknown and it remains to be seen whether it would create a surge in cases of dementia and cognitive decline years later, which is already a global public health challenge. Our group has previously shown that participants cognitive functioning as measured via mobile‐based assessments using smartphone‐based cognitive tests did not differ based on their COVID status. The goal of the present study was to examine participants longitudinal cognitive performance with the hypothesis that participants with a previous COVID‐19 diagnosis (COVID+) will have worse cognitive performance over time than those without COVID‐19 (COVID‐). Method: Participants (n = 45) with self‐reported positive (n = 25) or negative COVID‐19 (n = 20) statuses based on polymerase chain reaction or antigen testing were recruited from the Boston area. Inclusion criteria included access to a smartphone with an Android or iOS operation system and to internet connectivity, along with proficiency in English. Cognitive performance was measured using Defense Automated Neurobehavioral Assessment (DANA) from AnthroTronix. Participants were asked to complete DANA monthly over six months. Generalized estimating equations (GEE) were used to compare longitudinal cognitive performance among those with and without COVID‐19. Result: The sample was, on average, 53 years of age and comprised primarily of COVID+ (56%), female (78%), and Caucasian (50%) participants that were generally well educated (42% with at least a bachelor's degree), and had ≥1 COVID vaccination (95%). Participants completed an average of 5.5 DANA assessments over the six‐month period. Results indicated that after adjusting for age, sex, and education, COVID+ group had significantly greater decline in performance on the Code Substitution (β = ‐2.14, 95% CI = ‐4.05 – ‐0.24, p = 0.028) and Match to Sample tasks (β = ‐2.01, 95% CI = ‐3.80 – ‐0.25, p = 0.026) in comparison to the COVID‐ group. Conclusion: Results indicate that while cognitive performance at baseline does not differ based on COVID status, having COVID may impact working memory and sensory processing abilities over time. Future directions include examining the impact of COVID disease severity and reinfection on cognition. [ABSTRACT FROM AUTHOR]

Objective The Colorado Cognitive Assessment (CoCA) was designed to improve upon existing screening tests in a number of ways, including enhanced psychometric properties and minimization of bias across diverse groups. This paper describes the initial validation study of the CoCA, which seeks to describe the test; demonstrate its construct validity; measurement invariance to age, education, sex, and mood symptoms; and compare it to the Montreal Cognitive Assessment (MoCA). Method Participants included 151 older adults (M Age = 71.21, SD = 8.05) who were administered the CoCA, MoCA, Judgment test from the Neuropsychological Assessment Battery (NAB), 15-item version of the Geriatric Depression Scale (GDS-15), and 10-item version of the Geriatric Anxiety Scale (GAS-10). Results A single-factor confirmatory factor analysis model of the CoCA fit the data well, CFI = 0.955; RMSEA = 0.033. The CoCA factor score reliability was.84, compared to.74 for the MoCA. The CoCA had stronger disattenuated correlations with the MoCA (r  = .79) and NAB Judgment (r  = .47) and weaker correlations with the GDS-15 (r  = −.36) and GAS-10 (r  = −.15), supporting its construct validity. Finally, when analyzed using multiple-indicators, multiple-causes (MIMIC) modeling, the CoCA showed no evidence of measurement noninvariance, unlike the MoCA. Conclusions These results provide initial evidence to suggest that the CoCA is a valid cognitive screening tool that offers numerous advantages over the MoCA, including superior psychometric properties and measurement noninvariance. Additional validation and normative studies are warranted. [ABSTRACT FROM AUTHOR]