The Role of Alzheimer's and Cerebrovascular Pathology in Mediating the Effects of Age, Race, and Apolipoprotein E Genotype on Dementia Severity in Pathologically-Confirmed Alzheimer's Disease.

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

The effectiveness and unique contribution of neuropsychological tests and the δ latent phenotype in the differential diagnosis of dementia in the uniform data set.

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 Recor

The effectiveness and unique contribution of neuropsychological tests and the δ latent phenotype in the differential diagnosis of dementia in the uniform data set.

OBJECTIVE: Two 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 two approaches on their ability to differentially diagnose with accuracy, while controlling for the influence of other relevant demographic and risk variables. METHOD: Archival data requested from the NACC provided clinical diagnostic groups that were paired to one another through a genetic matching procedure. For each diagnostic pairing, two 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 one 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. RESULTS: Examining 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. CONCLUSION: Implications for clinical practice are discussed, including test selection and interpretation

Practice Effects on Story Memory and List Learning Tests in the Neuropsychological Assessment of Older Adults.

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

Practice Effects on Story Memory and List Learning Tests in the Neuropsychological Assessment of Older Adults.

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 &lt; .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

Baseline Demographic Characteristics of the Current Sample.

<p>Baseline Demographic Characteristics of the Current Sample.</p

Results of the Linear Mixed Effects Model for Delayed Recall.

<p>Results of the Linear Mixed Effects Model for Delayed Recall.</p

Clinical Diagnosis by Visit.

<p>Heatmap depicting the clinical diagnosis assigned to each participant at each study visit. The left panel represents participants whose most recent diagnosis was Control. The middle panel represents participants whose most recent diagnosis was MCI. The right panel represents participants whose most recent diagnosis was AD. Colors reflect the diagnosis made at a given visit, which does not always correspond to the most recent diagnosis. Participants' most recent visit may have occurred beyond the 5 visits used in the current study.</p

Immediate Recall Practice Effects.

<p>Standardized test scores on the immediate recall condition as a function of visit number, test, and clinical diagnosis. Error bars represent 95% confidence intervals and account for within-subjects variability.</p

Participant Flow.

<p>Flowchart illustrating application of inclusion and exclusion criteria for the current study.</p