Alzheimer's Disease Research Center Research Articles

Profiling the metabolic landscape of AD

Metabolic dysfunction, including perturbations in lipid, neurotransmitter, and polyamine metabolism, is an early indicator of cognitive impairment and Alzheimer disease (AD) risk. Further investigation is needed to elucidate the role of genetic heterogeneity in these metabolic disturbances. Here, we interrogate metabolomic signatures in the brains of carriers of pathological mutations in APP, PSEN1, and PSEN2 (Autosomal Dominant AD; ADAD), risk variants in TREM2, non-carrier sporadic AD cases (sAD), individuals with neuropathology but without clinical symptoms (Presymptomatic), and neuropathology-free controls (CO). Metabolomic data from parietal brain tissue of donors to the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer Network (ADAD, n=25; TREM2, n=21; sAD, n=305; Presymptomatic, n=15; CO, n=27) were generated using the Metabolon global metabolomics platform. A total of 627 metabolites passed our QC process. Differential abundance between AD strata and controls was tested using linear regression corrected for sex, age, and post-mortem interval. Age was excluded from ADAD models. Benjamini-Hochberg multiple testing correction was applied, and pathway analysis was performed with MetaboAnalyst and IMPaLA. In total, we identified 138 metabolites associated with distinct genetic strata (FDR q-value<0.05). For sAD, these included tryptophan betaine (β=-0.55) and N-acetylputrescine (β=-0.14). Metabolites associated with both sAD and ADAD were ergothioneine (β=-0.22 and -0.26 respectively) and serotonin (β=-0.34 and -0.57). TREM2 and ADAD showed association with α-tocopherol (β=-0.12 and -0.12). β-citrylglutamate abundance decreased in sAD, ADAD, and TREM2 versus controls (β=-0.14; -0.22; and -0.29). Pathways identified included glutamate, vitamin, and antioxidant metabolism. A 16-metabolite subset showed consistent direction of effect among the genetic strata with the magnitude of effect of ADAD greater than that of TREM2, in turn greater than sAD. A representation of these (eigengene) is associated with disease duration in sAD (p=5.65x10-03 ), possibly driven by tau accumulation. Hierarchical clustering identified 41 "early stage" sAD individuals with Braak tau stage similar to Presymptomatic (p=0.35), but lower than other sAD individuals (β=-0.56, p=3.09x10-04 ) (Figure 1). Our findings suggest distinct and characteristic metabolic perturbations in ADAD and TREM2 brains. Investigation of these differentially abundant metabolites may lead to greater insight into the metabolic etiology of AD and its impact on clinical presentation.

APOE-e4 alters the microglial phenotype in the presence of Alzheimer's disease pathology compared to APOE-e3.

APOE is the largest genetic risk factor for late-onset Alzheimer's disease (AD) with the APOE-e4 allele conferring an increased risk for AD compared to the APOE- e3 allele. While APOE in the brain is a lipid transporter produced by astrocytes, research has shown that APOE can impact diverse biochemical pathways. Interestingly, APOE isoforms have also been shown to modulate levels of neuroinflammation in the brain, yet the exact impact on inflammation remains unknown. As microglia are considered to be a primary source of brain inflammation, this study explores how APOE isoforms impact microglial morphology and activation state in human brains. Two methods were used in this study to assess the impact of APOE isoforms on microglia in human brain sections. First, NanoString Digital Spatial Profiling (DSP) was used to investigate protein levels of inflammatory markers specific for microglia on fixed tissue in the hippocampus with AD pathology in both APOE- e3 (n=7) and APOE- e4 (n=8) subjects. Immunohistochemistry (IHC) was then performed using samples from APOE- e3/3 (n=33 control n=23 AD), APOE- e4/4 (n=19 AD), and APOE-e3/4 (n=15 control) subjects from the University of Kentucky AD Research Center. IBA-1 IHC was used to investigate microglial activation and morphology differences between APOE isoforms. Using both DSP and IHC, the results indicate that APOE isoforms play a role in the microglial changes seen in the presence of AD pathology- both in activation state and morphology. The DSP experiments showed significant changes in microglial markers throughout the hippocampal region between APOE- e3 and APOE- e4. Of interest, in APOE-e3 subjects, we show an alteration of the microglial phenotype based on pathology level, however, in APOE-e4 subjects, this change due to pathology is reduced. Additionally, in the IHC experiments we found changes in microglial morphology and activation that parallel those seen in DSP. The findings from this study suggest that with APOE- e3, microglia are able to respond in the presence of AD pathology. By contrast, APOE- e4 microglia cannot produce an appropriate response to AD pathology. Overall, these findings help highlight the role of the APOE isoforms in AD and neuroinflammation.

Is comprehensiveness critical? Comparing short and long format cognitive assessments in preclinical Alzheimer disease

BackgroundComprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a “sampling” of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers.MethodsSurvival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal older adults (n = 6230) from the National Alzheimer’s Coordinating Center (NACC) cohort who had, on average, 2.3 ± 1.2 annual assessments. Multiple regression models in a separate sample (n = 416) from the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) compared the sensitivity of the MoCA and long-form measures to neuroimaging biomarkers including amyloid PET, tau PET, and cortical thickness.ResultsHazard ratios suggested that both the MoCA and the long-form measures are similarly and modestly efficacious in predicting symptomatic conversion, although model comparison analyses indicated that the long-form measures slightly outperformed the MoCA (HRs > 1.57). AUC analyses indicated no difference between the measures in predicting conversion (DeLong’s test, Z = 1.48, p = 0.13). Sensitivity to AD neuroimaging biomarkers was similar for the two measures though there were only modest associations with tau PET (rs = − 0.13, ps < 0.02) and cortical thickness in cognitively normal participants (rs = 0.15–0.16, ps < 0.007).ConclusionsBoth test formats showed weak associations with symptom onset, AUC analyses indicated low diagnostic accuracy, and biomarker correlations were modest in cognitively normal participants. Alternative assessment approaches are needed to improve how clinicians and researchers monitor cognitive changes and disease progression prior to symptom onset.

Cerebral Amyloid Angiopathy Pathology and Its Association With Amyloid-β PET Signal.

To determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)-PET tracer retention. Participants from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center with antemortem PiB-PET imaging for β-amyloid (Aβ) who later underwent autopsy were included in this study. Pathologic regional leptomeningeal, parenchymal, capillary CAA, and Aβ plaque burden were calculated from one hemisphere. Regional lobar amyloid standardized uptake value ratio (SUVR) on PET was calculated from the same hemisphere sampled at autopsy. Single- and multiple-predictor linear regression models were used to evaluate the relative contributions of pathologically determined regional CAA and Aβ plaques to antemortem PiB-PET SUVR. Forty-one participants (30 male, 11 female) with a mean (SD) age at death of 75.7 (10.6) years were included. Twenty-seven (66%) had high PiB signal with a mean (SD) of 2.3 (1.2) years from time of PET scan to death; 24 (59%) had a pathologic diagnosis of Alzheimer disease. On multivariate analysis, CAA was not associated with PiB-PET SUVR, while plaques remained associated with PiB-PET SUVR in all regions (all p < 0.05). In patients without frequent amyloid plaques, CAA was not associated with PiB-PET in any region. We did not find evidence that pathologically confirmed regional CAA burden contributes significantly to proximal antemortem regional PiB-PET signal, suggesting that amyloid PET imaging for measurement of cortical amyloid burden is unconfounded by CAA on a lobar level. Whether CAA burden contributes to PiB-PET signal in patients with severe CAA phenotypes, such as lobar hemorrhage, requires further investigation.

Striatal oxidative damages and neuroinflammation correlate with progression and survival of Lewy body and Alzheimer diseases.

Neurodegenerative diseases are a class of chronic and complex disorders featuring progressive loss of neurons in distinct brain areas. The mechanisms responsible for the disease progression in neurodegeneration are not fully illustrated. In this observational study, we have examined diverse biochemical parameters in the caudate and putamen of patients with Lewy body diseases (LBDs) and Alzheimer disease (AD), shedding some light on the involvement of oxidative damage and neuroinflammation in advanced neurodegeneration. We performed Spearman and Mantel-Cox analyses to investigate how oxidative stress and neuroinflammation exert comprehensive effects on disease progression and survival. Disease progression in LBDs correlated positively with poly (ADP-Ribose) and triggering receptors expressed on myeloid cell 2 levels in the striatum of LBD cohorts, indicating that potential parthanatos was a dominant feature of worsening disease progression and might contribute to switching microglial inflammatory phenotypes. Disease progression in AD corresponds negatively with 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and myeloperoxidase concentrations in the striatum, suggesting that possible mitochondria dysfunction may be involved in the progression of AD via a mechanism of β-amyloid entering the mitochondria and subsequent free radicals generation. Patients with lower striatal 8-oxo-dG and myeloperoxidase levels had a survival advantage in AD. The age of onset also affected disease progression. Tissue requests for the postmortem biochemistry, genetics, and autoradiography studies were approved by the Washington University Alzheimer's Disease Research Center (ADRC) Biospecimens Committee (ethics approval reference number: T1705, approval date: August 6, 2019). Recombinant DNA and Hazardous Research Materials were approved by the Washington University Environmental Health & Safety Biological Safety Committee (approval code: 3739, approval date: February 25, 2020). Radioactive Material Authorization was approved by the Washington University Environmental Health & Safety Radiation Safety Committee (approval code: 1056, approval date: September 18, 2019).

Data-Driven vs Consensus Diagnosis of MCI: Enhanced Sensitivity for Detection of Clinical, Biomarker, and Neuropathologic Outcomes.

Given prior work demonstrating that mild cognitive impairment (MCI) can be empirically differentiated into meaningful cognitive subtypes, we applied actuarial methods to comprehensive neuropsychological data from the University of California San Diego Alzheimer's Disease Research Center (ADRC) in order to identify cognitive subgroups within ADRC participants without dementia and to examine cognitive, biomarker, and neuropathologic trajectories. Cluster analysis was performed on baseline neuropsychological data (n = 738; mean age 71.8). Survival analysis examined progression to dementia (mean follow-up 5.9 years). CSF Alzheimer disease (AD) biomarker status and neuropathologic findings at follow-up were examined in a subset with available data. Five clusters were identified: optimal cognitively normal (CN; n = 130) with above-average cognition, typical CN (n = 204) with average cognition, nonamnestic MCI (naMCI; n = 104), amnestic MCI (aMCI; n = 216), and mixed MCI (mMCI; n = 84). Progression to dementia differed across MCI subtypes (mMCI > aMCI > naMCI), with the mMCI group demonstrating the highest rate of CSF biomarker positivity and AD pathology at autopsy. Actuarial methods classified 29.5% more of the sample with MCI and outperformed consensus diagnoses in capturing those who had abnormal biomarkers, progressed to dementia, or had AD pathology at autopsy. We identified subtypes of MCI and CN with differing cognitive profiles, clinical outcomes, CSF AD biomarkers, and neuropathologic findings over more than 10 years of follow-up. Results demonstrate that actuarial methods produce reliable cognitive phenotypes, with data from a subset suggesting unique biological and neuropathologic signatures. Findings indicate that data-driven algorithms enhance diagnostic sensitivity relative to consensus diagnosis for identifying older adults at risk for cognitive decline.

Functional Disabilities and Psychiatric Symptoms in Primary Progressive Aphasia

ObjectiveThe aims of this study are to describe the chronology of functional disabilities in primary progressive aphasia (PPA), and to examine associations between psychiatric comorbidities and functional disabilities. MethodsWe conducted a retrospective data analysis using subjects enrolled at Alzheimer's Disease Research Centers between 2005 and 2019. Data were obtained from the National Alzheimer's Coordinating Center database. We included subjects whose primary diagnosis was PPA. Functional status was coded as a binary variable for the following functions: ambulation, transaction skills, verbal communication, meal preparation, and self-care. Behavioral data derived from the Neuropsychiatric Inventory Questionnaire. Descriptive statistics and cox proportional hazard analyses were used to characterize the emergence of disabilities and their association with psychiatric comorbidities. ResultsData included 91 subjects with a clinical dementia rating scale of zero at baseline. At the initial visit, no individuals had impairments in self-care, while 7% had impairments in transactions, 3% in ambulation, and 2% in meal preparation. Ninety-three percent had language impairments at the onset of the study, and all by visit 4. By visit 5, 41% of patients had impairments in ambulation and in self-care, 49% were impaired in meal preparation and 70% had impairment in transactions. The presence of anxiety, depression, sleep disturbance and psychosis were all significantly associated with an increased risk for multiple functional disabilities. ConclusionThese findings provide clinicians with guidance for forecasting disabilities and targeting interventions in PPA.

Detection of Alzheimer's disease amyloid beta 1-42, p-tau, and t-tau assays.

IntroductionWe aimed to provide cut points for the automated Elecsys Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers.MethodsCut points for Elecsys amyloid beta 42 (Aβ42), total tau (t‐tau), hyperphosphorylated tau (p‐tau), and t‐tau/Aβ42 and p‐tau/Aβ42 ratios were evaluated in Mayo Clinic Study of Aging (n = 804) and Mayo Clinic Alzheimer's Disease Research Center (n = 70) participants.ResultsThe t‐tau/Aβ42 and p‐tau/Aβ42 ratios had a higher percent agreement with normal/abnormal amyloid positron emission tomography (PET) than the individual CSF markers. Reciever Operating Characteristic (ROC)‐based cut points were 0.26 (0.24–0.27) for t‐tau/Aβ42 and 0.023 (0.020–0.025) for p‐tau/Aβ42. Ratio cut points derived from other cohorts performed as well in our cohort as our own did. Individual biomarkers had worse diagnostic properties and more variable results in terms of positive and negative percent agreement (PPA and NPA).ConclusionCSF t‐tau/Aβ42 and p‐tau/Aβ42 ratios are very robust indicators of AD. For individual biomarkers, the intended use should determine which cut point is chosen.

Neighborhood racial/ethnic segregation and cognitive decline in older adults

Social determinants of health, including neighborhood factors, play a key role in the health of diverse older adults. However, few longitudinal studies have examined the role of neighborhood racial/ethnic segregation on cognitive decline in diverse samples. We examined older non-Hispanic White (NHW), Black, and Latino participants evaluated at an Alzheimer's Disease Research Center. Neighborhood racial/ethnic segregation was measured using the Getis-Ord Gi* statistic, a spatial measure of clustering that was created for Latino and Black clustering separately. Cognitive outcomes included episodic memory, semantic memory, and executive function. We used mixed effects multivariable regression models to evaluate associations between segregation and cognitive function and decline. We had 452 individuals: 46% NHW, 26% Black, and 21% Latino in 309 census tracts with an average of 5.2 years of follow-up data (range 0.6–15.0). In analyses that adjusted for a variety of covariates (including neighborhood SES), individuals in neighborhoods with a higher clustering of Latino residents (higher Gi* statistic) had slower declines over time on semantic memory and those in neighborhoods with a higher clustering of Black residents had slower declines over time on episodic memory. In race/ethnicity-stratified adjusted analyses: for Black participants, the association between clustering and cognition was present for episodic memory and executive function, showing lower baseline scores in highly clustered Black and Latino neighborhoods, respectively. There was no association with cognitive change. Among Latino participants, highly clustered Latino neighborhoods were associated with lower baseline scores in semantic memory, but slower declines in episodic memory; Latinos living in neighborhoods with a greater clustering of Black residents also had slower declines in episodic memory. Among NHWs, residing in neighborhoods with a higher clustering of Latino residents was associated with slower declines over time on semantic memory. Segregated neighborhoods may be differentially associated with cognitive outcomes depending on individual race/ethnicity.

Exploration of Rapid Automatized Naming and Standard Visual Tests in Prodromal Alzheimer Disease Detection.

Visual tests in Alzheimer disease (AD) have been examined over the last several decades to identify a sensitive and noninvasive marker of the disease. Rapid automatized naming (RAN) tasks have shown promise for detecting prodromal AD or mild cognitive impairment (MCI). The purpose of this investigation was to determine the capacity for new rapid image and number naming tests and other measures of visual pathway structure and function to distinguish individuals with MCI due to AD from those with normal aging and cognition. The relation of these tests to vision-specific quality of life scores was also examined in this pilot study. Participants with MCI due to AD and controls from well-characterized NYU research and clinical cohorts performed high and low-contrast letter acuity (LCLA) testing, as well as RAN using the Mobile Universal Lexicon Evaluation System (MULES) and Staggered Uneven Number test, and vision-specific quality of life scales, including the 25-Item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and 10-Item Neuro-Ophthalmic Supplement. Individuals also underwent optical coherence tomography scans to assess peripapillary retinal nerve fiber layer and ganglion cell/inner plexiform layer thicknesses. Hippocampal atrophy on brain MRI was also determined from the participants' Alzheimer disease research center or clinical data. Participants with MCI (n = 14) had worse binocular LCLA at 1.25% contrast compared with controls (P = 0.009) and longer (worse) MULES test times (P = 0.006) with more errors in naming images (P = 0.009) compared with controls (n = 16). These were the only significantly different visual tests between groups. MULES test times (area under the receiver operating characteristic curve [AUC] = 0.79), MULES errors (AUC = 0.78), and binocular 1.25% LCLA (AUC = 0.78) showed good diagnostic accuracy for distinguishing MCI from controls. A combination of the MULES score and 1.25% LCLA demonstrated the greatest capacity to distinguish (AUC = 0.87). These visual measures were better predictors of MCI vs control status than the presence of hippocampal atrophy on brain MRI in this cohort. A greater number of MULES test errors (rs = -0.50, P = 0.005) and worse 1.25% LCLA scores (rs = 0.39, P = 0.03) were associated with lower (worse) NEI-VFQ-25 scores. Rapid image naming (MULES) and LCLA are able to distinguish MCI due to AD from normal aging and reflect vision-specific quality of life. Larger studies will determine how these easily administered tests may identify patients at risk for AD and serve as measures in disease-modifying therapy clinical trials.

The relationship of glucose-stimulated insulin secretion to cerebral glucose metabolism and cognition in healthy middle-aged and older adults

Insulin resistance (IR) has been related to reduced cerebral glucose metabolism in regions identified as hypometabolic in Alzheimer's clinical syndrome. Insulin secretion (IS) has been less studied than IR despite findings that decreased IS is an early indicator of future type 2 diabetes and a potential predictor of Alzheimer's clinical syndrome. We investigated whether higher IR and lower IS would be associated with greater age-related reductions in regional cerebral glucose metabolism and worse cognitive performance. Two-hour oral glucose tolerance testing and 18F-fluorodeoxyglucose positron emission tomography were performed on 1–2 occasions on a sample of healthy middle-aged and older adults from the Wisconsin Alzheimer's Disease Research Center. Neuropsychological tests were completed during Alzheimer's Disease Research Center Clinical Core visits. Pattern of findings suggested that lower (not higher) IS was related to higher regional cerebral glucose metabolism in middle aged but not older adults, and lower (not higher) IS was also related to better immediate recall. In the context of healthy insulin sensitivity, lower IS may be beneficial to brain health.

Alzheimer's Disease Alters Oligodendrocytic Glycolytic and Ketolytic Gene Expression

Sporadic Alzheimer's disease (AD) is the most common form of senescence-related dementia, and is clinically characterized by neurodegeneration that progressively impairs memory and behavior. It is widely accepted that AD is strongly correlated with impaired brain glucose metabolism, which may contribute to disease onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain. In the present study, RNA-seq profiles of postmortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes. In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in regions of the brain relevant to AD. However, ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia. These results indicate that oligodendrocytes may contribute to brain hypometabolism and AD pathology more than previously thought. These findings are also suggestive of a potential link between AD hypometabolism and dysmyelination, and suggest that ketones may be therapeutic in AD due to their ability to fuel neurons despite impairments in glycolytic metabolism.

Association of Neighborhood Context, Cognitive Decline, and Cortical Change in an Unimpaired Cohort.

To test the hypothesis that neighborhood-level disadvantage is associated with longitudinal measures of neurodegeneration and cognitive decline in an unimpaired cohort. Longitudinal MRI and cognitive testing data were collected from 601 cognitively unimpaired participants in the Wisconsin Registry for Alzheimer's Prevention Study and the Wisconsin Alzheimer's Disease Research Center clinical cohort. Area Deprivation Index was geospatially determined based on participant residence geocode and ranked relative to state of residence. Linear regression models were fitted to test associations between neighborhood-level disadvantage and longitudinal change in cortical thickness and cognitive test performance. Mediation tests were used to assess whether neurodegeneration and cognitive decline were associated with neighborhood-level disadvantage along the same theoretical causal path. In our middle- to older-aged study population (mean baseline age 59 years), living in the 20% most disadvantaged neighborhoods (n = 19) relative to state of residence was associated with cortical thinning in Alzheimer signature regions (p = 0.002) and decline in the Preclinical Alzheimer's Disease Cognitive Composite (p = 0.04), particularly the Trail-Making Test, part B (p < 0.001), but not Rey Auditory Verbal Learning Test (p = 0.77) or Story Memory Delayed Recall (p = 0.49) subtests. Associations were attenuated but remained significant after controlling for racial and demographic differences between neighborhood-level disadvantage groups. Cortical thinning partially mediated the association between neighborhood-level disadvantage and cognitive decline. In this longitudinal study of cognitively unimpaired adults, living in the most highly disadvantaged neighborhoods was associated with accelerated degeneration in Alzheimer signature regions and cognitive decline. This study provides further evidence for neighborhood-level disadvantage as a risk factor for preclinical neurodegeneration and cognitive decline in certain populations. Limitations of the present study, including a small number of participants from highly disadvantaged neighborhoods and a circumscribed geographic setting, should be explored in larger and more diverse study cohorts.

Characterization of dementia with Lewy bodies (DLB) and mild cognitive impairment using the Lewy body dementia module (LBD-MOD).

The National Institute on Aging Alzheimer's Disease Research Center program added the Lewy body dementia module (LBD-MOD) to the Uniform Data Set to facilitate LBD characterization and distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). We tested the performance of the LBD-MOD. The LBD-MOD was completed in a single-site study in 342 participants: 53 controls, 78 AD, and 110 DLB; 79 mild cognitive impairment due to AD (MCI-AD); and 22 MCI-DLB. DLB differed from AD in extrapyramidal symptoms, hallucinations, apathy, autonomic features, REM sleep behaviors, daytime sleepiness, cognitive fluctuations, timed attention tasks, and visual perception. MCI-DLB differed from MCI-AD in extrapyramidal features, mood, autonomic features, fluctuations, timed attention tasks, and visual perception. Descriptive data on LBD-MOD measures are provided for reference. The LBD-MOD provided excellent characterization of core and supportive features to differentiate DLB from AD and healthy controls while also characterizing features of MCI-DLB.

Adapting Alzheimer Disease and Related Dementias Clinical Research Evaluations in the Age of COVID-19.

In March 2020, the novel coronavirus (COVID-19) became a global pandemic that would cause most in-person visits for clinical studies to be put on pause. Coupled with protective stay at home guidelines, clinical research at the Icahn School of Medicine at Mount Sinai Alzheimer's Disease Research Center (ISMMS ADRC) needed to quickly adapt to remain operational and maintain our cohort of research participants. Data collected by the ISMMS ADRC as well as from other National Institute on Aging (NIA) Alzheimer Disease centers, follows the guidance of the National Alzheimer Coordinating Center (NACC). However, at the start of this pandemic, NACC had no alternative data collection mechanisms that could accommodate these safety guidelines. To stay in touch with our cohort and to ensure continued data collection under different stages of quarantine, the ISMMS ADRC redeployed their work force to continue their observational study via telehealth assessment. On the basis of this experience and that of other centers, NACC was able to create a data collection process to accommodate remote assessment in mid-August. Here we review our experience in filling the gap during this period of isolation and describe the adaptations for clinical research, which informed the national dialog for conducting dementia research in the age of COVID-19 and beyond.

Reduced rank multinomial logistic regression in Markov chains with application to cognitive data.

Finite Markov chains are useful tools for studying transitions among health states; these chains can be complex consisting of a mix of transient and absorbing states. The transition probabilities, which are often affected by covariates, can be difficult to estimate due to the presence of many covariates and/or a subset of transitions that are rarely observed. The purpose of this article is to show how to estimate the effect of a subset of covariates of interest after adjusting for the presence of multiple other covariates by applying multidimensional dimension reduction to the latter. The case in which transitions within each row of the one-step transition probability matrix are estimated by multinomial logistic regression is discussed in detail. Dimension reduction for the adjustment covariates involves estimating the effect of the covariates by a product of matrices iteratively; at each iteration one matrix in the product is fixed while the second is estimated using either standard software or nonlinear estimation, depending on which of the matrices in the product is fixed. The algorithm is illustrated by an application where the effect of at least one Apolipoprotein-E (APOE) gene allele on transition probability is estimated in a Markov Chain that includes adjustment for eight covariates and focuses on transitions from normal cognition to several forms of mild cognitive impairment, with possible absorption into dementia. Data were drawn from annual cognitive assessments of 649 participants enrolled in the BRAiNS cohort at the University of Kentucky's Alzheimer's Disease Research Center.

Test-Retest Reliability of Audiometric Assessment in Individuals With Mild Dementia

Accurate assessment of hearing is critically important regardless of a person's cognitive ability. The degree to which hearing can be reliably measured in adults with mild dementia has not been determined. To obtain quantitative measures of reliability to evaluate the degree to which audiologic testing can be accurately conducted in older adults with mild dementia. This repeated-measures cross-sectional study consisted of a comprehensive audiologic assessment on 2 occasions separated by 1 to 2 weeks performed in the department of otolaryngology at the Washington University School of Medicine from December 3, 2018, to March 4, 2020. Participants were 15 older adults with a verified diagnosis of mild dementia and 32 older adults without a verified diagnosis of mild dementia who were recruited from the Knight Alzheimer Disease Research Center at Washington University in St Louis. Test-retest reliability was assessed for tympanometry, acoustic reflex thresholds, otoacoustic emissions, hearing sensitivity, speech reception threshold, speech perception in noise, and hearing handicap, using standard clinical audiology measures. A total of 47 older adults (26 women; mean [SD] age, 74.8 [6.0] years [range, 53-87 years]), including 32 with normal cognitive function and 15 with very mild or mild dementia, completed the study protocol. For participants with mild dementia, high test-retest reliability (Spearman ρ > 0.80) was found for most measures typically included in a comprehensive audiometric evaluation. For acoustic reflex thresholds, agreement was moderate to high, averaging approximately 83% across frequencies for both groups. Scores for the screening Hearing Handicap Inventory for the Elderly at time 1 and time 2 were highly correlated for the group with normal cognitive function (r = 0.84 [95% CI, 0.70-0.93]) and for the group with mild dementia (r = 0.96 [95% CI, 0.88-0.99]). For hearing thresholds, all rank-order correlations were above 0.80 with 95% CIs at or below 15% in width, with the exception of a moderate correlation of bone conduction thresholds at 500 Hz for the group with normal cognitive function (r = 0.69 [95% CI, 0.50-0.84]) and slightly wider 95% CIs for low-frequency bone conduction thresholds for both groups. For speech reception thresholds, correlations were high for groups with normal cognitive function (r = 0.91 [95% CI, 0.84-0.95]) and mild dementia (r = 0.83 [95% CI, 0.63-0.94]). Test-retest reliability for hearing measures obtained from participants with mild dementia was comparable to that obtained from cognitively normal participants. These findings suggest that mild cognitive impairment does not preclude accurate audiologic assessment.

Alzheimer's disease alters oligodendrocytic glycolytic and ketolytic gene expression.

IntroductionSporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain.MethodsRNA‐seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes.ResultsIn oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia.DiscussionOligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism.

Predictors of the importance of everyday preferences for older adults with cognitive impairment.

Among older people with cognitive impairment and mild dementia, relatively little is known about the factors that predict preferences for everyday living activities and experiences and that influence the relative importance of those activities and experiences. Cross-sectional study. Participants were recruited from the Massachusetts Alzheimer's Disease Research Center (MADRC) Clinical Core longitudinal cohort. The sample included 62 community-dwelling older adults with cognitive impairment (Clinical Dementia Rating global score ≥ 0.5). We used the Preferences for Everyday Living Inventory (PELI) to assess preferences for activities and lifestyle experiences among persons with cognitive impairment. Within-subjects analysis of variance was used to test for significant differences in the mean ratings of importance for four domains of the PELI ("autonomous choice," "social engagement," "personal growth," and "keeping a routine"). Multiple regression models were used to relate predictors, including neuropsychiatric symptoms, to importance ratings for each domain. Significant differences were noted in the mean importance ratings of the preferences domains: "social engagement" preferences were rated as most important, followed by "autonomous choice," "personal growth," and "keeping a routine." For the "social engagement" preferences domain, female sex was significantly associated with higher importance of "social engagement," while depressive symptoms (Geriatric Depression Scale-15 scores) were significantly associated with lower importance. This study adds novel insight into the everyday preferences of community-dwelling older adults with cognitive impairment and highlights the impact of a number of factors, particularly level of depression, on how important various everyday experiences are perceived.

Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes.

Identification of new genetic variants that modify Alzheimer's disease (AD) risk will elucidate novel targets for curbing the disease progression or delaying symptom onset. To examine whether the functionally advantageous KLOTHO gene KL-VS variant attenuates age-related alteration in cerebrospinal fluid (CSF) biomarkers or cognitive function in middle-aged and older adults enriched for AD risk. Sample included non-demented adults (N = 225, mean age = 63±8, 68% women) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center who were genotyped for KL-VS, underwent CSF sampling and had neuropsychological testing data available proximal to CSF draw. Covariate-adjusted multivariate regression examined relationships between age group (Younger versus Older; mean split at 63 years), AD biomarkers, and neuropsychological performance tapping memory and executive function, and whether these relationships differed between KL-VS non-carriers (KL-VSNC) and heterozygote (KL-VSHET). In the pooled analyses, older age was associated with higher levels of total tau (tTau), phosphorylated tau (pTau), and their respective ratios to amyloid-β (Aβ)42 (ps ≤ 0.002), and with poorer performance on neuropsychological tests (ps ≤ 0.001). In the stratified analyses, KL-VSNC exhibited this age-related pattern of associations with CSF biomarkers (all ps ≤ 0.001), and memory and executive function (ps ≤ 0.003), which were attenuated in KL-VSHET (ps ≥ 0.14). Worse memory and executive function, and higher tau burden with age were attenuated in carriers of a functionally advantageous KLOTHO variant. KL-VS heterozygosity seems to be protective against age-related cognitive and biomolecular alterations that confer risk for AD.