Browsing by Author "Gross, Alden L."

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    A harmonized memory composite score for cross‐cohort Alzheimer’s disease and related dementia research: development and validation
    (Wiley, 2025-01-03) Sanderson-Cimino, Mark E.; Gross, Alden L.; Gaynor, Leslie S.; Paolillo, Emily W.; Casaletto, Kaitlin B.; Chatterjee, Ankita; Albert, Marilyn S.; Apostolova, Liana G.; Boersema, Brooke; Boxer, Adam L.; Boeve, Brad F.; Clark, Lindsay R.; La Joie, Renaud; Eloyan, Ani; Tomaszewski Farias, Sarah; Gonzales, Mitzi M.; Hammers, Dustin B.; Wise, Amy B.; Cobigo, Yann; Yballa, Claire; Schonhaut, Daniel R.; Hampstead, Benjamin M.; Mechanic-Hamilton, Dawn; Miller, Bruce L.; Rabinovici, Gil D.; Rascovsky, Katya; Ringman, John M.; Rosen, Howard J.; Ryman, Sephira; Salmon, David P.; Smith, Glenn E.; Decarli, Charles; Kramer, Joel H.; Staffaroni, Adam M.; Neurology, School of Medicine
    Background: The Uniform Data Set (UDS) neuropsychological battery, administered across Alzheimer’s Disease Centers (ADC), includes memory tests but lacks a list‐learning paradigm. ADCs often supplement the UDS with their own preferred list‐learning task. Given the importance of list‐learning for characterizing memory, we aimed to develop a harmonized memory score that incorporates UDS memory tests while allowing centers to contribute differing list‐learning tasks. Method: We applied item‐banking confirmatory factor analysis to develop a composite memory score in 5,287 participants (mean age 67.1; SD = 12.2) recruited through 18 ADCs and four consortia (DiverseVCID, MarkVCID, ALLFTD, LEADS) who completed UDS memory tasks (used as linking‐items) and one of five list‐learning tasks. All analyses used linear regression. We tested whether memory scores were affected by which list‐learning task was administered. To assess construct validity, we tested associations of memory scores with demographics, disease severity (CDR Box Score), an independent memory task (TabCAT Favorites, n = 675), and hippocampal volume (n = 811). We compared performances between cognitively unimpaired (n = 279), AD‐biomarker+ MCI (n = 26), and AD‐biomarker+ dementia (n = 98). In a subsample with amyloid‐ and tau‐PET (n = 49), we compared memory scores from participants with positive vs negative scans determined using established quantitative cutoffs. Result: Model fit indices were excellent (e.g., CFI = 0.998) and factor loadings were strong (0.43‐0.93). Differences in list‐learning task had a negligible effect on scores (average Cohen’s d = 0.11). Higher memory scores were significantly (p’s<.001) correlated with younger age (β = ‐0.18), lower CDR Box Scores (β = ‐0.63), female sex (β = 0.12), higher education (β = 0.19), larger hippocampal volume (β = 0.42), and an independent memory task (β = 0.71, p<0.001). The memory composite declined in a stepwise fashion by diagnosis (cognitively unimpaired>MCI>AD dementia, p<0.001). On average, amyloid‐PET positivity was associated with lower composite scores, but was not statistically significant (β = ‐0.34; p = 0.25; d = 0.40). Tau‐PET positivity was associated with worse performance, demonstrating a large effect size (β = ‐0.75; p<0.002; d = 0.91). Conclusion: The harmonized memory score developed in a large national sample was stable regardless of contributing list‐learning task and its validity for cross‐cohort ADRD research is supported by expected associations with demographics, clinical measures, and Alzheimer’s biomarkers. A processing script will be made available to enhance cross‐cohort ADRD research.
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    Alzheimer's disease genetic risk variants beyond APOE ε4 predict mortality
    (Elsevier, 2017-08-24) Mez, Jesse; Marden, Jessica R.; Mukherjee, Shubhabrata; Walter, Stefan; Gibbons, Laura E.; Gross, Alden L.; Zahodne, Laura B.; Gilsanz, Paola; Brewster, Paul; Nho, Kwangsik; Crane, Paul K.; Larson, Eric B.; Glymour, M. Maria; Radiology and Imaging Sciences, School of Medicine
    • A genetic risk score from 21 non-APOE late-onset Alzheimer's disease risk variants predicts mortality. • The genetic risk score likely confers risk for mortality through its effect on dementia incidence. • Late-onset Alzheimer's disease risk loci effect estimates from genome-wide association unlikely suffer from selection bias.
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    Application of Neuropsychological Criteria to Classify Mild Cognitive Impairment in the ACTIVE Study
    (American Psychological Association, 2020-11) Thomas, Kelsey R.; Cook, Sarah E.; Bondi, Mark W.; Unverzagt, Frederick W.; Gross, Alden L.; Willis, Sherry L.; Marsiske, Michael; Psychiatry, School of Medicine
    Objective: Comprehensive neuropsychological criteria (NP criteria) for mild cognitive impairment (MCI) has reduced diagnostic errors and better predicted progression to dementia than conventional MCI criteria that rely on a single impaired score and/or subjective report. This study aimed to implement an actuarial approach to classifying MCI in the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study. Method: ACTIVE study participants (N = 2,755) were classified as cognitively normal (CN) or as having MCI using NP criteria. Estimated proportion of MCI participants and reversion rates were examined as well as baseline characteristics by MCI subtype. Mixed effect models examined associations of MCI subtype with 10-year trajectories of self-reported independence and difficulty performing instrumental activities of daily living (IADLs). Results: The proportion of MCI participants was estimated to be 18.8%. Of those with MCI at baseline, 19.2% reverted to CN status for all subsequent visits. At baseline, the multidomain-amnestic MCI group generally had the greatest breadth and depth of cognitive impairment and reported the most IADL difficulty. Longitudinally, MCI participants showed faster IADL decline than CN participants (multidomain-amnestic MCI > single domain-amnestic MCI > nonamnestic MCI). Conclusion: NP criteria identified a proportion of MCI and reversion rate within ACTIVE that is consistent with prior studies involving community-dwelling samples. The pattern of everyday functioning change suggests that being classified as MCI, particularly amnestic MCI, is predictive of future loss of independence. Future work will apply these classifications in ACTIVE to better understand the relationships between MCI and health, social, and cognitive intervention-related factors.
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    Combined neuropathological pathways account for age-related risk of dementia
    (Wiley, 2018-07) Power, Melinda C.; Mormino, Elizabeth; Soldan, Anja; James, Bryan D.; Yu, Lei; Armstrong, Nicole M.; Bangen, Katherine J.; Delano-Wood, Lisa; Lamar, Melissa; Lim, Yen Ying; Nudelman, Kelly; Zahodne, Laura; Gross, Alden L.; Mungas, Dan; Widaman, Keith F.; Schneider, Julie; Radiology and Imaging Sciences, School of Medicine
    OBJECTIVE: Our objectives were to characterize the inter-relation of known dementia-related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia. METHODS: We used data from 1,362 autopsied participants of three community-based clinicopathological cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively. RESULTS: At time of death (mean age, 89 years), 44% of our sample had a clinical dementia diagnosis. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathology pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of amyloid beta plaques in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, wheraes the remaining three inter-related degenerative pathways together accounted for 68% (amyloid/tau, 24%; the Lewy body, 1%; and TDP-43/hippocampal sclerosis, 43%). INTERPRETATION: Age-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies.
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    Development and validation of a harmonized memory score for multicenter Alzheimer's disease and related dementia research
    (medRxiv, 2025-04-03) Sanderson-Cimino, Mark; Gross, Alden L.; Gaynor, Leslie S.; Paolillo, Emily W.; Saloner, Rowan; Albert, Marilyn S.; Apostolova, Liana G.; Boersema, Brooke; Boxer, Adam L.; Boeve, Bradley F.; Casaletto, Kaitlin B.; Hallgarth, Savannah R.; Diaz, Valentina E.; Clark, Lindsay R.; Maillard, Pauline; Eloyan, Ani; Tomaszewski Farias, Sarah; Gonzales, Mitzi M.; Hammers, Dustin B.; La Joie, Renaud; Cobigo, Yann; Wolf, Amy; Hampstead, Benjamin M.; Mechanic-Hamilton, Dawn; Miller, Bruce L.; Rabinovici, Gil D.; Ringman, John M.; Rosen, Howie J.; Ryman, Sephira G.; Prestopnik, Jillian L.; Salmon, David P.; Smith, Glenn E.; DeCarli, Charles; Rajan, Kumar B.; Jin, Lee-Way; Hinman, Jason; Johnson, David K.; Harvey, Danielle; Fornage, Myriam; Kramer, Joel H.; Staffaroni, Adam M.; Neurology, School of Medicine
    Introduction: List-learning tasks are important for characterizing memory in ADRD research, but the Uniform Data Set neuropsychological battery (UDS-NB) lacks a list-learning paradigm; thus, sites administer a range of tests. We developed a harmonized memory composite that incorporates UDS memory tests and multiple list-learning tasks. Methods: Item-banking confirmatory factor analysis was applied to develop a memory composite in a diagnostically heterogenous sample (n=5943) who completed the UDS-NB and one of five list-learning tasks. Construct validity was evaluated through associations with demographics, disease severity, cognitive tasks, brain volume, and plasma phosphorylated tau (p-tau181 and p-tau217). Test-retest reliability was assessed. Analyses were replicated in a racially/ethnically diverse cohort (n=1058). Results: Fit indices, loadings, distributions, and test-retest reliability were adequate. Expected associations with demographics and clinical measures within development and validation cohorts supported validity. Discussion: This composite enables researchers to incorporate multiple list-learning tasks with other UDS measures to create a single metric.
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    Incidence of cognitively defined late-onset Alzheimer's dementia subgroups from a prospective cohort study
    (Elsevier, 2017-12) Crane, Paul K.; Trittschuh, Emily; Mukherjee, Shubhabrata; Saykin, Andrew J.; Sanders, Elizabeth; Larson, Eric B.; McCurry, Susan M.; McCormick, Wayne; Bowen, James D.; Grabowski, Thomas; Moore, Mackenzie; Gross, Alden L.; Keene, Dirk; Bird, Thomas E.; Gibbons, Laura E.; Mez, Jesse; Radiology and Imaging Sciences, School of Medicine
    INTRODUCTION: There may be biologically relevant heterogeneity within typical late-onset Alzheimer's dementia. METHODS: We analyzed cognitive data from people with incident late-onset Alzheimer's dementia from a prospective cohort study. We determined individual averages across memory, visuospatial functioning, language, and executive functioning. We identified domains with substantial impairments relative to that average. We compared demographic, neuropathology, and genetic findings across groups defined by relative impairments. RESULTS: During 32,286 person-years of follow-up, 869 people developed Alzheimer's dementia. There were 393 (48%) with no domain with substantial relative impairments. Some participants had isolated relative impairments in memory (148, 18%), visuospatial functioning (117, 14%), language (71, 9%), and executive functioning (66, 8%). The group with isolated relative memory impairments had higher proportions with ≥ APOE ε4 allele, more extensive Alzheimer's-related neuropathology, and higher proportions with other Alzheimer's dementia genetic risk variants. DISCUSSION: A cognitive subgrouping strategy may identify biologically distinct subsets of people with Alzheimer's dementia.
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    Initiation of antidepressant medication and risk of incident stroke: using the Adult Changes in Thought cohort to address time-varying confounding
    (Elsevier, 2019-07) Glymour, M. Maria; Gibbons, Laura E.; Gilsanz, Paola; Gross, Alden L.; Mez, Jesse; Brewster, Paul W.; Marden, Jessica; Zahodne, Laura B.; Nho, Kwangsik; Hamilton, Jamie; Li, Gail; Larson, Eric B.; Crane, Paul K.; Radiology and Imaging Sciences, School of Medicine
    Purpose Depression strongly predicts stroke incidence, suggesting that treating depression may reduce stroke risk. Antidepressant medications, however, may increase stroke risk via direct pathways. Previous evidence on antidepressant medication and stroke incidence is mixed. We evaluated associations between antidepressant use and incident stroke. Methods For 2302 Adult Changes in Thought cohort participants with no stroke at study entry, we characterized antidepressant use from pharmacy records, biennial depressive symptoms with a 10-item Centers for Epidemiologic Study–Depression scale, and incident strokes from ICD codes. We used discrete-time survival models with inverse probability weighting to compare stroke risk associated with filling antidepressant prescriptions and by medication category: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors, or other. Results Over an average 8.4-year follow-up, 441 incident strokes occurred. Filling antidepressant medications 3+ times versus 0–2 times predicted 35% increased odds of stroke (OR = 1.35; 95% CI: 0.98, 1.66). Use of TCAs was associated with stroke onset (OR per 10 fills = 1.28; CI: 1.04, 1.57), but use of selective serotonin reuptake inhibitors (OR = 0.98; CI: 0.80, 1.20) or other antidepressants (OR = 0.99; CI: 0.67, 1.45) was not. Conclusions Although patients who received antidepressant medication were at higher risk of stroke, this association appeared specific to TCA prescriptions.