Browsing by Subject "Cognitive decline"
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Item APOE ε4 carrier status and sex differentiate rates of cognitive decline in early- and late-onset Alzheimer's disease(Wiley, 2023) Polsinelli, Angelina J.; Logan, Paige E.; Lane, Kathleen A.; Manchella, Mohit K.; Nemes, Sára; Sanjay, Apoorva Bharthur; Gao, Sujuan; Apostolova, Liana G.; Neurology, School of MedicineBackground: We studied the effect of apolipoprotein E (APOE) ε4 status and sex on rates of cognitive decline in early- (EO) and late- (LO) onset Alzheimer's disease (AD). Method: We ran mixed-effects models with longitudinal cognitive measures as dependent variables, and sex, APOE ε4 carrier status, and interaction terms as predictor variables in 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center. Results: APOE ε4 carriers showed accelerated cognitive decline relative to non-carriers in both EOAD and LOAD, although the patterns of specific cognitive domains that were affected differed. Female participants showed accelerated cognitive decline relative to male participants in EOAD only. The effect of APOE ε4 was greater in EOAD for executive functioning (p < 0.0001) and greater in LOAD for language (p < 0.0001). Conclusion: We found APOE ε4 effects on cognitive decline in both EOAD and LOAD and female sex in EOAD only. The specific patterns and magnitude of decline are distinct between the two disease variants. Highlights: Apolipoprotein E (APOE) ε4 carrier status and sex differentiate rates of cognitive decline in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD). APOE ε4 in EOAD accelerated decline in memory, executive, and processing speed domains. Female sex in EOAD accelerated decline in language, memory, and global cognition. The effect of APOE ε4 was stronger for language in LOAD and for executive function in EOAD. Sex effects on language and executive function decline differed between EOAD and LOAD.Item BrainAGE Estimation: Influence of Field Strength, Voxel Size, Race, and Ethnicity(medRxiv, 2023-12-05) Dempsey, Desarae A.; Deardorff, Rachael; Wu, Yu-Chien; Yu, Meichen; Apostolova, Liana G.; Brosch, Jared; Clark, David G.; Farlow, Martin R.; Gao, Sujuan; Wang, Sophia; Saykin, Andrew J.; Risacher, Shannon L.; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineThe BrainAGE method is used to estimate biological brain age using structural neuroimaging. However, the stability of the model across different scan parameters and races/ethnicities has not been thoroughly investigated. Estimated brain age was compared within- and across- MRI field strength and across voxel sizes. Estimated brain age gap (BAG) was compared across demographically matched groups of different self-reported races and ethnicities in ADNI and IMAS cohorts. Longitudinal ComBat was used to correct for potential scanner effects. The brain age method was stable within field strength, but less stable across different field strengths. The method was stable across voxel sizes. There was a significant difference in BAG between races, but not ethnicities. Correction procedures are suggested to eliminate variation across scanner field strength while maintaining accurate brain age estimation. Further studies are warranted to determine the factors contributing to racial differences in BAG.Item Comparison of CSF phosphorylated tau 181 and 217 for cognitive decline(Wiley, 2022) Mielke, Michelle M.; Aakre, Jeremiah A.; Algeciras-Schimnich, Alicia; Proctor, Nicholas K.; Machulda, Mary M.; Eichenlaub, Udo; Knopman, David S.; Vemuri, Prashanthi; Graff-Radford, Jonathan; Jac, Clifford R., Jr.; Petersen, Ronald C.; Dage, Jeffrey L.; Neurology, School of MedicineIntroduction: The prognostic utility of cerebrospinal fluid (CSF) phosphorylated tau 217 (p-tau217) and p-tau181 is not understood. Methods: Analyses included 753 Mayo Clinic Study on Aging participants (median age = 71.6; 57% male). CSF amyloid beta (Aβ)42 and p-tau181 were measured with Elecsys immunoassays. CSF p-tau181 and p-tau217 were also measured with Meso Scale Discovery (MSD). We used Cox proportional hazards models for risk of mild cognitive impairment (MCI) and linear mixed models for risk of global and domain-specific cognitive decline and cortical thickness. Analyses were stratified by elevated brain amyloid based on CSF Aβ42 or amyloid positron emission tomography for those with imaging. Results: CSF p-tau217 was superior to p-tau181 for the diagnosis of Alzheimer's disease (AD) pathology. CSF MSD p-tau181 and p-tau217 were associated with risk of MCI among amyloid-positive individuals. Differences between CSF p-tau measures predicting cortical thickness were subtle. Discussion: There are subtle differences for CSF p-tau217 and p-tau181 as prognostic AD markers.Item Differential effects of risk factors on the cognitive trajectory of early- and late-onset Alzheimer’s disease(BMC, 2021-06-14) Kim, Jaeho; Woo, Sook-Young; Kim, Seonwoo; Jang, Hyemin; Kim, Junpyo; Kim, Jisun; Kang, Sung Hoon; Na, Duk L.; Chin, Juhee; Apostolova, Liana G.; Seo, Sang Won; Kim, Hee Jin; Neurology, School of MedicineBackground: Although few studies have shown that risk factors for Alzheimer's disease (AD) are associated with cognitive decline in AD, not much is known whether the impact of risk factors differs between early-onset AD (EOAD, symptom onset < 65 years of age) versus late-onset AD (LOAD). Therefore, we evaluated whether the impact of Alzheimer's disease (AD) risk factors on cognitive trajectories differ in EOAD and LOAD. Methods: We followed-up 193 EOAD and 476 LOAD patients without known autosomal dominant AD mutation for 32.3 ± 23.2 months. Mixed-effects model analyses were performed to evaluate the effects of APOE ε4, low education, hypertension, diabetes, dyslipidemia, and obesity on cognitive trajectories. Results: APOE ε4 carriers showed slower cognitive decline in general cognitive function, language, and memory domains than APOE ε4 carriers in EOAD but not in LOAD. Although patients with low education showed slower cognitive decline than patients with high education in both EOAD and LOAD, the effect was stronger in EOAD, specifically in frontal-executive function. Patients with hypertension showed faster cognitive decline than did patients without hypertension in frontal-executive and general cognitive function in LOAD but not in EOAD. Patients with obesity showed slower decline in general cognitive function than non-obese patients in EOAD but not in LOAD. Conclusions: Known risk factors for AD were associated with slower cognitive decline in EOAD but rapid cognitive decline in LOAD.Item Genetic architecture of age-related cognitive decline in African Americans(American Academy of Neurology, 2016-12-21) Raj, Towfique; Chibnik, Lori B.; McCabe, Cristin; Wong, Andus; Replogle, Joseph M.; Yu, Lei; Gao, Sujuan; Unverzagt, Frederick W.; Stranger, Barbara; Murrell, Jill; Barnes, Lisa; Hendrie, Hugh C.; Foroud, Tatiana; Krichevsky, Anna; Bennett, David A.; Hall, Kathleen S.; Evans, Denis A.; De Jager, Philip L.; Department of Biostatistics, Richard M. Fairbanks School of Public HealthOBJECTIVE: To identify genetic risk factors associated with susceptibility to age-related cognitive decline in African Americans (AAs). METHODS: We performed a genome-wide association study (GWAS) and an admixture-mapping scan in 3,964 older AAs from 5 longitudinal cohorts; for each participant, we calculated a slope of an individual's global cognitive change from neuropsychological evaluations. We also performed a pathway-based analysis of the age-related cognitive decline GWAS. RESULTS: We found no evidence to support the existence of a genomic region which has a strongly different contribution to age-related cognitive decline in African and European genomes. Known Alzheimer disease (AD) susceptibility variants in the ABCA7 and MS4A loci do influence this trait in AAs. Of interest, our pathway-based analyses returned statistically significant results highlighting a shared risk from lipid/metabolism and protein tyrosine signaling pathways between cognitive decline and AD, but the role of inflammatory pathways is polarized, being limited to AD susceptibility. CONCLUSIONS: The genetic architecture of aging-related cognitive in AA individuals is largely similar to that of individuals of European descent. In both populations, we note a surprising lack of enrichment for immune pathways in the genetic risk for cognitive decline, despite strong enrichment of these pathways among genetic risk factors for AD.Item Genome-wide association study of rate of cognitive decline in Alzheimer’s Disease patients identifies novel genes and pathways(Wiley, 2020-08) Sherva, Richard; Gross, Alden; Mukherjee, Shubhabrata; Koesterer, Ryan; Amouyel, Philippe; Philippe, Celine; Dufouil, Carole; Bennett, David A.; Chibnik, Lori; Cruchaga, Carlos; del-Aguila, Jorge; Farrer, Lindsay A.; Mayeux, Richard; Munsie, Leanne; Winslow, Ashley; Ashley, Stephen; Saykin, Andrew J.; Kauwe, John S.K.; Crane, Paul K.; Green, Robert C.; Radiology and Imaging Sciences, School of MedicineIntroduction: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD. Methods: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. Results: Suggestive associations (P < 1.0 × 10-6 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10-7 ), chromosome 7 (rs60465337,P = 4.06 × 10-7 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10-7 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10-7 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10-7 ) and 4 (rs1304013, P = 7.73 × 10-7 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. Discussion: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.Item Immunity gene IFITM3 variant: Relation to cognition and Alzheimer's disease pathology(Alzheimer’s Association, 2022-06-21) Pyun, Jung-Min; Park, Young Ho; Hodges, Angela; Jang, Jae-Won; Bice, Paula J.; Kim, SangYun; Saykin, Andrew J.; Nho, Kwangsik; AddNeuroMed Consortium; Alzheimer's Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineIntroduction: We investigated single-nucleotide polymorphisms (SNPs) in IFITM3, an innate immunity gene and modulator of amyloid beta in Alzheimer's disease (AD), for association with cognition and AD biomarkers. Methods: We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1565) and AddNeuroMed (N = 633) as discovery and replication samples, respectively. We performed gene-based association analysis of SNPs in IFITM3 with cognitive performance and SNP-based association analysis with cognitive decline and amyloid, tau, and neurodegeneration biomarkers for AD. Results: Gene-based association analysis showed that IFITM3 was significantly associated with cognitive performance. Particularly, rs10751647 in IFITM3 was associated with less cognitive decline, less amyloid and tau burden, and less brain atrophy in ADNI. The association of rs10751647 with cognitive decline and brain atrophy was replicated in AddNeuroMed. Discussion: This suggests that rs10751647 in IFITM3 is associated with less vulnerability for cognitive decline and AD biomarkers, providing mechanistic insight regarding involvement of immunity and infection in AD. Highlights: IFITM3 is significantly associated with cognitive performance.rs10751647 in IFITM3 is associated with cognitive decline rates with replication.rs10751647 is associated with amyloid beta load, cerebrospinal fluid phosphorylated tau levels, and brain atrophy.rs10751647 is associated with IFITM3 expression levels in blood and brain.rs10751647 in IFITM3 is related to less vulnerability to Alzheimer's disease pathogenesis.Item Independent and joint associations of cardiometabolic multimorbidity and depression on cognitive function: findings from multi-regional cohorts and generalisation from community to clinic(Elsevier, 2024-09-12) Zhao, Xuhao; Xu, Xiaolin; Yan, Yifan; Lipnicki, Darren M.; Pang, Ting; Crawford, John D.; Chen, Christopher; Cheng, Ching-Yu; Venketasubramanian, Narayanaswamy; Chong, Eddie; Blay, Sergio Luis; Lima-Costa, Maria Fernanda; Castro-Costa, Erico; Lipton, Richard B.; Katz, Mindy J.; Ritchie, Karen; Scarmeas, Nikolaos; Yannakoulia, Mary; Kosmidis, Mary H.; Gureje, Oye; Ojagbemi, Akin; Bello, Toyin; Hendrie, Hugh C.; Gao, Sujuan; Guerra, Ricardo Oliveira; Auais, Mohammad; Gomez, José Fernando; Rolandi, Elena; Davin, Annalisa; Rossi, Michele; Riedel-Heller, Steffi G.; Löbner, Margit; Roehr, Susanne; Ganguli, Mary; Jacobsen, Erin P.; Chang, Chung-Chou H.; Aiello, Allison E.; Ho, Roger; Sanchez-Juan, Pascual; Valentí-Soler, Meritxell; Del Ser, Teodoro; Lobo, Antonio; De-la-Cámara, Concepción; Lobo, Elena; Sachdev, Perminder S.; Xu, Xin; Cohort Studies of Memory in an International Consortium (COSMIC); Psychiatry, School of MedicineBackground: Cardiometabolic multimorbidity (CMM) and depression are often co-occurring in older adults and associated with neurodegenerative outcomes. The present study aimed to estimate the independent and joint associations of CMM and depression on cognitive function in multi-regional cohorts, and to validate the generalizability of the findings in additional settings, including clinical. Methods: Data harmonization was performed across 14 longitudinal cohort studies within the Cohort Studies of Memory in an International Consortium (COSMIC) group, spanning North America, South America, Europe, Africa, Asia, and Australia. Three external validation studies with distinct settings were employed for generalization. Participants were eligible for inclusion if they had data for CMM and were free of dementia at baseline. Baseline CMM was defined as: 1) CMM 5, ≥2 among hypertension, hyperlipidemia, diabetes, stroke, and heart disease and 2) CMM 3 (aligned with previous studies), ≥2 among diabetes, stroke, and heart disease. Baseline depression was primarily characterized by binary classification of depressive symptom measurements, employing the Geriatric Depression Scale and the Center for Epidemiological Studies-Depression scale. Global cognition was standardized as z-scores through harmonizing multiple cognitive measures. Longitudinal cognition was calculated as changes in global cognitive z-scores. A pooled individual participant data (IPD) analysis was utilized to estimate the independent and joint associations of CMM and depression on cognitive outcomes in COSMIC studies, both cross-sectionally and longitudinally. Repeated analyses were performed in three external validation studies. Findings: Of the 32,931 older adults in the 14 COSMIC cohorts, we included 30,382 participants with complete data on baseline CMM, depression, and cognitive assessments for cross-sectional analyses. Among them, 22,599 who had at least 1 follow-up cognitive assessment were included in the longitudinal analyses. The three external studies for validation had 1964 participants from 3 multi-ethnic Asian older adult cohorts in different settings (community-based, memory clinic, and post-stroke study). In COSMIC studies, each of CMM and depression was independently associated with cross-sectional and longitudinal cognitive function, without significant interactions between them (Ps > 0.05). Participants with both CMM and depression had lower cross-sectional cognitive performance (e.g. β = -0.207, 95% CI = (-0.255, -0.159) for CMM5 (+)/depression (+)) and a faster rate of cognitive decline (e.g. β = -0.040, 95% CI = (-0.047, -0.034) for CMM5 (+)/depression (+)), compared with those without either condition. These associations remained consistent after additional adjustment for APOE genotype and were robust in two-step random-effects IPD analyses. The findings regarding the joint association of CMM and depression on cognitive function were reproduced in the three external validation studies. Interpretation: Our findings highlighted the importance of investigating age-related co-morbidities in a multi-dimensional perspective. Targeting both cardiometabolic and psychological conditions to prevent cognitive decline could enhance effectiveness.Item Longitudinal cognitive performance of Alzheimer's disease neuropathological subtypes(Alzheimer’s Association, 2021-09-27) Uretsky, Madeline; Gibbons, Laura E.; Mukherjee, Shubhabrata; Trittschuh, Emily H.; Fardo, David W.; Boyle, Patricia A.; Keene, C. Dirk; Saykin, Andrew J.; Crane, Paul K.; Schneider, Julie A.; Mez, Jesse; Radiology and Imaging Sciences, School of MedicineIntroduction: Alzheimer's disease (AD) neuropathological subtypes (limbic predominant [lpAD], hippocampal sparing [HpSpAD], and typical [tAD]), defined by relative neurofibrillary tangle (NFT) burden in limbic and cortical regions, have not been studied in prospectively characterized epidemiological cohorts with robust cognitive assessments. Methods: Two hundred ninety-two participants with neuropathologically confirmed AD from the Religious Orders Study and Memory and Aging Project were categorized by neuropathological subtype based on previously specified diagnostic criteria using quantitative regional NFT counts. Rates of cognitive decline were compared across subtypes using linear mixed-effects models that included subtype, time, and a subtype-time interaction as predictors and four cognitive domain factor scores (memory, executive function, language, visuospatial) and a global score as outcomes. To assess if memory was relatively preserved in HpSpAD, non-memory factor scores were included as covariates in the mixed-effects model with memory as the outcome. Results: There were 57 (20%) with lpAD, 22 (8%) with HpSpAD and 213 (73%) with tAD. LpAD died significantly later than the participants with tAD (2.4 years, P = .01) and with HpSpAD (3.8 years, P = .03). Compared to tAD, HpSpAD, but not lpAD, performed significantly worse in all cognitive domains at the time of initial impairment and declined significantly faster in memory, language, and globally. HpSpAD did not have relatively preserved memory performance at any time point. Conclusion: The relative frequencies of AD neuropathological subtypes in an epidemiological sample were consistent with a previous report in a convenience sample. People with HpSpAD decline rapidly, but may not have a memory-sparing clinical syndrome. Cohort-specific differences in regional tau burden and comorbid neuropathology may explain the lack of clinicopathological correlation.Item Measuring Subjective Cognitive Decline in Older Adults: Harmonization Between the Cognitive Change Index and the Measurement of Everyday Cognition Instruments(IOS Press, 2022) Wells, Lindsey F.; Risacher, Shannon L.; McDonald, Brenna C.; Farlow, Martin R.; Brosch, Jared; Gao, Sujuan; Apostolova, Liana G.; Saykin, Andrew J.; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineBackground: Self and informant (proxy or study partner) reports of everyday cognitive functioning have been shown to be associated with incipient neurodegenerative disease. The 20-item Cognitive Change Index (CCI) and the 39-item Measurement of Everyday Cognition (ECog) were each developed to characterize early subjective changes in cognitive function. Objective: We examined the relationship between CCI and ECog self and informant-based evaluations to determine content overlap and provide a co-calibration for converting between these widely used instruments. Methods: 950 participants (57.1% female, mean age = 71.2 years) from ADNI and the Indiana ADRC with self-based evaluations and 279 participants (60.9% female, mean age = 71.8 years) with informant-based evaluations (Indiana ADRC) were included. Analyzed variables for the CCI and ECog included domain mean scores, memory domain total scores, and total scores for all items. Spearman correlations, regression analyses, and frequency distributions were used to assess the relationship between CCI and ECog. Sex, age, years of education, race/ethnicity, APOE ε4 carrier status, and baseline diagnosis were also analyzed as potentially relevant covariates. Results: CCI and ECog total scores were highly correlated for the self (r = 0.795, p < 0.001) and informant-based (r = 0.840, p < 0.001) versions, as expected. Frequency distributions of self and informant total scores were generated and plotted separately. Quadratic regressions for self (r2 = 0.626) and informant (r2 = 0.741) scores were used to create a translation table between the CCI and ECog total scores. Conclusion: Self and informant total scores can be harmonized and translated between the CCI and ECog to facilitate cross-study and longitudinal assessment of perceived cognitive change, an important patient-reported outcome.