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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 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 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.Item Neurological Correlates of Social Bonding and Bridging(Oxford University Press, 2022-12-20) Manchella, Mohit; Logan, Paige; Perry, Brea; Peng, Siyun; Hamilton, Lucas; Risacher, Shannon; Saykin, Andrew; Apostolova, Liana; Neurology, School of MedicineSocial connectedness has been linked to decreased rates of cognitive decline in later life. However, recent work suggests that particular social network characteristics (i.e., bonding and bridging) may buffer against age-related degeneration. The present study analyzes social network and structural MRI data of 176 older adults from the Social Networks and Alzheimer’s Disease (SNAD) study. Results indicate that increased social bridging is associated with greater grey matter (GM) volume in several limbic structures. Increased social bonding is associated with greater GM volumes in several cerebral cortex structures as well as greater volumes in some components of the limbic system. Most notably, the effects of bridging are primarily lateralized in the left hemisphere while the effects of bonding are observed mostly in the right hemisphere. These results suggest that the neurocognitive benefits of social connectedness depend on the preponderance of bridging and/or bonding ties in older adults’ social networks.Item Primary prevention recommendations to reduce the risk of cognitive decline(Wiley, 2022) Sabbagh, Marwan N.; Perez, Adriana; Holland, Thomas M.; Boustani, Malaz; Peabody, Stephanie R.; Yaffe, Kristine; Bruno, Michelle; Paulsen, Russell; O’Brien, Kelly; Wahid, Naila; Tanzi, Rudolph E.; Medicine, School of MedicineIntroduction: Few resources address steps clinicians can take to help patients reduce their risk of dementia, despite growing recognition that brain health can be optimized and that risk reduction for cognitive decline can be accomplished by lifestyle modifications. Methods: To address this gap, UsAgainstAlzheimer's convened a risk reduction workgroup (RRWG) to review existing evidence and develop recommendations for primary care clinicians discussing cognitive decline and risk reduction with their patients. Results: The RRWG produced 11 consensus‐based recommendations and implementation strategies across six topics: neurovascular risk management, physical activity, sleep, nutrition, social isolation, and cognitive stimulation. Discussion: These recommendations are a first step for clinicians to address brain health with patients and potentially help them prevent cognitive decline. To ensure there is routine care for brain health, proper incentives and policies must be instituted and more education for consumers should be provided.Item Racial Differences in the Relationship Between Loneliness and Cognition Among Older Adults in the Midwest(Oxford University Press, 2023-12-21) Catt, Wade; Fowler, Nicole; Perry, Brea; Peng, Siyun; Williams-Farrelly, Monica; Medicine, School of MedicineFindings from various studies have revealed a relationship between loneliness and negative health outcomes, including cognitive decline and dementia. The strength and direction of this relationship has been contested as there is wide variability in definitions and testing criteria for loneliness. If loneliness is risk factor for cognitive decline, it may represent a cost-effective site for interventional design. We used data from the Precision Health Initiative’s Person to Person Health Interview Study (P2P), a cross-sectional survey conducted in Indiana from 2020-2021, to investigate the relationship between loneliness (UCLA 3-item loneliness scale) and cognition (The Montreal Cognitive Assessment; MoCA) among older adults and to determine if the strength of the relationship varies for black and white adults. Among our subsample of adults 55 and older, over one quarter (26.7%) reported loneliness, with white respondents reporting more loneliness than black respondents (26.8 and 22.0%, respectively). Being lonely was associated with lower cognition, as was being older, male, black, and having no college education. However, we found that loneliness was associated with worse cognition, for white adults only. Although black respondents in our sample reported more loneliness than older white adults after age 70, we did not have adequate power to determine if advanced age moderated the relationship. Our findings highlight the role of loneliness in cognition for older, white adults and the need for more research to assess this relationship for the “mid-“ and “oldest-old” black adults who may be more susceptible to loneliness due, in part, to racial disparities in mortality.