Browsing by Subject "Alzheimer disease (AD)"

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    Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers
    (American Medical Association, 2019-07) Nho, Kwangsik; Kueider-Paisley, Alexandra; Ahmad, Shahzad; MahmoudianDehkordi, Siamak; Arnold, Matthias; Risacher, Shannon L.; Louie, Gregory; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Kastenmüller, Gabi; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; van Duijn, Cornelia; Saykin, Andrew J.; Kaddurah-Daouk, Rima; Radiology and Imaging Sciences, School of Medicine
    Importance: Increasing evidence suggests an important role of liver function in the pathophysiology of Alzheimer disease (AD). The liver is a major metabolic hub; therefore, investigating the association of liver function with AD, cognition, neuroimaging, and CSF biomarkers would improve the understanding of the role of metabolic dysfunction in AD. Objective: To examine whether liver function markers are associated with cognitive dysfunction and the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD. Design, Setting, and Participants: In this cohort study, serum-based liver function markers were measured from September 1, 2005, to August 31, 2013, in 1581 AD Neuroimaging Initiative participants along with cognitive measures, cerebrospinal fluid (CSF) biomarkers, brain atrophy, brain glucose metabolism, and amyloid-β accumulation. Associations of liver function markers with AD-associated clinical and A/T/N biomarkers were assessed using generalized linear models adjusted for confounding variables and multiple comparisons. Statistical analysis was performed from November 1, 2017, to February 28, 2019. Exposures: Five serum-based liver function markers (total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase) from AD Neuroimaging Initiative participants were used as exposure variables. Main Outcomes and Measures: Primary outcomes included diagnosis of AD, composite scores for executive functioning and memory, CSF biomarkers, atrophy measured by magnetic resonance imaging, brain glucose metabolism measured by fludeoxyglucose F 18 (18F) positron emission tomography, and amyloid-β accumulation measured by [18F]florbetapir positron emission tomography. Results: Participants in the AD Neuroimaging Initiative (n = 1581; 697 women and 884 men; mean [SD] age, 73.4 [7.2] years) included 407 cognitively normal older adults, 20 with significant memory concern, 298 with early mild cognitive impairment, 544 with late mild cognitive impairment, and 312 with AD. An elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio and lower levels of ALT were associated with AD diagnosis (AST to ALT ratio: odds ratio, 7.932 [95% CI, 1.673-37.617]; P = .03; ALT: odds ratio, 0.133 [95% CI, 0.042-0.422]; P = .004) and poor cognitive performance (AST to ALT ratio: β [SE], -0.465 [0.180]; P = .02 for memory composite score; β [SE], -0.679 [0.215]; P = .006 for executive function composite score; ALT: β [SE], 0.397 [0.128]; P = .006 for memory composite score; β [SE], 0.637 [0.152]; P < .001 for executive function composite score). Increased AST to ALT ratio values were associated with lower CSF amyloid-β 1-42 levels (β [SE], -0.170 [0.061]; P = .04) and increased amyloid-β deposition (amyloid biomarkers), higher CSF phosphorylated tau181 (β [SE], 0.175 [0.055]; P = .02) (tau biomarkers) and higher CSF total tau levels (β [SE], 0.160 [0.049]; P = .02) and reduced brain glucose metabolism (β [SE], -0.123 [0.042]; P = .03) (neurodegeneration biomarkers). Lower levels of ALT were associated with increased amyloid-β deposition (amyloid biomarkers), and reduced brain glucose metabolism (β [SE], 0.096 [0.030]; P = .02) and greater atrophy (neurodegeneration biomarkers). Conclusions and Relevance: Consistent associations of serum-based liver function markers with cognitive performance and A/T/N biomarkers for AD highlight the involvement of metabolic disturbances in the pathophysiology of AD. Further studies are needed to determine if these associations represent a causative or secondary role. Liver enzyme involvement in AD opens avenues for novel diagnostics and therapeutics.
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    Comparison of amyloid accumulation between Down syndrome and autosomal-dominant Alzheimer disease
    (Wiley, 2022) Boerwinkle, Anna H.; Gordon, Brian A.; Wisch, Julie K.; Flores, Shaney; Henson, Rachel L.; Butt, Omar Hameed; Chen, Charles D.; Benzinger, Tammie L. S.; Fagan, Anne M.; Handen, Benjamin L.; Christian, Bradley T.; Head, Elizabeth; Mapstone, Mark; Klunk, William E.; Rafii, Michael S.; O’Bryant, Sid E.; Price, Julie C.; Schupf, Nicole; Laymon, Charles M.; Krinsky-McHale, Sharon J.; Lai, Florence; Rosas, H. Diana; Hartley, Sigan L.; Zaman, Shahid; Lott, Ira T.; Silverman, Wayne; Brickman, Adam M.; Lee, Joseph H.; Allegri, Ricardo Francisco; Berman, Sarah; Chhatwal, Jasmeer P.; Chui, Helena C.; Cruchaga, Carlos; Farlow, Martin R.; Fox, Nick C.; Goate, Alison; Day, Gregory S.; Graff-Radford, Neill R.; Jucker, Mathias; Lee, Jae-Hong; Levin, Johannes; Martins, Ralph N.; Mori, Hiroshi; Perrin, Richard J.; Salloway, Stephen P.; Sanchez-Valle, Raquel; Schofield, Peter R.; Xiong, Chengjie; Karch, Celeste M.; Hassenstab, Jason J.; McDade, Eric; Bateman, Randall J.; Ances, Beau M.; Neurology, School of Medicine
    Background: Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)-like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development. Method: We assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) and 265 mutation-carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated-years-to-symptom-onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC-DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40. Result: The relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ -23 but was not elevated in DS until EYO ≥ -15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5). Conclusion: These results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5-10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.
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    Unraveling The Ambiguity Between Cognition And Depression: A Longitudinal Analysis Of Older Adults
    (Oxford University Press, 2022) Roessler, Meghann; Manchella, Mohit; Singh, Anmoldeep; Coleman, Max; Francis, Heather; Saykin, Andrew; Risacher, Shannon; Apostolova, Liana; Radiology and Imaging Sciences, School of Medicine
    Research on directionality of the relationship between cognitive functioning and depression is ambiguous, especially when considering implications for patients with mild cognitive impairment or Alzheimer disease (AD). Previous research suggests that depression in late life could be a pre-clinical manifestation of AD before other cognitive symptoms are detectable. Some research supports the hypothesis that level of depression can independently predict level of cognition. Other research suggests that depression is a risk factor for developing dementia or AD late in life. Further research on the impact of subjective cognitive decline versus objective cognitive performance in association with depressive symptoms is a critical area to explore. Using data from the Social Networks in Alzheimer Disease (SNAD) study and the Indiana Alzheimer Disease Research Center (IADRC), we conducted a preliminary longitudinal analysis of 196 focal subjects (Mage = 71.6 years, Pfemale = 63%). Interviews conducted one year apart were leveraged to elucidate the bidirectional relationship between depressive symptomology and cognition. Using a lagged dependent variable approach controlling for age, sex, race, and education, the results indicate that only executive function predicts depression at timepoint 2 (-0.31 SD, p< 0.001). However, depression predicts focal Cognitive Change Index (CCI) (0.06 SD, p< 0.05), processing speed (-0.04 SD, p< 0.05), and episodic memory (-0.04 SD, p< 0.05). Other cognitive domains examined, including attention, language, visual/spatial skills, MoCA score, and informant-rated CCI, were not significant as predictors or as outcomes. These results suggest that depression may be a more robust predictor of cognition than cognition is of depression.