Adiposity and insulin resistance moderate the links between neuroelectrophysiology and working and episodic memory functions in young adult males but not females.

INTRODUCTION: Obesity and insulin resistance negatively influence neural activity and cognitive function, but electrophysiological mechanisms underlying these interrelationships remain unclear. This study investigated whether adiposity and insulin resistance moderated neural activity and underlying cognitive functions in young adults. METHODS: Real-time electroencephalography (EEG) was recorded in 38 lean (n = 12) and obese (n = 26) young adults with (n = 15) and without (n = 23) insulin resistance (18-38 years, 55.3% female) as participants completed three neurocognitive tasks in working memory (Operation Span), inhibitory control (Stroop), and episodic memory (Visual Association Test). Body fat percentage was quantified by a dual-energy X-ray absorptiometry scan (DEXA/DXA). Fasting serum insulin and glucose were quantified to calculate Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) values, for which a higher value indicates more insulin resistance. Hierarchical moderated regression analysis tested these interrelationships. RESULTS: In males, greater frontal negative slow wave (fNSW) and positive slow wave (PSW) amplitudes were linked to higher working memory accuracy in participants with low, but not high, body fat percentage and HOMA-IR levels. In contrast, body fat percentage and HOMA-IR did not moderate these associations in females. Furthermore, body fat percentage and HOMA-IR values moderated the relationship between greater fNSW amplitudes and better episodic memory accuracy in males, but not females. Finally, body fat percentage and insulin resistance did not moderate the link between neural activity and inhibitory control for either sex. CONCLUSION: Young adult males, but not females, with higher body adiposity and insulin resistance showed reduced neural activity and worse underlying working and episodic memory functions.

Measurement precision across cognitive domains in the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set.

OBJECTIVE: To demonstrate measurement precision of cognitive domains in the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set. METHOD: Participants with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) were included from all ADNI waves. We used data from each person's last study visit to calibrate scores for memory, executive function, language, and visuospatial functioning. We extracted item information functions for each domain and used these to calculate standard errors of measurement. We derived scores for each domain for each diagnostic group and plotted standard errors of measurement for the observed range of scores. RESULTS: Across all waves, there were 961 people with NC, 825 people with MCI, and 694 people with AD at their most recent study visit (data pulled February 25, 2019). Across ADNI's battery there were 34 memory items, 18 executive function items, 20 language items, and seven visuospatial items. Scores for each domain were highest on average for people with NC, intermediate for people with MCI, and lowest for people with AD, with most scores across all groups in the range of -1 to +1. Standard error of measurement in the range from -1 to +1 was highest for memory, intermediate for language and executive functioning, and lowest for visuospatial. CONCLUSION: Modern psychometric approaches provide tools to help understand measurement precision of the scales used in studies. In ADNI, there are important differences in measurement precision across cognitive domains. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A genome-wide search for pleiotropy in more than 100,000 harmonized longitudinal cognitive domain scores.

BACKGROUND: More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes. METHODS: We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. RESULTS: Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10-9). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10-8) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10-8). GRN (rs5848, P = 4.21 × 10-8) and PURG (rs117523305, P = 1.73 × 10-8) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10-8) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10-9) and PTPRD (rs145989094, P = 8.34 × 10-9) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10-8) and PTPRD (rs145989094, P = 3.85 × 10-8) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. CONCLUSION: Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias.

Exploring the secrets of super-aging: a UK Biobank study on brain health and cognitive function.

Communities across the globe are faced with a rapidly aging society, where age is the main risk factor for cognitive decline and development of Alzheimer's and related diseases. Despite extensive research, there have been no successful treatments yet. A rare group of individuals called "super-agers" have been noted to thrive with their exceptional ability to maintain a healthy brain and normal cognitive function even in old age. Studying their traits, lifestyles, and environments may provide valuable insight. This study used a data-driven approach to identify potential super-agers among 7121 UK Biobank participants and found that these individuals have the highest total brain volume, best cognitive performance, and lowest functional connectivity. The researchers suggest a novel hypothesis that these super-agers possess enhanced neural processing efficiency that increases with age and introduce a definition of the "neural efficiency index." Furthermore, several other types of aging were identified and significant structural-functional differences were observed between them, highlighting the benefit of research efforts in personalized medicine and precision nutrition.

Associations Between Insulin-Like Growth Factor-1 and Resting-State Functional Connectivity in Cognitively Unimpaired Midlife Adults.

BACKGROUND: Insulin-like growth factor (IGF)-1 plays an important role in Alzheimer's disease (AD) pathogenesis and increases disease risk. However, prior research examining IGF-1 levels and brain neural network activity is mixed. OBJECTIVE: The present study investigated the relationship between IGF-1 levels and 21 neural networks, as measured by functional magnetic resonance imaging (fMRI) in 13,235 UK Biobank participants. METHODS: Linear mixed models were used to regress IGF-1 against the intrinsic functional connectivity (i.e., degree of network activity) for each neural network. Interactions between IGF-1 and AD risk factors such as Apolipoprotein E4 (APOE4) genotype, sex, AD family history, and age were also tested. RESULTS: Higher IGF-1 was associated with more network activity in the right Executive Function neural network. IGF-1 interactions with APOE4 or sex implicated motor, primary/extrastriate visual, and executive function related neural networks. Neural network activity trends with increasing IGF-1 were different in different age groups. Higher IGF-1 levels relate to much more network activity in the Sensorimotor Network and Cerebellum Network in early-life participants (40-52 years old), compared with mid-life (52-59 years old) and late-life (59-70 years old) participants. CONCLUSION: These findings suggest that sex and APOE4 genotype may modify the relationship between IGF-1 and brain network activities related to visual, motor, and cognitive processing. Additionally, IGF-1 may have an age-dependent effect on neural network connectivity.

Bioenergetic and vascular predictors of potential super-ager and cognitive decline trajectories-a UK Biobank Random Forest classification study.

Aging has often been characterized by progressive cognitive decline in memory and especially executive function. Yet some adults, aged 80 years or older, are "super-agers" that exhibit cognitive performance like younger adults. It is unknown if there are adults in mid-life with similar superior cognitive performance ("positive-aging") versus cognitive decline over time and if there are blood biomarkers that can distinguish between these groups. Among 1303 participants in UK Biobank, latent growth curve models classified participants into different cognitive groups based on longitudinal fluid intelligence (FI) scores over 7-9 years. Random Forest (RF) classification was then used to predict cognitive trajectory types using longitudinal predictors including demographic, vascular, bioenergetic, and immune factors. Feature ranking importance and performance metrics of the model were reported. Despite model complexity, we achieved a precision of 77% when determining who would be in the "positive-aging" group (n = 563) vs. cognitive decline group (n = 380). Among the top fifteen features, an equal number were related to either vascular health or cellular bioenergetics but not demographics like age, sex, or socioeconomic status. Sensitivity analyses showed worse model results when combining a cognitive maintainer group (n = 360) with the positive-aging or cognitive decline group. Our results suggest that optimal cognitive aging may not be related to age per se but biological factors that may be amenable to lifestyle or pharmacological changes.

Beer, wine, and spirits differentially influence body composition in older white adults-a United Kingdom Biobank study.

BACKGROUND: Aging is characterized by body composition alterations, including increased visceral adiposity accumulation and bone loss. Alcohol consumption may partially drive these alterations, but findings are mixed. This study primarily aimed to investigate whether different alcohol types (beer/cider, red wine, white wine/Champagne, spirits) differentially associated with body composition. METHODS: The longitudinal UK Biobank study leveraged 1869 White participants (40-80 years; 59% male). Participants self-reported demographic, alcohol/dietary consumption, and lifestyle factors using a touchscreen questionnaire. Anthropometrics and serum for proteomics were collected. Body composition was obtained via dual-energy X-ray absorptiometry. Structural equation modeling was used to probe direct/indirect associations between alcohol types, cardiometabolic biomarkers, and body composition. RESULTS: Greater beer/spirit consumptions were associated with greater visceral adiposity (ß = 0.069, p < 0.001 and ß = 0.014, p < 0.001, respectively), which was driven by dyslipidemia and insulin resistance. In contrast, drinking more red wine was associated with less visceral adipose mass (ß = -0.023, p < 0.001), which was driven by reduced inflammation and elevated high-density lipoproteins. White wine consumption predicted greater bone density (ß = 0.051, p < 0.005). DISCUSSION: Beer/spirits may partially contribute to the "empty calorie" hypothesis related to adipogenesis, while red wine may help protect against adipogenesis due to anti-inflammatory/eulipidemic effects. Furthermore, white wine may benefit bone health in older White adults.1.

Using machine learning to predict COVID-19 infection and severity risk among 4510 aged adults: a UK Biobank cohort study.

Many risk factors have emerged for novel 2019 coronavirus disease (COVID-19). It is relatively unknown how these factors collectively predict COVID-19 infection risk, as well as risk for a severe infection (i.e., hospitalization). Among aged adults (69.3 ± 8.6 years) in UK Biobank, COVID-19 data was downloaded for 4510 participants with 7539 test cases. We downloaded baseline data from 10 to 14 years ago, including demographics, biochemistry, body mass, and other factors, as well as antibody titers for 20 common to rare infectious diseases in a subset of 80 participants with 124 test cases. Permutation-based linear discriminant analysis was used to predict COVID-19 risk and hospitalization risk. Probability and threshold metrics included receiver operating characteristic curves to derive area under the curve (AUC), specificity, sensitivity, and quadratic mean. Model predictions using the full cohort were marginal. The "best-fit" model for predicting COVID-19 risk was found in the subset of participants with antibody titers, which achieved excellent discrimination (AUC 0.969, 95% CI 0.934-1.000). Factors included age, immune markers, lipids, and serology titers to common pathogens like human cytomegalovirus. The hospitalization "best-fit" model was more modest (AUC 0.803, 95% CI 0.663-0.943) and included only serology titers, again in the subset group. Accurate risk profiles can be created using standard self-report and biomedical data collected in public health and medical settings. It is also worthwhile to further investigate if prior host immunity predicts current host immunity to COVID-19.

APOE, TOMM40, and sex interactions on neural network connectivity.

The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 ('650) G versus A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE. We examined 21 orthogonal neural networks among 8,222 middle-aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 '650 genotypes, and if age and sex acted as moderators. APOE ε4 was associated with less strength in multiple networks, while '650 G versus A carriage was related to more language comprehension network strength. In APOE ε4 carriers, '650 G-carriage led to less network strength with increasing age, while in non-G-carriers this was only seen in women but not men. TOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.

Inflammation, negative affect, and amyloid burden in Alzheimer's disease: Insights from the kynurenine pathway.

BACKGROUND: Depressive symptoms in Alzheimer's disease (AD) predict worse cognitive and functional outcomes. Both AD and major depression inflammatory processes are characterized by shunted tryptophan metabolism away from serotonin (5-HT) and toward the neuroinflammatory kynurenine (Kyn) pathway. The present study assessed associations between Kyn and behavioral, neuroanatomical, neuropathological, and physiological outcomes common to both AD and negative affect across the AD continuum. METHODS: In 58 cognitively normal, 396 mild cognitive impairment, and 112 AD participants from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI1) cohort, serum markers of 5-HT, tryptophan, and Kyn were measured and their relationships investigated with immunologic markers, affect and functional outcomes, CSF markers of beta-amyloid (Aß) and tau, and regional gray matter. RESULTS: A higher Kyn/Tryptophan ratio was linked to many inflammatory markers, as well as lower functional independence and memory scores. A higher Kyn/5-HT ratio showed similar associations, but also strong relationships with negative affect and neuropsychiatric disturbance, executive dysfunction, and global cognitive decline. Further, gray matter atrophy was seen in hippocampus, anterior cingulate, and prefrontal cortices, as well as greater amyloid and total tau deposition. Finally, using moderated-mediation, several pro-inflammatory factors partially mediated Kyn/5-HT and negative affect scores in participants with subclinical Aß (i.e., Aß-), whereas such associations were fully mediated by Complement 3 in Aß+ participants. CONCLUSION: These findings suggest that inflammatory signaling cascades may occur during AD, which is associated with increased Kyn metabolism that influences the pathogenesis of negative affect. Aß and the complement system may be critical contributing factors in this process.

Using machine learning to predict COVID-19 infection and severity risk among 4,510 aged adults: a UK Biobank cohort study.

BACKGROUND: Many risk factors have emerged for novel 2019 coronavirus disease (COVID-19). It is relatively unknown how these factors collectively predict COVID-19 infection risk, as well as risk for a severe infection (i.e., hospitalization). METHODS: Among aged adults (69.3 ± 8.6 years) in UK Biobank, COVID-19 data was downloaded for 4,510 participants with 7,539 test cases. We downloaded baseline data from 10-14 years ago, including demographics, biochemistry, body mass, and other factors, as well as antibody titers for 20 common to rare infectious diseases. Permutation-based linear discriminant analysis was used to predict COVID-19 risk and hospitalization risk. Probability and threshold metrics included receiver operating characteristic curves to derive area under the curve (AUC), specificity, sensitivity, and quadratic mean. RESULTS: The "best-fit" model for predicting COVID-19 risk achieved excellent discrimination (AUC=0.969, 95% CI=0.934-1.000). Factors included age, immune markers, lipids, and serology titers to common pathogens like human cytomegalovirus. The hospitalization "best-fit" model was more modest (AUC=0.803, 95% CI=0.663-0.943) and included only serology titers. CONCLUSIONS: Accurate risk profiles can be created using standard self-report and biomedical data collected in public health and medical settings. It is also worthwhile to further investigate if prior host immunity predicts current host immunity to COVID-19.

Genetic Factors of Alzheimer's Disease Modulate How Diet is Associated with Long-Term Cognitive Trajectories: A UK Biobank Study.

BACKGROUND: Fluid intelligence (FI) involves abstract problem-solving without prior knowledge. Greater age-related FI decline increases Alzheimer's disease (AD) risk, and recent studies suggest that certain dietary regimens may influence rates of decline. However, it is uncertain how long-term food consumption affects FI among adults with or without familial history of AD (FH) or APOE4 (ɛ4). OBJECTIVE: Observe how the total diet is associated with long-term cognition among mid- to late-life populations at-risk and not-at-risk for AD. METHODS: Among 1,787 mid-to-late-aged adult UK Biobank participants, 10-year FI trajectories were modeled and regressed onto the total diet based on self-reported intake of 49 whole foods from a Food Frequency Questionnaire (FFQ). RESULTS: Daily cheese intake strongly predicted better FIT scores over time (FH-: ß= 0.207, p < 0.001; ɛ4-: ß= 0.073, p = 0.008; ɛ4+: ß= 0.162, p = 0.001). Alcohol of any type daily also appeared beneficial (ɛ4+: ß= 0.101, p = 0.022) and red wine was sometimes additionally protective (FH+: ß= 0.100, p = 0.014; ɛ4-: ß= 0.59, p = 0.039). Consuming lamb weekly was associated with improved outcomes (FH-: ß= 0.066, p = 0.008; ɛ4+: ß= 0.097, p = 0.044). Among at risk groups, added salt correlated with decreased performance (FH+: ß= -0.114, p = 0.004; ɛ4+: ß= -0.121, p = 0.009). CONCLUSION: Modifying meal plans may help minimize cognitive decline. We observed that added salt may put at-risk individuals at greater risk, but did not observe similar interactions among FH- and AD- individuals. Observations further suggest in risk status-dependent manners that adding cheese and red wine to the diet daily, and lamb on a weekly basis, may also improve long-term cognitive outcomes.

CSF glucose tracks regional tau progression based on Alzheimer's disease risk factors.

INTRODUCTION: Glucose hypometabolism and tau formation are key features of Alzheimer's disease (AD). Less is known about the relationship between fasting glucose and regional tau accumulation. METHODS: Cerebrospinal fluid (CSF) glucose was linearly regressed on regional tau (flortaucipir) among 169 Alzheimer's Disease Neuroimaging Initiative (ADNI3) participants. Flortaucipir uptake was examined by Braak stages and regions of interest (ROIs). Interactions were explored between CSF glucose and AD risk factors including regional amyloid beta (Aß), sex, Apolipoprotein E ε4 (APOEε4) status, AD parental family history (AD FH), and cognitive impairment (CI). RESULTS: Interactions found higher CSF glucose tracked less tau in ROIs or Braak stages I/II (women, APOE ε4+, regional Aß), III/IV (AD FH+, regional Aß), and V/VI (AD FH+). CI drove Braak III-VI associations. DISCUSSION: Among women and APOE ε4 carriers, higher CSF glucose tracked less early-stage tau. Higher CSF glucose may reflect compensation against tau spreading in CI, Aß+, or AD FH+.

Walking in the Light: How History of Physical Activity, Sunlight, and Vitamin D Account for Body Fat-A UK Biobank Study.

OBJECTIVE: The high prevalence of vitamin D deficiency and obesity drives the need for successful strategies that elevate vitamin D levels, prevent adipogenesis, and stimulate lipolysis. This study provides a theoretical model to evaluate how physical activity (PA) and sunlight exposure influence serum vitamin D levels and regional adiposity. This study hypothesized a posteriori that sunlight is associated with undifferentiated visceral adiposity by increasing the ratio of brown to white adipose tissue. METHODS: Using 10-year longitudinal data, accelerometry, a sun-exposure questionnaire, and regional adiposity quantified by dual-energy x-ray absorptiometry imaging, a structural-equation mediation model of growth curves was constructed with a data-driven methodology. RESULTS: Sunlight and PA conjointly increased serum vitamin D. Changes in vitamin D levels partially mediated how sunlight and PA impacted adiposity in visceral and subcutaneous regions within a subjective PA model. In an objective PA model, vitamin D was a mediator for subcutaneous regions only. Interestingly, sunlight was associated with less adiposity in subcutaneous regions but greater adiposity in visceral regions. CONCLUSIONS: Sunlight and PA may increase vitamin D levels. For the first time, this study characterizes a positive association between sunlight and visceral adiposity. Further investigation and experimentation are necessary to clarify the physiological role of sunlight exposure on adipose tissue.

Aging-related changes in fluid intelligence, muscle and adipose mass, and sex-specific immunologic mediation: A longitudinal UK Biobank study.

BACKGROUND: Obesity in midlife and early late-life is associated with worse normal cognitive aging. Dual-energy X-ray absorptiometry (DEXA) suggests that visceral adipose mass (VAM) plays a predominant role, whereas non-visceral adipose mass (NVAM) and lean muscle mass (LMM) have shown conflicting relationships. It is unknown how longitudinal, cognitive changes in age-sensitive domains like fluid intelligence (FI) correspond to VAM, NVAM, and LMM in women and men. Furthermore, changes over time in blood leukocyte sub-populations may partially or fully account for sex-specific associations. METHODS: Data on 4431 late middle-aged, cognitively unimpaired adults (mean = 64.5 y) was obtained from the UK Biobank prospective cohort across 22 centers. FI scores, blood leukocyte counts, and covariates (age, social class, education) were measured at three 2-year intervals over 6 years. DEXA collection overlapped with these intervals. Sex-stratified growth curves, structural equations, and Preacher-Hayes mediation were used to estimate direct and indirect effects. ß-weights were standardized. RESULTS: More LMM predicted gains in FI scores among women (ß = 0.130, p < .001) and men (ß = 0.089, p < .001). Conversely, more VAM and NVAM independently predicted FI decline equally among sexes (e.g., NVAM: women: ß = -0.082, p < .001; men: ß = -0.076, p < .001). Among women, FI associations were fully mediated by higher eosinophil counts via VAM (λ = 30.8%, p = .028) and lower lymphocyte counts via LMM (λ = 69.2%, p = .021). Among men, FI associations were partially mediated by lower basophils counts via LMM (λ = 4.5%, p = .042) and higher counts via VAM (λ = 50%, p = .037). CONCLUSION: The proportion of LMM and VAM equally influenced male FI changes over 6 years, whereas higher LMM among women appeared to more strongly influence. FI changes. Leukocyte counts strongly mediated VAM- and LMM-related FI changes in a sex-specific manner, but not for NVAM. For clinical translation, exercise studies in older adults may benefit from assessing sex-specific values of DEXA-based tissue mass, FI, and leukocyte sub-populations to gauge potential cognitive benefits of less VAM and more LMM.

Is Cerebrospinal Fluid Superoxide Dismutase 1 a Biomarker of Tau But Not Amyloid-Induced Neurodegeneration in Alzheimer's Disease?

Copper/zinc superoxide dismutase 1 (SOD1) scavenges free radicals that may otherwise damage brain parenchyma. Impaired SOD1 activity drives Alzheimer's disease (AD) neuropathology in animal models and postmortem AD brains. Yet, it is unknown how cerebrospinal fluid (CSF) SOD1 is related in vivo to AD-relevant cognitive, neuroimaging, and CSF neurotoxic factors, and what potential mechanisms underlie these associations. We found that higher CSF SOD1 correlated with better global cognition scores, yet less gray matter (GM) and glucose metabolism in AD-sensitive parietal and frontal regions. Higher CSF SOD1 was also associated with more CSF total tau and phosphorylated tau-181, but not beta-amyloid 1-42. Through mediation analyses, higher total tau largely mitigated higher CSF SOD1 and better global cognition associations, and it fully accounted for less predicted regional GM but not glucose metabolism. Among participants who developed AD over 2 years or had AD at baseline, higher CSF SOD1 was initially related to more regional GM. This association became nonsignificant with full mediation via higher CSF total tau, through which higher CSF SOD1 predicted more total tau and in turn less GM. Our observations lead to the hypothesis that SOD1 antioxidation reflects tau but not amyloid accumulation, which may lead to pro-oxidant-based neurodegeneration and cognitive dysfunction. Antioxid. Redox Signal. 31, 572-578.

Cholecystokinin and Alzheimer's disease: a biomarker of metabolic function, neural integrity, and cognitive performance.

Cholecystokinin (CCK) is a satiety hormone that is highly expressed in brain regions like the hippocampus. CCK is integral for maintaining or enhancing memory and thus may be a useful marker of cognitive and neural integrity in participants with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD). Cerebrospinal fluid (CSF) CCK levels were examined in 287 subjects from the Alzheimer's Disease Neuroimaging Initiative. Linear or voxelwise regression was used to examine associations between CCK, regional gray matter, CSF AD biomarkers, and cognitive outcomes. Briefly, higher CCK was related to a decreased likelihood of having mild cognitive impairment or AD, better global and memory scores, and more gray matter volume primarily spanning posterior cingulate cortex, parahippocampal gyrus, and medial prefrontal cortex. CSF CCK was also strongly related to higher CSF total tau (R2 = 0.342) and p-tau-181 (R2 = 0.256) but not Aß1-42. Tau levels partially mediated CCK and cognition associations. In conclusion, CCK levels may reflect compensatory protection as AD pathology progresses.