Acute versus chronic inflammatory markers and cognition in older black adults: Results from the Minority Aging Research Study.

Peripheral inflammation is elevated in older Black adults, an elevation which prior work has suggested may be due to chronic stress associated with systemic racism and related adverse cardiovascular health conditions. Inflammation is also involved in the pathogenic processes of dementia; however, limited (and mixed) results exist concerning inflammation and cognitive decline in Black adults. We characterized patterns of inflammation and their role in cognitive decline in 280 older Black adults (age = 72.99 ± 6.00 years; 69.6% female) from the Minority Aging Research Study (MARS) who were without dementia at baseline and followed between 2 and 15 years (mean = 9 years). Participants completed a blood draw at baseline and annual cognitive evaluations. Serum was assayed for 9 peripheral inflammatory markers; 19 neuropsychological test scores were used to create indices of global cognition and five cognitive domains. Principal component analysis with varimax rotation characterized patterns of inflammation with factor loadings > 0.6 per component contributing to two composite scores representing acute/upstream and chronic/downstream inflammation. These composites were used as separate predictors in linear mixed regression models to determine associations with level and change in cognition adjusting for relevant covariates. Higher baseline upstream/acute inflammation associated with lower baseline semantic memory (p = .040) and perceptual speed (p = .046); it was not related to cognitive decline. By contrast, higher baseline downstream/chronic inflammation associated with faster declines in global cognition (p = .010), episodic (p = .027) and working memory (p = .006); it was not related to baseline cognition. For older Black adults, chronic, but not acute, inflammation may be a risk factor for changes in cognition.

Inflammatory markers and tract-based structural connectomics in older adults with a preliminary exploration of associations by race.

Peripheral inflammation has been implicated in cognitive dysfunction and dementia. While studies outline the relationship between elevated inflammation and individual gray or white matter alterations, less work has examined inflammation as related to connectivity between gray and white matter or variability in these associations by race. We examined the relationship between peripheral inflammation and tract-based structural connectomics in 74 non-demented participants (age = 69.19 ± 6.80 years; 53% female; 45% Black) who underwent fasting venipuncture and MRI. Serum was assayed for C-reactive protein, interleukin-6, and interleukin-1ß. Graph theory analysis integrated T1-derived gray matter volumes and DTI-derived white matter tractography into connectivity matrices analyzed for local measures of nodal strength and efficiency in a priori regions of interest associated with cardiovascular disease risk factors and dementia. Linear regressions adjusting for relevant covariates showed associations between inflammatory markers and nodal strength in the isthmus, posterior and caudal anterior cingulate (p's ≤ .042). Adding an inflammatory marker*race term showed race-modified associations between C-reactive protein and efficiency in the thalamus and amygdala, and nodal strength in the putamen (p's ≤ .048), between interleukin-6 and efficiency in the pars triangularis and amygdala (p's ≤ .024), and between interleukin-1ß and nodal strength in the pars opercularis (p = .048). Higher levels of inflammation associated with lower efficiency and higher strength for White participants but higher efficiency and lower strength for Black participants. Results suggest inflammation is associated with tract-based structural connectomics in an older diverse cohort and that differential relationships may exist by race within prefrontal and limbic brain regions.

Liver kinase B1 rs9282860 polymorphism and risk for multiple sclerosis in White and Black Americans.

BACKGROUND: We previously reported that the single nucleotide polymorphism (SNP) rs9282860 in serine threonine kinase 11 (STK11) gene which codes for liver kinase B1 (LKB1) has higher prevalence in White relapsing-remitting multiple sclerosis (RRMS) patients than controls. However it is not known if this SNP is a risk factor for MS in other populations. METHODS: We assessed the prevalence of the STK11 SNP in samples collected from African American (AA) persons with MS (PwMS) and controls at multiple Veterans Affairs (VA) Medical Centers and from a network of academic MS centers. Genotyping was carried out using a specific Taqman assay. Comparisons of SNP frequencies were made using Fisher's exact test to determine significance and odds ratios. Group means were compared by appropriate t-tests based on normality and variance using SPSS V27. RESULTS: There were no significant differences in average age at first symptom onset, age at diagnosis, disease duration, or disease severity between RRMS patients recruited from VAMCs versus non-VAMCs. The SNP was more prevalent in AA than White PwMS, however only in secondary progressive MS (SPMS) patients was that difference statistically significant. AA SPMS patients had higher STK11 SNP prevalence than controls; and in that cohort the SNP was associated with older age at symptom onset and at diagnosis. CONCLUSIONS: The results suggest that the STK11 SNP represents a risk factor for SPMS in AA patients, and can influence both early (onset) and later (conversion to SPMSS) events.

Adapting to the COVID-19 pandemic on Building Research in Diet and Cognition (BRIDGE) trial.

BACKGROUND: The COVID-19 pandemic has altered the research landscape for clinical trials, requiring thoughtful consideration regarding how to handle the risks and benefits of continuing them. DESIGN: This brief report describes the experience of adapting the Building Research in Diet and Cognition (BRIDGE) study, a randomized clinical trial examining the effects of the Mediterranean diet, with and without weight loss, on cognitive functioning in 185 older obese African American adults during the COVID-19 pandemic. MEASUREMENT: The University of Illinois at Chicago (UIC) developed an expedited amendment process for research shifting to remote data collection. We conducted the study in three consecutive groups. For group 3, 14-month data collection period, we adapted our protocol to allow data collection via telephone and e-mail. We were unable to collect certain measures that required face-to-face contact. RESULTS: For measures that could be collected remotely, 14-month retention was similar for group 3 compared to groups 1 and 2: data were collected for 86.9% of group 3 (remote) and 87.9% of groups 1 and 2 (face to face), p = .84. CONCLUSIONS: In order to preserve the integrity of our clinical trial and ensure the safety of our participants and staff during the COVID-19 pandemic, we had to carefully and efficiently adapt our data collection procedures. The procedures put in place allowed us to collect our primary outcomes and the majority of our secondary outcomes and will enable us to examine the role of dietary intake, with and without weight loss, on cognitive functioning in a vulnerable and high-risk population. TRIAL REGISTRATION: ClinicalTrials.gov NCT3129048. Registration Date: 4/17/2017.

Latent Profile Analysis of Cognition in a Non-Demented Diverse Cohort: A Focus on Modifiable Cardiovascular and Lifestyle Factors.

BACKGROUND: Cognitively-defined subgroups are well-documented within neurodegeneration. OBJECTIVE: We examined such profiles in diverse non-demented older adults and considered how resulting subgroups relate to modifiable factors associated with neurodegeneration. METHODS: 121 non-demented (MMSE = 28.62) diverse (46%non-Latino Black, 40%non-Latino White, 15%Latino) community-dwelling adults (age = 67.7 years) completed cognitive, cardiovascular, physical activity, and diet evaluations. Latent profile analyses (LPA) employed six cognitive scores (letter fluency, letter-number sequencing, confrontational naming, 'animal' fluency, list-learning delayed recall, and recognition discriminability) to characterize cognitively-defined subgroups. Differences between resulting subgroups on cardiovascular (composite scores of overall health; specific health components including fasting blood levels) and lifestyle (sedentary behavior; moderate-to-vigorous physical activity; Mediterranean diet consumption) factors were examined using ANCOVAs adjusting for relevant confounders. RESULTS: Based on sample means across cognitive scores, LPA resulted in the following cognitive subgroups: 1) high-average cognition, 55%non-Latino White and 64%female participants; 2) average cognition, 58%non-Latino Black and 68%male participants; 3) lower memory, 58%non-Latino Black participants; and 4) lower executive functioning, 70%Latinos. The high-average subgroup reported significantly higher Mediterranean diet consumption than the average subgroup (p = 0.001). The lower executive functioning group had higher fasting glucose and hemoglobin A1c than all other subgroups (p-values<0.001). CONCLUSION: LPA revealed two average subgroups reflecting level differences in cognition previously reported between non-Latino White and Black adults, and two lower cognition subgroups in domains similar to those documented in neurodegeneration. These subgroups, and their differences, suggest the importance of considering social determinants of health in cognitive aging and modifiable risk.

Neighborhood Socioeconomic Resources and Crime-Related Psychosocial Hazards, Stroke Risk, and Cognition in Older Adults.

Living in neighborhoods with lower incomes, lower education/occupational levels, and/or higher crime increases one's risk of developing chronic health problems including cardiovascular disease risk factors and stroke. These cardiovascular health problems are known to contribute to cognitive decline and dementia. The purpose of this study was to determine the association of neighborhood socioeconomic resources and crime-related psychosocial hazards on stroke risk and cognition, hypothesizing that cardiovascular health would mediate any relationship between the neighborhood-level environment and cognition. The study evaluated 121 non-demented Chicago-area adults (~67 years; 40% non-Latino White) for cardiovascular health problems using the Framingham Stroke Risk Profile 10-year risk of stroke (FSRP-10). The cognitive domains that were tested included memory, executive functioning, and attention/information processing. Neighborhood socioeconomic resources were quantified at the census tract level (income, education, and occupation); crime-related psychosocial hazards were quantified at the point level. Structural equation modeling (SEM) did not show that the FSRP-10 mediated the relationship between neighborhood characteristics and domain-specific cognition. The SEM results did suggest that higher crime rates were associated with a higher FSRP-10 (ß(105) = 2.38, p = 0.03) and that higher FSRP-10 is associated with reduced attention/information processing performance (ß(105) = -0.04, p = 0.02) after accounting for neighborhood socioeconomic resources. Clinicians may wish to query not only individual but also neighborhood-level health when considering cognition.

Adapting to the impact of the COVID-19 pandemic on a randomized controlled trial examining lifestyle behaviors on cognitive functioning in obese African American adults: Building Research in Diet and Cognition (BRIDGE).

Background . The COVID-19 pandemic has significantly altered the research landscape for clinical trials, requiring thoughtful consideration regarding how to handle the risks and benefits of continuing them. Design . This brief report describes the experience of adapting the Building Research in Diet and Cognition (BRIDGE) study, a randomized clinical trial examining the effects of the Mediterranean Diet, with and without weight loss, on cognitive functioning in 185 older obese African American adults during the COVID-19 pandemic. Measurement . The University of Illinois at Chicago (UIC) developed an expedited amendment process for research shifting to remote data collection. For the Cohort 3, 14-month data collection period, we adapted our protocol to allow data collection via telephone and e-mail. We were unable to collect certain measures that required face-to face contact. Results . For measures that could be collected remotely, 14-month retention was similar for Cohort 3 and earlier cohorts: data were collected for 86.9% of cohort 3 (remote) and 87.9% of cohorts 1 and2 (face to face), p = .84. Conclusions . In order to preserve the integrity of our clinical trial and ensure the safety of our participants and staff during the COVID-19 pandemic, we had to carefully and efficiently adapt our data collection procedures. The procedures put in place allowed us to collect our primary outcomes and the majority of our secondary outcomes and will enable us to examine the role of dietary intake, with and without weight loss, on cognitive functioning in a vulnerable and high-risk population. ClinicalTrials.gov NCT03129048.

Inflammation, Cognition, and White Matter in Older Adults: An Examination by Race.

OBJECTIVES: Non-Latino Black adults have greater risk for Alzheimer's dementia compared to non-Latino White adults, possibly due to factors disproportionally affecting Black adults including cardiovascular disease (CVD). Chronic peripheral inflammation is implicated in both Alzheimer's dementia and CVD and is known to impact cognition and cerebral white matter, yet little work has examined these associations by race. This study examined associations between inflammation, cognition, and cerebral white matter generally, and by race. METHODS: Eighty-six non-demented older Black and White participants (age = 69.03; 50% female; 45% Black participants) underwent fasting venipuncture, cognitive testing, and MRI. Serum was assayed for interleukin-6 (IL-6), C-reactive protein (CRP), and interleukin 1-beta. Cognitive domains included memory, executive function, and attention/information processing. MRI measures included white matter hyperintensity volumes (WMH) and quantification of white matter integrity in areas outside WMHs via DTI-derived fractional anisotropy (FA) and mean diffusivity, as well as multi-component relaxometry derived myelin water fraction (MWF). RESULTS: Black and White participants did not differ on age, sex, or CVD risk. Separate linear regression models adjusting for relevant confounders revealed that higher IL-6 associated with lower executive function and higher CRP levels associated with lower FA and MWF. Stratified analyses revealed that these association were significant for Black participants only. DISCUSSION: These findings suggest that peripheral inflammation is inversely associated with select cognitive domains and white matter integrity (but not WMHs), particularly in older Black adults. It is important to consider race when investigating inflammatory associates of brain and behavior.

Common Brain Structural Alterations Associated with Cardiovascular Disease Risk Factors and Alzheimer's Dementia: Future Directions and Implications.

Recent reports suggest declines in the age-specific risk of Alzheimer's dementia in higher income Western countries. At the same time, investigators believe that worldwide trends of increasing mid-life modifiable risk factors [e.g., cardiovascular disease (CVD) risk factors] coupled with the growth of the world's oldest age groups may nonetheless lead to an increase in Alzheimer's dementia. Thus, understanding the overlap in neuroanatomical profiles associated with CVD risk factors and AD may offer more relevant targets for investigating ways to reduce the growing dementia epidemic than current targets specific to isolated AD-related neuropathology. We hypothesized that a core group of common brain structural alterations exist between CVD risk factors and Alzheimer's dementia. Two co-authors conducted independent literature reviews in PubMed using search terms for CVD risk factor burden (separate searches for 'cardiovascular disease risk factors', 'hypertension', and 'Type 2 diabetes') and 'aging' or 'Alzheimer's dementia' with either 'grey matter volumes' or 'white matter'. Of studies that reported regionally localized results, we found support for our hypothesis, determining 23 regions commonly associated with both CVD risk factors and Alzheimer's dementia. Within this context, we outline future directions for research as well as larger cerebrovascular implications for these commonalities. Overall, this review supports previous as well as more recent calls for the consideration that both vascular and neurodegenerative factors contribute to the pathogenesis of dementia.

Protocol of Aerobic Exercise and Cognitive Health (REACH): A Pilot Study.

A growing body of evidence supports that aerobic exercise can decrease the risk of future cognitive impairment and Alzheimer's disease (AD). There is a pressing need to rigorously determine whether cognitively normal yet at-risk individuals stand to benefit from the protective effects of exercise. The present study will test the feasibility of an aerobic exercise intervention in such a population and inform the design of a larger-scale randomized, controlled trial examining the effect of aerobic exercise on biomarkers of AD in late-middle-aged, at-risk individuals. This was a single-site, 1 : 1 block-randomized, parallel, two-arm trial. Cognitively normal participants aged 45-80 with documentation of familial and genetic AD risk factors were randomly assigned to one of two interventions. The Usual Physical Activity group was provided educational materials about exercise. The Enhanced Physical Activity intervention delivered 26 weeks of individualized and supervised aerobic exercise. Exercise duration and intensity were incrementally increased to 150 min/week and 70-80% of heart rate reserve, respectively. Retention and adherence were measured to assess study feasibility. In addition, pre- and post- intervention differences between the two arms were evaluated for cardiorespiratory fitness, physical activity, brain glucose metabolism, cerebral structure, vascular health, memory, executive function, and mood. Data from randomized controlled trials of exercise training are needed to identify the proper exercise prescription for reducing accumulation of AD biomarkers in cognitively normal individuals. The current trial will contribute to filling that gap while informing the design of large-scale trials.

Fitness, independent of physical activity is associated with cerebral blood flow in adults at risk for Alzheimer's disease.

Patterns of decreased resting cerebral blood flow (CBF) within the inferior temporal gyri, angular gyri, and posterior cingulate are a feature of aging and Alzheimer's disease (AD) and have shown to be predictive of cognitive decline among older adults. Fitness and physical activity are both associated with many indices of brain health and may positively influence CBF, however, the majority of research to date has examined these measures in isolation, leaving the potential independent associations unknown. The purpose of this study was to determine the unique contributions of fitness and physical activity when predicting CBF in cognitively healthy adults at risk for AD. One hundred participants (63% female) from the Wisconsin Registry for Alzheimer's Prevention underwent a maximal exercise test, physical activity monitoring, and a 3-D arterial spin labeling magnetic resonance imaging scan. For the entire sample, fitness was significantly associated with CBF while accounting for physical activity, age, gender, APOE ε4, family history of AD, education, and handedness (p = .026). Further, fitness explained significantly more variance than the combined effect of the covariates on CBF (R2 change = .059; p = .047). These results appear to be gender dependent, our data suggest fitness level, independent of physical activity, is associated with greater CBF in regions that are known to decline with age and AD for female (p = .011), but not male participants.

The oblique effect: The relationship between profiles of visuospatial preference, cognition, and brain connectomics in older adults.

The oblique effect (OE) describes the visuospatial advantage for identifying stimuli oriented horizontally or vertically rather than diagonally; little is known about brain aging and the OE. We investigated this relationship using the Judgment of Line Orientation (JLO) in 107 older adults (∼age = 67.8 ± 6.6; 51% female) together with neuropsychological tests of executive functioning (EF), attention/information processing (AIP), and neuroimaging. Only JLO lines falling between 36-54° or 126-144° were considered oblique. To quantify the oblique effect, we calculated z-scores for oblique errors (zOblique = #oblique errors/#oblique lines), and similarly, horizontal + vertical line errors (zHV), and a composite measure of oblique relative to HV errors (zOE). Composite z-scores of EF and AIP reflected domains associated with JLO performance. Graph theory analysis integrated T1-derived volumetry and diffusion MRI-derived white matter tractography into connectivity matrices analyzed for select network properties. Participants produced more zOblique than zHV errors (p < 0.001). Age was not associated with zOE adjusting for sex, education, and MMSE. Similarly adjusted linear regression models revealed that lower EF was associated with a larger oblique effect (p < 0.001). Modular analyses of neural connectivity revealed a differential patterns of network affiliation that varied by high versus low group status determined via median split of zOblique and zHV errors, separately. Older adults exhibit the oblique effect and it is associated with specific cognitive processes and regional brain networks that may facilitate future investigations of visuospatial preference in aging.

Cardiovascular disease risk factors, tract-based structural connectomics, and cognition in older adults.

Cardiovascular disease risk factors (CVD-RFs) are associated with decreased gray and white matter integrity and cognitive impairment in older adults. Less is known regarding the interplay between CVD-RFs, brain structural connectome integrity, and cognition. We examined whether CVD-RFs were associated with measures of tract-based structural connectivity in 94 non-demented/non-depressed older adults and if alterations in connectivity mediated associations between CVD-RFs and cognition. Participants (age = 68.2 years; 52.1% female; 46.8% Black) underwent CVD-RF assessment, MRI, and cognitive evaluation. Framingham 10-year stroke risk (FSRP-10) quantified CVD-RFs. Graph theory analysis integrated T1-derived gray matter regions of interest (ROIs; 23 a-priori ROIs associated with CVD-RFs and dementia), and diffusion MRI-derived white matter tractography into connectivity matrices analyzed for local efficiency and nodal strength. A principal component analysis resulted in three rotated factor scores reflecting executive function (EF; FAS, Trail Making Test (TMT) B-A, Letter-Number Sequencing, Matrix Reasoning); attention/information processing (AIP; TMT-A, TMT-Motor, Digit Symbol); and memory (CVLT-II Trials 1-5 Total, Delayed Free Recall, Recognition Discriminability). Linear regressions between FSRP-10 and connectome ROIs adjusting for word reading, intracranial volume, and white matter hyperintensities revealed negative associations with nodal strength in eight ROIs (p-values<.05) and negative associations with efficiency in two ROIs, and a positive association in one ROI (p-values<.05). There was mediation of bilateral hippocampal strength on FSRP-10 and AIP, and left rostral middle frontal gyrus strength on FSRP-10 and AIP and EF. Stroke risk plays differential roles in connectivity and cognition, suggesting the importance of multi-modal neuroimaging biomarkers in understanding age-related CVD-RF burden and brain-behavior.

Sedentary Time and White Matter Hyperintensity Volume in Older Adults.

PURPOSE: Cerebrovascular disease in the form of white matter hyperintensities (WMH) increases with age and is associated separately with sedentary time and reduced kidney function. A better understanding of the relationships among these variables would help clarify whether sedentary time should be considered more closely in older adults at particular levels of kidney function to reduce the risk of WMH. METHODS: We analyzed information from 94 healthy community-dwelling older adults to determine the association of sedentary time and WMH in nondemented, nondepressed older adults, and whether level of kidney function was an effect modifier of the relationship between sedentary time and WMH. Sedentary behavior was measured using the Sedentary Behavior Questionnaire. White matter hyperintensity was assessed using whole-brain 3T magnetic resonance imaging T1- and T2-weighted images. Kidney function was calculated by the epi-chronic kidney disease formula for estimated glomerular filtration rate (eGFR). Exposures or predictors were sedentary time, age, sex, education in years, Framingham stroke risk 10-yr prediction score, and eGFR. The analytical approach was multiple linear regression. RESULTS: Adjusting for age, sex, education in years, Framingham stroke risk 10-yr prediction score, greater sedentary time was associated with greater WMH but this effect was dependent on level of eGFR (sedentary time-eGFR interaction b = -0.0005, P = 0.022). At eGFR values of 69, 81, and 93 mL·min per 1.73 m (the 25th, 50th, and 75th percentiles), sedentary time b coefficients were b = 0.021 (95% confidence interval [CI], 0.011-0.031), b = 0.015 (95% CI, 0.008-0.022), and b = 0.009 (95% CI, 0.003-0.016). The effect weakened linearly as eGFR increased, with no significant association at eGFR ≥97 mL·min per 1.73 m. CONCLUSIONS: Findings suggest that sedentary time is associated with WMH in persons with an eGFR ≤96 mL·min per 1.73 m and that this association is stronger with lower levels of kidney function.

Brain Glucose Metabolism, Cognition, and Cardiorespiratory Fitness Following Exercise Training in Adults at Risk for Alzheimer's Disease.

Aerobic exercise has been associated with reduced burden of brain and cognitive changes related to Alzheimer's disease (AD). However, it is unknown whether exercise training in asymptomatic individuals harboring risk for AD improves outcomes associated with AD. We investigated the effect of 26 weeks of supervised aerobic treadmill exercise training on brain glucose metabolism and cognition among 23 late-middle-aged adults from a cohort enriched with familial and genetic risk of AD. They were randomized to Usual Physical Activity (PA) or Enhanced PA conditions. Usual PA received instruction about maintaining an active lifestyle. Enhanced PA completed a progressive exercise training program consisting of 3 sessions of treadmill walking per week for 26 weeks. By week seven, participants exercised at 70- 80% heart rate reserve for 50 minutes per session to achieve 150 minutes of moderate intensity activity per week in accordance with public health guidelines. Before and after the intervention, participants completed a graded treadmill test to assess VO2peak as a measure of cardiorespiratory fitness (CRF), wore an accelerometer to measure free-living PA, underwent 18F-fluorodeoxyglucose positron emission tomography imaging to assess brain glucose metabolism, and a neuropsychological battery to assess episodic memory and executive function. VO2peak increased, sedentary behavior decreased, and moderate-to-vigorous PA increased significantly in the Enhanced PA group as compared to Usual PA. Glucose metabolism in the posterior cingulate cortex (PCC) did not change significantly in Enhanced PA relative to Usual PA. However, change in PCC glucose metabolism correlated positively with change in VO2peak. Executive function, but not episodic memory, was significantly improved after Enhanced PA relative to Usual PA. Improvement in executive function correlated with increased VO2peak. Favorable CRF adaptation after 26 weeks of aerobic exercise training was associated with improvements in PCC glucose metabolism and executive function, important markers of AD.

Cardiorespiratory fitness attenuates age-associated aggregation of white matter hyperintensities in an at-risk cohort.

BACKGROUND: Age is the cardinal risk factor for Alzheimer's disease (AD), and white matter hyperintensities (WMH), which are more prevalent with increasing age, may contribute to AD. Higher cardiorespiratory fitness (CRF) has been shown to be associated with cognitive health and decreased burden of AD-related brain alterations in older adults. Accordingly, the aim of this study was to determine whether CRF attenuates age-related accumulation of WMH in middle-aged adults at risk for AD. METHODS: One hundred and seven cognitively unimpaired, late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention underwent 3 T magnetic resonance imaging and performed graded maximal treadmill exercise testing from which we calculated the oxygen uptake efficiency slope (OUES) as our measure of CRF. Total WMH were quantified using the Lesion Segmentation Tool and scaled to intracranial volume. Linear regression adjusted for APOE4 carriage, family history, body mass index, systolic blood pressure, and sex was used to examine relationships between age, WMH, and CRF. RESULTS: As expected, there was a significant association between age and WMH (p < .001). Importantly, there was a significant interaction between age and OUES on WMH (p = .015). Simple main effects analyses revealed that the effect of age on WMH remained significant in the Low OUES group (p < .001) but not in the High OUES group (p = .540), indicating that higher CRF attenuates the deleterious age association with WMH. CONCLUSIONS: Higher CRF tempers the adverse effect of age on WMH. This suggests a potential pathway through which increased aerobic fitness facilitates healthy brain aging, especially among individuals at risk for AD.

BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention.

OBJECTIVE: To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether ß-amyloid (Aß) burden plays a moderating role in this relationship. METHODS: One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aß burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories. RESULTS: Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Aß burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aß burden showed even steeper cognitive decline (p = 0.033). CONCLUSIONS: In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aß burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics.

Moderate Physical Activity is Associated with Cerebral Glucose Metabolism in Adults at Risk for Alzheimer's Disease.

The objective of this study was to investigate the relationship between accelerometer-measured physical activity (PA) and glucose metabolism in asymptomatic late-middle-aged adults. Ninety-three cognitively healthy late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention participated in this cross-sectional study. They underwent 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and wore an accelerometer (ActiGraph GT3X+) to measure free-living PA. Accelerometer data yielded measures of light (LPA), moderate (MPA), and vigorous (VPA) intensity PA. FDG-PET images were scaled to the cerebellum and pons, and cerebral glucose metabolic rate was extracted from specific regions of interest (ROIs) known to be hypometabolic in AD, i.e., hippocampus, posterior cingulate, inferior temporal cortex, and angular gyrus. Regression analyses were utilized to examine the association between PA and glucose metabolism, while adjusting for potential confounds. There were associations between MPA and glucose metabolism in all ROIs examined. In contrast, LPA was not associated with glucose uptake in any ROI and VPA was only associated with hippocampal FDG uptake. Secondary analyses did not reveal associations between sedentary time and glucose metabolism in any of the ROIs. Exploratory voxel-wise analysis identified additional regions where MPA was significantly associated with glucose metabolism including the precuneus, supramarginal gyrus, amygdala, and middle frontal gyrus. These findings suggest that the intensity of PA is an important contributor to neuronal function in a late-middle-aged cohort, with MPA being the most salient. Prospective studies are necessary for fully elucidating the link between midlife engagement in PA and later life development of AD.

Relationships between cardiorespiratory fitness, hippocampal volume, and episodic memory in a population at risk for Alzheimer's disease.

INTRODUCTION: Cardiorespiratory fitness (CRF) has been shown to be related to brain health in older adults. In individuals at risk for developing Alzheimer's disease (AD), CRF may be a modifiable risk factor that could attenuate anticipated declines in brain volume and episodic memory. The objective of this study was to determine the association between CRF and both hippocampal volume and episodic memory in a cohort of cognitively healthy older adults with familial and/or genetic risk for Alzheimer's disease (AD). METHODS: Eighty-six enrollees from the Wisconsin Registry for Alzheimer's Prevention participated in this study. Participants performed a graded maximal exercise test, underwent a T-1 anatomical magnetic resonance imaging scan, and completed the Rey Auditory Verbal Learning Test (RAVLT). RESULTS: There were no significant relationships between CRF and HV or RAVLT memory scores for the entire sample. When the sample was explored on the basis of gender, CRF was significantly associated with hippocampal volume for women. For men, significant positive associations were observed between CRF and RAVLT memory scores. SUMMARY: These results suggest that CRF may be protective against both hippocampal volume and episodic memory decline in older adults at risk for AD, but that the relationships may be gender specific.

Cardiorespiratory fitness alters the influence of a polygenic risk score on biomarkers of AD.

OBJECTIVE: To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers. METHODS: Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. ß-Amyloid 42 (Aß42), Aß40, total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and Aß42/Aß40 and tau/Aß42 ratios were computed. CRF was estimated from a validated equation incorporating sex, age, body mass index, resting heart rate, and self-reported physical activity. Covariate-adjusted regression analyses were used to test for associations between the PRS and CSF biomarkers. In addition, by including a PRS×CRF term in the models, we examined whether these associations were modified by CRF. RESULTS: A higher PRS was associated with lower Aß42/Aß40 (p < 0.001), higher t-tau/Aß42 (p = 0.012), and higher p-tau/Aß42 (p = 0.040). Furthermore, we observed PRS × CRF interactions for Aß42/Aß40 (p = 0.003), t-tau/Aß42 (p = 0.003), and p-tau/Aß42 (p = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF. CONCLUSIONS: In a late-middle-aged cohort, CRF attenuates the adverse influence of genetic vulnerability on CSF biomarkers. These findings support the notion that increased cardiorespiratory fitness may be beneficial to those at increased genetic risk for AD.