Alzheimer's disease biomarker burden in primary motor cortices is associated with poorer dexterity performance.

INTRODUCTION: Motor function has correlated with longevity and functionality; however, there is limited research on those with Alzheimer's disease (AD). We studied the association between motor functionality and AD pathology in primary motor and medial temporal cortices. METHODS: A total of 206 participants with a clinical diagnosis of cognitively healthy, AD, or mild cognitive impairment (MCI) underwent imaging and motor assessment. Linear regressions and analyses of variance were applied to test the prediction from AD imaging biomarkers to motor performance and the diagnosis group differences in motor performance. RESULTS: Increased neurodegeneration was associated with worsening dexterity and lower walking speed, and increased amyloid and tau were associated with worsening dexterity. AD and MCI participants had lower motor performance than the cognitively healthy participants. DISCUSSION: Increased AD pathology is associated with worsening dexterity performance. The decline in dexterity in those with AD pathology may offer an opportunity for non-pharmacological therapy intervention. HIGHLIGHTS: Noted worsening dexterity performance was associated with greater Alzheimer's disease (AD) pathology (tau, amyloid beta, and neurodegeneration) in primary motor cortices. Similarly, increased neurodegeneration and tau pathology in parahippocampal, hippocampal, and entorhinal cortices is associated with worsening dexterity performance. Motor performance declined in those with clinical and preclinical AD among an array of motor assessments.

Longitudinal white matter microstructural change in Parkinson's disease.

Postmortem studies of Parkinson's disease (PD) suggest that Lewy body pathology accumulates in a predictable topographical sequence, beginning in the olfactory bulb, followed by caudal brainstem, substantia nigra, limbic cortex, and neocortex. Diffusion-weighted imaging (DWI) is sensitive, if not specific, to early disease-related white matter (WM) change in a variety of traumatic and degenerative brain diseases. Although numerous cross-sectional studies have reported DWI differences in cerebral WM in PD, only a few longitudinal studies have investigated whether DWI change exceeds that of normal aging or coincides with regional Lewy body accumulation. This study mapped regional differences in the rate of DWI-based microstructural change between 29 PD patients and 43 age-matched controls over 18 months. Iterative within- and between-subject tensor-based registration was completed on motion- and eddy current-corrected DWI images, then baseline versus follow-up difference maps of fractional anisotropy, mean, radial, and axial diffusivity were analyzed in the Biological Parametric Mapping toolbox for MATLAB. This analysis showed that PD patients had a greater decline in WM integrity in the rostral brainstem, caudal subcortical WM, and cerebellar peduncles, compared with controls. In addition, patients with unilateral clinical signs at baseline experienced a greater rate of WM change over the 18-month study than patients with bilateral signs. These findings suggest that rate of WM microstructural change in PD exceeds that of normal aging and is maximal during early stage disease. In addition, the neuroanatomic locations (rostral brainstem and subcortical WM) of accelerated WM change fit with current theories of topographic disease progression.

Family history and TOMM40 '523 interactive associations with memory in middle-aged and Alzheimer's disease cohorts.

INTRODUCTION: Family history (FH) of Alzheimer's disease (AD) affects mitochondrial function and may modulate effects of translocase of the outer mitochondrial membrane 40 kDa (TOMM40) rs10524523 ('523) poly-T length on memory decline. METHODS: For 912 nonapolipoprotein ε4 middle-aged adults and 365 aged adults across the AD spectrum, linear mixed models gauged FH and TOMM40 '523 interactions on memory and global cognition between baseline and up to 10 years later. A cerebrospinal fluid mitochondrial function biomarker was also assessed. RESULTS: For FH negative participants, gene-dose preservation of memory and global cognition was seen for "very long" versus "short" carriers. For FH positive, an opposite gene-dose decline was seen for very long versus short carriers. Maternal FH was a stronger predictor in aged, but not middle-aged, participants. Similar gene-dose effects were seen for the mitochondrial biomarker aspartate aminotransferase. DISCUSSION: These results may clarify conflicting findings on TOMM40 poly-T length and AD-related decline.

Fornix Microstructure and Memory Performance Is Associated with Altered Neural Connectivity during Episodic Recognition.

OBJECTIVES: The purpose of this study was to assess whether age-related differences in white matter microstructure are associated with altered task-related connectivity during episodic recognition. METHODS: Using functional magnetic resonance imaging and diffusion tensor imaging from 282 cognitively healthy middle-to-late aged adults enrolled in the Wisconsin Registry for Alzheimer's Prevention, we investigated whether fractional anisotropy (FA) within white matter regions known to decline with age was associated with task-related connectivity within the recognition network. RESULTS: There was a positive relationship between fornix FA and memory performance, both of which negatively correlated with age. Psychophysiological interaction analyses revealed that higher fornix FA was associated with increased task-related connectivity amongst the hippocampus, caudate, precuneus, middle occipital gyrus, and middle frontal gyrus. In addition, better task performance was associated with increased task-related connectivity between the posterior cingulate gyrus, middle frontal gyrus, cuneus, and hippocampus. CONCLUSIONS: The findings indicate that age has a negative effect on white matter microstructure, which in turn has a negative impact on memory performance. However, fornix microstructure did not significantly mediate the effect of age on performance. Of interest, dynamic functional connectivity was associated with better memory performance. The results of the psychophysiological interaction analysis further revealed that alterations in fornix microstructure explain-at least in part-connectivity among cortical regions in the recognition memory network. Our results may further elucidate the relationship between structural connectivity, neural function, and cognition.

Beta-amyloid and cognitive decline in late middle age: Findings from the Wisconsin Registry for Alzheimer's Prevention study.

INTRODUCTION: The present study investigated the relationship between beta-amyloid (Aß) and cognition in a late middle-aged cohort at risk for Alzheimer's disease (AD). METHODS: One eighty-four participants (mean age = 60; 72% parental history of AD) completed a [C-11]Pittsburgh compound B positron emission tomography scan and serial cognitive evaluations. A global measure of Aß burden was calculated, and composite scores assessing learning, delayed memory, and executive functioning were computed. RESULTS: Higher Aß was associated with classification of psychometric mild cognitive impairment (MCI) at follow-up (P < .01). Linear mixed effects regression results indicated higher Aß was associated with greater rates of decline in delayed memory (P < .01) and executive functioning (P < .05). Apolipoprotein E (APOE) ε4 status moderated the relationship between Aß and cognitive trajectories (P values <.01). DISCUSSION: In individuals at risk for AD, greater Aß in late middle age is associated with increased likelihood of MCI at follow-up and steeper rates of cognitive decline.

Cardiorespiratory Fitness Attenuates the Influence of Amyloid on Cognition.

The aim of this study was to examine cross-sectionally whether higher cardiorespiratory fitness (CRF) might favorably modify amyloid-ß (Aß)-related decrements in cognition in a cohort of late-middle-aged adults at risk for Alzheimer's disease (AD). Sixty-nine enrollees in the Wisconsin Registry for Alzheimer's Prevention participated in this study. They completed a comprehensive neuropsychological exam, underwent 11C Pittsburgh Compound B (PiB)-PET imaging, and performed a graded treadmill exercise test to volitional exhaustion. Peak oxygen consumption (VO2peak) during the exercise test was used as the index of CRF. Forty-five participants also underwent lumbar puncture for collection of cerebrospinal fluid (CSF) samples, from which Aß42 was immunoassayed. Covariate-adjusted regression analyses were used to test whether the association between Aß and cognition was modified by CRF. There were significant VO2peak*PiB-PET interactions for Immediate Memory (p=.041) and Verbal Learning & Memory (p=.025). There were also significant VO2peak*CSF Aß42 interactions for Immediate Memory (p<.001) and Verbal Learning & Memory (p<.001). Specifically, in the context of high Aß burden, that is, increased PiB-PET binding or reduced CSF Aß42, individuals with higher CRF exhibited significantly better cognition compared with individuals with lower CRF. In a late-middle-aged, at-risk cohort, higher CRF is associated with a diminution of Aß-related effects on cognition. These findings suggest that exercise might play an important role in the prevention of AD.

Cerebral blood flow is diminished in asymptomatic middle-aged adults with maternal history of Alzheimer's disease.

Cerebral blood flow (CBF) provides an indication of the metabolic status of the cortex and may have utility in elucidating preclinical brain changes in persons at risk for Alzheimer's disease (AD) and related diseases. In this study, we investigated CBF in 327 well-characterized adults including patients with AD (n = 28), patients with amnestic mild cognitive impairment (aMCI, n = 23), older cognitively normal (OCN, n = 24) adults, and asymptomatic middle-aged adults (n = 252) with and without a family history (FH) of AD. Compared with the asymptomatic cohort, AD patients displayed significant hypoperfusion in the precuneus, posterior cingulate, lateral parietal cortex, and the hippocampal region. Patients with aMCI exhibited a similar but less marked pattern of hypoperfusion. Perfusion deficits within the OCN adults were primarily localized to the inferior parietal lobules. Asymptomatic participants with a maternal FH of AD showed hypoperfusion in hippocampal and parietofrontal regions compared with those without a FH of AD or those with only a paternal FH of AD. These observations persisted when gray matter volume was included as a voxel-wise covariate. Our findings suggest that having a mother with AD might confer a particular risk for AD-related cerebral hypoperfusion in midlife. In addition, they provide further support for the potential utility of arterial spin labeling for the measurement of AD-related neurometabolic dysfunction, particularly in situations where [18F]fluorodeoxyglucose imaging is infeasible or clinically contraindicated.

Amyloid burden, neuronal function, and cognitive decline in middle-aged adults at risk for Alzheimer's disease.

The relative influence of amyloid burden, neuronal structure and function, and prior cognitive performance on prospective memory decline among asymptomatic late middle-aged individuals at risk for Alzheimer's disease (AD) is currently unknown. We investigated this using longitudinal cognitive data from 122 middle-aged adults (21 "Decliners" and 101 "Stables") enrolled in the Wisconsin Registry for Alzheimer's Prevention who underwent multimodality neuroimaging [11C-Pittsburgh Compound B (PiB), 18F-fluorodeoxyglucose (FDG), and structural/functional magnetic resonance imaging (fMRI)] 5.7 ± 1.4 years (range = 2.9-8.9) after their baseline cognitive assessment. Covariate-adjusted regression analyses revealed that the only imaging measure that significantly distinguished Decliners from Stables (p = .027) was a Neuronal Function composite derived from FDG and fMRI. In contrast, several cognitive measures, especially those that tap episodic memory, significantly distinguished the groups (p's<.05). Complementary receiver operating characteristic curve analyses identified the Brief Visuospatial Memory Test-Revised (BVMT-R) Total (.82 ± .05, p < .001), the BVMT-R Delayed Recall (.73 ± .06, p = .001), and the Reading subtest from the Wide-Range Achievement Test-III (.72 ± .06, p = .002) as the top three measures that best discriminated the groups. These findings suggest that early memory test performance might serve a more clinically pivotal role in forecasting future cognitive course than is currently presumed.

Cardiorespiratory fitness and cognition in persons at risk for Alzheimer's disease.

Introduction: This study examined the relationship between cardiorespiratory fitness (CRF) and longitudinal cognitive functioning in a cohort enriched with risk factors for Alzheimer's disease (AD). Methods: A total of 155 enrollees in the Wisconsin Registry for Alzheimer's Prevention completed repeat comprehensive neuropsychological evaluations that assessed six cognitive domains. Peak oxygen consumption (VO2peak) was the primary measure of CRF. Random effects regression was used to investigate the effect of CRF on cognitive trajectories. Results: Higher CRF was associated with slower decline in the cognitive domains of verbal learning and memory (P < .01) and visual learning and memory (P < .042). Secondary analyses indicated that these effects were stronger among men than women, and for noncarriers of the apolipoprotein E ε4 allele. Discussion: Higher CRF was associated with a slower rate of the decline in episodic memory that occurs as a natural consequence of aging in a cohort enriched with risk factors for AD.

Age-related differences in white matter microstructure measured by advanced diffusion MRI in healthy older adults at risk for Alzheimer's disease.

Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion imaging technique, which can detect more distinct microstructural features compared to conventional Diffusion Tensor Imaging (DTI). NODDI allows the signal to be divided into multiple water compartments and derive measures for orientation dispersion index (ODI), neurite density index (NDI) and volume fraction of isotropic diffusion compartment (FISO). This study aimed to investigate which diffusion metric-fractional anisotropy (FA), mean diffusivity (MD), NDI, ODI, or FISO-is most influenced by aging and reflects cognitive function in a population of healthy older adults at risk for Alzheimer's disease (AD). Age was significantly associated with all but one diffusion parameters and regions of interest. NDI and MD in the cingulate region adjacent to the cingulate cortex showed a significant association with a composite measure of Executive Function and was proven to partially mediate the relationship between aging and Executive Function decline. These results suggest that both DTI and NODDI parameters are sensitive to age-related differences in white matter regions vulnerable to aging, particularly among older adults at risk for AD.

The relationship of glucose-stimulated insulin secretion to cerebral glucose metabolism and cognition in healthy middle-aged and older adults.

Insulin resistance (IR) has been related to reduced cerebral glucose metabolism in regions identified as hypometabolic in Alzheimer's clinical syndrome. Insulin secretion (IS) has been less studied than IR despite findings that decreased IS is an early indicator of future type 2 diabetes and a potential predictor of Alzheimer's clinical syndrome. We investigated whether higher IR and lower IS would be associated with greater age-related reductions in regional cerebral glucose metabolism and worse cognitive performance. Two-hour oral glucose tolerance testing and 18F-fluorodeoxyglucose positron emission tomography were performed on 1-2 occasions on a sample of healthy middle-aged and older adults from the Wisconsin Alzheimer's Disease Research Center. Neuropsychological tests were completed during Alzheimer's Disease Research Center Clinical Core visits. Pattern of findings suggested that lower (not higher) IS was related to higher regional cerebral glucose metabolism in middle aged but not older adults, and lower (not higher) IS was also related to better immediate recall. In the context of healthy insulin sensitivity, lower IS may be beneficial to brain health.

Impact of sex and APOE ε4 on age-related cerebral perfusion trajectories in cognitively asymptomatic middle-aged and older adults: A longitudinal study.

Cerebral hypoperfusion is thought to contribute to cognitive decline in Alzheimer's disease, but the natural trajectory of cerebral perfusion in cognitively healthy adults has not been well-studied. This longitudinal study is consisted of 950 participants (40-89 years), who were cognitively unimpaired at their first visit. We investigated the age-related changes in cerebral perfusion, and their associations with APOE-genotype, biological sex, and cardiometabolic measurements. During the follow-up period (range 0.13-8.24 years), increasing age was significantly associated with decreasing cerebral perfusion, in total gray-matter (ß=-1.43), hippocampus (-1.25), superior frontal gyrus (-1.70), middle frontal gyrus (-1.99), posterior cingulate (-2.46), and precuneus (-2.14), with all P-values < 0.01. Compared with male-ɛ4 carriers, female-ɛ4 carriers showed a faster decline in global and regional cerebral perfusion with increasing age, whereas the age-related decline in cerebral perfusion was similar between male- and female-ɛ4 non-carriers. Worse cardiometabolic profile (i.e., increased blood pressure, body mass index, total cholesterol, and blood glucose) was associated with lower cerebral perfusion at all the visits. When time-varying cardiometabolic measurements were adjusted in the model, the synergistic effect of sex and APOE-ɛ4 on age-related cerebral perfusion-trajectories became largely attenuated. Our findings demonstrate that APOE-genotype and sex interactively impact cerebral perfusion-trajectories in mid- to late-life. This effect may be partially explained by cardiometabolic alterations.

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.

Cross-sectional and longitudinal associations between total and regional white matter hyperintensity volume and cognitive and motor function in Parkinson's disease.

BACKGROUND: White matter hyperintensities (WMH) are frequently observed on T2-weighted brain magnetic resonance imaging studies of healthy older adults and have been linked with impairments in balance, gait, and cognition. Nonetheless, few studies have investigated the longitudinal effects of comorbid WMH on cognition and motor function in Parkinson's disease. METHODS: The Lesion Segmentation Tool for Statistical Parametric Mapping was used to obtain total lesion volume and map regional WMH probabilities in 29 PD and 42 control participants at two study visits 18 months apart. Both cross-sectional and longitudinal comparisons were made between composite scores in the domains of executive function, memory, and language, and Unified Parkinson's Disease Rating Scale (UPDRS) scores. RESULTS: We found no difference between disease and control groups in total WMH volume or progression during the study. Greater regional and global WMH at baseline was more strongly associated with lower executive function in PD subjects than in controls. Increased regional WMH was also more strongly associated with impaired memory performance in PD relative to controls. Longitudinally, no associations between cognitive change and total or regional WMH progression were detected in either group. A positive relationship between baseline regional WMH and total UPDRS scores was present in the control group, but not PD. However, greater WMH increase was associated with a greater increase in UPDRS motor sub-scores in PD. CONCLUSIONS: These findings suggest that although PD patients do not experience greater mean WMH load than normal aged adults, comorbid WMH do exacerbate cognitive and motor symptoms in PD.

KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD.

OBJECTIVE: To examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated ß-amyloid (Aß) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. METHODS: Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on Aß burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on Aß was different among KL-VS heterozygotes compared to noncarriers. RESULTS: APOE4 carriers exhibited greater Aß burden than APOE4-negative participants. This effect was stronger in CSF (t = -5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on Aß load was recapitulated among KL-VS noncarriers (CSF: t = -5.09, p < 0.001; PiB-PET: t = 3.77, p < 0 .001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher Aß burden than APOE4-negative individuals (CSF: t = -1.03, p = 0.308; PiB-PET: t = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex. CONCLUSION: In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated Aß aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in 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.

Evaluation of striatonigral connectivity using probabilistic tractography in Parkinson's disease.

The cardinal movement abnormalities of Parkinson's disease (PD), including tremor, muscle rigidity, and reduced speed and frequency of movements, are caused by degeneration of dopaminergic neurons in the substantia nigra that project to the putamen, compromising information flow through frontal-subcortical circuits. Typically, the nigrostriatal pathway is more severely affected on the side of the brain opposite (contralateral) to the side of the body that manifests initial symptoms. Several studies have suggested that PD is also associated with changes in white matter microstructural integrity. The goal of the present study was to further develop methods for measuring striatonigral connectivity differences between PD patients and age-matched controls using diffusion weighted magnetic resonance imaging (MRI). In this cross-sectional study, 40 PD patients and 44 controls underwent diffusion weighted imaging (DWI) using a 40-direction MRI sequence as well as an optimized 60-direction sequence with overlapping slices. Regions of interest (ROIs) encompassing the putamen and substantia nigra were hand drawn in the space of the 40-direction data using high-contrast structural images and then coregistered to the 60-direction data. Probabilistic tractography was performed in the native space of each dataset by seeding the putamen ROI with an ipsilateral substantia nigra classification target. The effect of disease group (PD versus control) on mean putamen-SN connection probability and streamline density were then analyzed using generalized linear models controlling for age, gender, education, as well as seed and target region characteristics. Mean putamen-SN streamline density was lower in PD on both sides of the brain and in both 40- and 60-direction data. The optimized sequence provided a greater separation between PD and control means; however, individual values overlapped between groups. The 60-direction data also yielded mean connection probability values either trending (ipsilateral) or significantly (contralateral) lower in the PD group. There were minor between-group differences in average diffusion measures within the substantia nigra ROIs that did not affect the results of the GLM analyses when included as covariates. Based on these results, we conclude that mean striatonigral structural connectivity differs between PD and control groups and that use of an optimized 60-direction DWI sequence with overlapping slices increases the sensitivity of the technique to putative disease-related differences. However, overlap in individual values between disease groups limits its use as a classifier.

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.

Insulin resistance is associated with lower arterial blood flow and reduced cortical perfusion in cognitively asymptomatic middle-aged adults.

Insulin resistance (IR) is associated with poor cerebrovascular health and increased risk for dementia. Little is known about the unique effect of IR on both micro- and macrovascular flow particularly in midlife when interventions against dementia may be most effective. We examined the effect of IR as indexed by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) on cerebral blood flow in macro- and microvessels utilizing magnetic resonance imaging (MRI) among cognitively asymptomatic middle-aged individuals. We hypothesized that higher HOMA-IR would be associated with reduced flow in macrovessels and lower cortical perfusion. One hundred and twenty cognitively asymptomatic middle-aged adults (57 ± 5 yrs) underwent fasting blood draw, phase contrast-vastly undersampled isotropic projection reconstruction (PC VIPR) MRI, and arterial spin labeling (ASL) perfusion. Higher HOMA-IR was associated with lower arterial blood flow, particularly within the internal carotid arteries (ICAs), and lower cerebral perfusion in several brain regions including frontal and temporal lobe regions. Higher blood flow in bilateral ICAs predicted greater cortical perfusion in individuals with lower HOMA-IR, a relationship not observed among those with higher HOMA-IR. Findings provide novel evidence for an uncoupling of macrovascular blood flow and microvascular perfusion among individuals with higher IR in midlife.

Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-ß Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer's Disease.

Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer's disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer's Project's meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-ß (Aß) deposition and neurodegeneration: Aß clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aß deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid Aß deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.