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Background: Social support may be a modifiable risk factor for cognitive impairment. However, few long-term, large prospective studies have examined associations of various forms of social support with incident mild cognitive impairment (MCI) and dementia. Objective: To examine associations of perceived social support with incident MCI and dementia among community-dwelling older women. Methods: This prospective cohort study included 6,670 women from the Women’s Health Initiative Memory Study who were cognitively unimpaired at enrollment. We used Cox proportional hazards models to assess associations between perceived social support with incident MCI, dementia, or either MCI/dementia during an average 10.7 (SD = 6.1)-year follow-up. Modelling was repeated for emotional/information support, affection support, tangible support, and positive social interaction subscales of social support. Results: Among 6,670 women (average age = 70 years [SD = 3.8]; 97.0% non-Hispanic/Latina; 89.8% White), greater perceived social support was associated with lower risk of MCI/dementia after adjustment for age, ethnicity, race, hormone therapy, education, income, diabetes, hypertension, and body mass index (Tertile [T]3 versus T1: HR = 0.85, 95% CI 0.74–0.99; ptrend = 0.08). Associations were significant for emotional/information support (T3 versus T1: HR = 0.84, 95% CI 0.72–0.97; ptrend = 0.04) and positive social interaction (T3 versus T1: HR = 0.85, 95% CI 0.73–0.99; ptrend = 0.06) subscales. Associations were attenuated and not significant after adjustment for depressive symptom severity. Objective: Perceived social support, emotional/information support, and positive social interaction were associated with incident MCI/dementia among older women. Results were not significant after adjustment for depressive symptom severity. Improving social support may reduce risk of MCI and dementia in older women.

Objective:To determine associations of alcohol use with cognitive aging among middle-aged men.Method:1,608 male twins (mean 57 years at baseline) participated in up to three visits over 12 years, from 2003–2007 to 2016–2019. Participants were classified into six groups based on current and past self-reported alcohol use: lifetime abstainers, former drinkers, very light (1–4 drinks in past 14 days), light (5–14 drinks), moderate (15–28 drinks), and at-risk drinkers (>28 drinks in past 14 days). Linear mixed-effects regressions modeled cognitive trajectories by alcohol group, with time-based models evaluating rate of decline as a function of baseline alcohol use, and age-based models evaluating age-related differences in performance by current alcohol use. Analyses used standardized cognitive domain factor scores and adjusted for sociodemographic and health-related factors.Results:Performance decreased over time in all domains. Relative to very light drinkers, former drinkers showed worse verbal fluency performance, by –0.21 SD (95% CI –0.35, –0.07), and at-risk drinkers showed faster working memory decline, by 0.14 SD (95% CI 0.02, –0.20) per decade. There was no evidence of protective associations of light/moderate drinking on rate of decline. In age-based models, light drinkers displayed better memory performance at advanced ages than very light drinkers (+0.14 SD; 95% CI 0.02, 0.20 per 10-years older age); likely attributable to residual confounding or reverse association.Conclusions:Alcohol consumption showed minimal associations with cognitive aging among middle-aged men. Stronger associations of alcohol with cognitive aging may become apparent at older ages, when cognitive abilities decline more rapidly.

Because longitudinal studies of aging typically lack cognitive data from earlier ages, it is unclear how general cognitive ability (GCA) changes throughout the life course. In 1173 Vietnam Era Twin Study of Aging (VETSA) participants, we assessed young adult GCA at average age 20 and current GCA at 3 VETSA assessments beginning at average age 56. The same GCA index was used throughout. Higher young adult GCA and better GCA maintenance were associated with stronger specific cognitive abilities from age 51 to 73. Given equivalent GCA at age 56, individuals who had higher age 20 GCA outperformed those whose GCA remained stable in terms of memory, executive function, and working memory abilities from age 51 to 73. Thus, paradoxically, despite poorer maintenance of GCA, high young adult GCA still conferred benefits. Advanced predicted brain age and the combination of elevated vascular burden and APOE-ε4 status were associated with poorer maintenance of GCA. These findings highlight the importance of distinguishing between peak and current GCA for greater understanding of cognitive aging.

OBJECTIVES To examine associations between alcohol use and cognitive performance among older adults in Greece and the United States, and assess potential differences due to differing drinking practices in the two countries. METHODS Data came from Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) and National Alzheimer's Coordinating Center Uniform Dataset (NACC). We examined those aged 65-90 years at baseline who had no cognitive impairment and complete data for cognitive and alcohol use variables (N = 1110 from HELIAD; N = 2455 from NACC). We examined associations between current alcohol use and frequency of such use with cognitive performance on various cognitive tasks stratified by gender. RESULTS In NACC, use of alcohol was associated with better cognitive performance. Men drinkers performed better than non-drinkers on Trail A (standardized mean 0.07 vs. -0.24, p

Background and aims Smoking is associated with increased risk for brain aging/atrophy and dementia. Few studies have examined early associations with brain aging. This study aimed to measure whether adult men with a history of heavier smoking in early mid-life would have older than predicted brain age 16-28 years later. Design Prospective cohort observational study, utilizing smoking pack years data from average age 40 (early mid-life) predicting predicted brain age difference scores (PBAD) at average ages 56, 62 (later mid-life) and 68 years (early old age). Early mid-life alcohol use was also evaluated. Setting Population-based United States sample. Participants/cases Participants were male twins of predominantly European ancestry who served in the United States military between 1965 and 1975. Structural magnetic resonance imaging (MRI) began at average age 56. Subsequent study waves included most baseline participants; attrition replacement subjects were added at later waves. Measurements Self-reported smoking information was used to calculate pack years smoked at ages 40, 56, 62, and 68. MRIs were processed with the Brain-Age Regression Analysis and Computation Utility software (BARACUS) program to create PBAD scores (chronological age-predicted brain age) acquired at average ages 56 (n = 493; 2002-08), 62 (n = 408; 2009-14) and 68 (n = 499; 2016-19). Findings In structural equation modeling, age 40 pack years predicted more advanced age 56 PBAD [β = -0.144, P = 0.012, 95% confidence interval (CI) = -0.257, -0.032]. Age 40 pack years did not additionally predict PBAD at later ages. Age 40 alcohol consumption, but not a smoking × alcohol interaction, predicted more advanced PBAD at age 56 (β = -0.166, P = 0.001, 95% CI = -0.261, -0.070) with additional influences at age 62 (β = -0.115, P = 0.005, 95% CI = -0.195, -0.036). Age 40 alcohol did not predict age 68 PBAD. Within-twin-pair analyses suggested some genetic mechanism partially underlying effects of alcohol, but not smoking, on PBAD. Conclusions Heavier smoking and alcohol consumption by age 40 appears to predict advanced brain aging by age 56 in men.

Clearance of cerebrospinal fluid (CSF) is important for the removal of toxins from the brain, with implications for neurodegenerative diseases. Imaging evaluation of CSF outflow in humans has been limited, relying on venous or invasive intrathecal injections of contrast agents. The objective of this study was to introduce a novel spin-labeling MRI technique to detect and quantify the movement of endogenously tagged CSF, and then apply it to evaluate CSF outflow in normal humans of varying ages.This study was performed on a clinical 3-Tesla MRI scanner in 16 healthy subjects with an age range of 19-71 years with informed consent. Our spin-labeling MRI technique applies a tag pulse on the brain hemisphere, and images the outflow of the tagged CSF into the superior sagittal sinus (SSS). We obtained 3D images in real time, which was analyzed to determine tagged-signal changes in different regions of the meninges involved in CSF outflow. Additionally, the signal changes over time were fit to a signal curve to determine quantitative flow metrics. These were correlated against subject age to determine aging effects.We observed the signal of the tagged CSF moving from the dura mater and parasagittal dura, and finally draining into the SSS. In addition, we observed a possibility of another pathway which is seen in some young subjects. Furthermore, quantitative CSF outflow metrics were shown to decrease significantly with age.We demonstrate a novel non-invasive MRI technique identifying two intrinsic CSF clearance pathways, and observe an age-related decline of CSF flow metrics in healthy subjects. Our work provides a new opportunity to better understand the relationships of these CSF clearance pathways during the aging process, which may ultimately provide insight into the age-related prevalence of neurodegenerative diseases.

The locus coeruleus (LC) is one of the earliest sites of tau pathology, making it a key structure in early Alzheimer’s disease (AD) progression. As the primary source of norepinephrine for the brain, reduced LC integrity may have negative consequences for brain health, yet macrostructural brain measures (e.g. cortical thickness) may not be sensitive to early stages of neurodegeneration. We therefore examined whether LC integrity was associated with differences in cortical gray matter microstructure among 435 men (mean age = 67.5; range = 62–71.7). LC structural integrity was indexed by contrast-to-noise ratio (LCCNR) from a neuromelanin-sensitive MRI scan. Restriction spectrum imaging (RSI), an advanced multi-shell diffusion technique, was used to characterize cortical microstructure, modeling total diffusion in restricted, hindered, and free water compartments. Higher LCCNR (greater integrity) was associated with higher hindered and lower free water diffusion in multiple cortical regions. In contrast, no associations between LCCNR and cortical thickness survived correction. Results suggest lower LC integrity is associated with patterns of cortical microstructure that may reflect a reduction in cytoarchitectural barriers due to broader neurodegenerative processes. These findings highlight the potential utility for LC imaging and advanced diffusion measures of cortical microstructure in assessing brain health and early identification of neurodegenerative processes.

BackgroundClearance of cerebrospinal fluid (CSF) is important for the removal of toxins from the brain, with implication for neurodegenerative diseases. Imaging evaluation of CSF outflow in humans has been limited, relying on injections of contrast agents. Objective of this study was to introduce a novel spin-labeling magnetic resonance imaging (MRI) technique to detect and quantify the movement of endogenously tagged CSF without administration of tracer or contrast media, and use the technique to evaluate CSF outflow in normal human subjects with varying ages.MethodsThis study was performed on a clinical 3-Tesla MRI scanner in healthy subjects (10 males and 6 females; mean age, 47.6 ± 18.9 years; range, 19-71 years) with informed consent. Our non-contrast spin-labeling MRI technique applies a tag pulse on the brain hemisphere, including subarachnoid space, dura mater, brain parenchyma, and images the outflow of the tagged CSF into the superior sagittal sinus. We obtained 3-dimensional images in real time, which was analyzed to determine tagged-signal changes in different regions of the brain involved in CSF outflow or clearance. Additionally, the signal changes over time were fit to a signal curve to determine quantitative flow metrics such as relative CSF flow and volume. These were correlated against subject age to determine aging effects.ResultsWe observed the signal of the tagged CSF moving from the subarachnoid space to the dura mater and parasagittal dura, and finally draining into the superior sagittal sinus. In addition, there was strong evidence of a direct pathway by which tagged CSF flows directly from the subarachnoid space to the superior sagittal sinus, via the lateral wall of superior sagittal sinus. Furthermore, quantitative CSF outflow metrics were shown to decrease significantly with age.ConclusionsWe demonstrated a novel non-invasive MRI technique to evaluate CSF clearance in humans. In this study, we identified possible two CSF clearance pathways, and determined normative values and decline of CSF flow metrics in normal ages. Our work provides a new opportunity to better understand the relationships of these CSF clearance pathways in ages, which may be a significant factor in the age-related prevalence of neurodegenerative diseases.FundingThis study was supported by the National Institutes of Health grants: RF1AG076692 (MM) and R01HL154092 (MM); and made possible by a grant from Canon Medical Systems. Corp., Japan.Clinical trialNot applicable.

Composite scores of MRI-derived metrics in brain regions associated with Alzheimer's disease (AD), commonly termed 'AD signatures,' have been developed to distinguish early AD-related atrophy from normal age-associated changes. Diffusion-based gray matter signatures may be more sensitive to early AD-related changes compared to thickness/volume-based signatures, demonstrating their potential clinical utility. The timing of early (i.e., midlife) changes in AD signatures from different modalities, and whether diffusion- and thickness/volume-based signatures each capture unique, AD-related phenotypic or genetic information, remains unknown.Our validated thickness/volume signature, our novel mean diffusivity (MD) signature, and an MRI-derived measure of brain age were used in biometrical analyses to examine genetic and environmental influences on the measures, as well as phenotypic and genetic relationships between measures over 12 years. Participants were 736 men from three waves of the Vietnam Era Twin Study of Aging (VETSA; baseline age=56.1, SD=2.6, range=51.1-60.2). Subsequent waves were at approximately 5.7-year intervals.MD and thickness/volume signatures were highly heritable (56-72%). Baseline MD signatures predicted thickness/volume signatures over a decade later, but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures. AD signatures and brain age were correlated, but each measure captured unique phenotypic and genetic variance.Cortical MD and thickness/volume AD signatures are heritable, and each signature captures unique variance that is also not explained by brain age. Moreover, results are in line with changes in MD emerging before changes in cortical thickness, underscoring the utility of MD as a very early predictor of AD risk.

Midlife vascular disease increases risk for dementia and effects of vascular dysfunction on brain health differ between men and women. Elevated pulse pressure, a surrogate for arterial stiffness, contributes to cerebrovascular pathology and white matter damage that may advance cognitive aging; however, it remains unclear how associations between pulse pressure and neural integrity differ by sex and age. This study used restriction spectrum imaging to examine associations between pulse pressure and brain microstructure in community-dwelling women (N=88) and men (N=55), aged 56 to 97 (mean, 76.3) years. Restricted isotropic (presumed intracellular), hindered isotropic (presumed extracellular), neurite density, and free water diffusion were computed in white matter tracts and subcortical regions. After adjustment for age and sex, higher pulse pressure correlated with lower restricted isotropic diffusion in global white matter, with more pronounced associations in parahippocampal cingulum, as well as in thalamus and hippocampus. Subgroup analyses demonstrated stronger correlations between pulse pressure and restricted isotropic diffusion in association fibers for participants ≤75 years than for older participants, with stronger effects for women than men of this age group. Microstructure in parahippocampal cingulum and thalamus differed by pulse pressure level regardless of antihypertensive treatment. Increased pulse pressure may lead to widespread injury to white matter and subcortical structures, with greatest vulnerability for women in late middle to early older age. Restriction spectrum imaging could be useful for monitoring microstructural changes indicative of neuronal loss or shrinkage, demyelination, or inflammation that accompany age-related cerebrovascular dysfunction.

Normal brain aging is characterized by declining neuronal integrity, yet it remains unclear how microstructural injury influences cognitive aging and whether such mechanisms differ between sexes. Using restriction spectrum imaging (RSI), we examined sex differences in associations between brain microstructure and cognitive function in 147 community-dwelling older men and women (56-99 years). Gray and white matter microstructure correlated with global cognition, executive function, visuospatial memory, episodic memory, and logical memory, with the strongest associations for restricted, hindered and free isotropic diffusion. Associations were stronger for women than for men, a difference likely due to greater age-related variability in cognitive scores and microstructure in women. Isotropic diffusion mediated effects of age on cognition for both sexes, though distinct mediation patterns were present for women and men. For women, hippocampal and corpus callosum microstructure mediated age effects on verbal and visuospatial memory, respectively, whereas for men fiber microstructure (mainly fornix and corpus callosum) mediated age effects on executive function and visuospatial memory. These findings implicate sex-specific pathways by which changing brain cytoarchitecture contributes to cognitive aging, and suggest that RSI may be useful for evaluating risk for cognitive decline or monitoring efficacy of interventions to preserve brain health in later life.

Background We examined the associations between dual impairments in visual and hearing acuity and aging-related cognitive decline. Methods This was a longitudinal study of adults who had visual and hearing acuity and cognitive function assessed in 1992–1996 and were followed for up to 24 years (mean = 7.3 years), with up to five additional cognitive assessments. Visual impairment was defined as vision worse than 20/40, hearing impairment as pure-tone average thresholds >25 dB. Associations were tested using linear mixed-effects regressions. Results Of 1,383 participants, 293 had visual impairment, 990 had a hearing impairment and 251 had both deficits. In fully adjusted models, low visual acuity was associated with poorer Mini-Mental State Examination (MMSE; β = −0.29) and Trail-Making Test Part B (Trails B; β = 13.22) performance, and with faster declines in MMSE (β = −0.12) and Trails B (β = 1.84). The combination of low visual and low hearing acuity was associated with poorer MMSE (β = −0.44) and Trails B (β = 11.20) scores, and with faster declines in MMSE (β = −0.19), Trails B (β = 3.50), and Verbal Fluency Test (VFT; β = −0.14) performance. Associations were similar in men and women. Conclusion Impairments in both vision and hearing are associated with a more rapid decline in cognitive function with aging.

We examined the association between dietary potassium intake and all-cause and cause-specific mortality among community-dwelling older adults. Potassium intake was assessed with a food frequency questionnaire administered to 1,363 older adults (mean age 71.0 ± 10.6 years). Cox proportional hazard regressions estimated hazard ratios for sex-specific quintiles of calorie-adjusted potassium in relation to all-cause and cause-specific (cardiovascular disease, CVD, and stroke) mortality, adjusting for numerous covariates. There were 855 deaths (63% mortality) during the 20-year follow-up. Relative to the third quintile, potassium intake in the lowest quintile only was associated with increased risk of all-cause mortality (fully-adjusted hazard ratio 1.33; 95% CI 1.06, 1.67). Potassium intake was not significantly associated with CVD or stroke mortality. These results suggest that low potassium intake is associated with increased risk of mortality independent of overall health status. Ensuring adequate potassium in the diet may be an important strategy for reducing risk of earlier mortality among older adults.

To determine if sex differences in verbal memory in AD are related to differences in extent or distribution of pathological tau, we studied 275 participants who were amyloid PET positive and carried clinical classifications of normal cognition, mild cognitive impairment (MCI) or dementia, and had tau (AV1451) PET. We compared tau distribution between men and women, and as a function of genetic risk. In MCI we further explored the relationship between quantity and distribution of tau in relation to verbal memory scores. Women had more tau burden overall, but this was driven by sex differences at the MCI stage. There was no significant difference in tau load by APOE e4 status. Within the MCI group the association between tau and performance in verbal memory tasks was stronger in women than men. The topography of the associations between tau and verbal memory also differed in MCI; women demonstrated stronger relationships between tau distribution and verbal memory performance, especially in the left hemisphere. These findings have implications for understanding tau distribution and spread, and in interpretation of verbal memory performance.

Integration of multi-omics data with molecular interaction networks enables elucidation of the pathophysiology of Alzheimer’s disease (AD). Using the latest genome-wide association studies (GWAS) including proxy cases and the STRING interactome, we identified an AD network of 142 risk genes and 646 network-proximal genes, many of which were linked to synaptic functions annotated by mouse knockout data. The proximal genes were confirmed to be enriched in a replication GWAS of autopsy-documented cases. By integrating the AD gene network with transcriptomic data of AD and healthy temporal cortices, we identified 17 gene clusters of pathways, such as up-regulated complement activation and lipid metabolism, down-regulated cholinergic activity, and dysregulated RNA metabolism and proteostasis. The relationships among these pathways were further organized by a hierarchy of the AD network pinpointing major parent nodes in graph structure including endocytosis and immune reaction. Control analyses were performed using transcriptomics from cerebellum and a brain-specific interactome. Further integration with cell-specific RNA sequencing data demonstrated genes in our clusters of immunoregulation and complement activation were highly expressed in microglia.

Background Epigenetic age acceleration (AgeAccel), which indicates faster biological aging relative to chronological age, has been associated with lower cognitive function. However, the association of AgeAccel with mild cognitive impairment (MCI) or dementia is not well-understood. We examined associations of 4 AgeAccel measures with incident MCI and dementia. Methods This prospective analysis included 578 older women from the Women’s Health Initiative Memory Study selected for a case–cohort study of coronary heart disease (CHD). Women were free of CHD and cognitive impairment at baseline. Associations of AgeAccel measures (intrinsic AgeAccel [IEAA], extrinsic AgeAccel [EEAA], AgeAccelPheno, and AgeAccelGrim) with risks for incident adjudicated diagnoses of MCI and dementia overall and stratified by incident CHD status were evaluated. Results IEAA was not significantly associated with MCI (HR, 1.23; 95% CI, 0.99–1.53), dementia (HR, 1.10; 95% CI, 0.88–1.38), or cognitive impairment (HR, 1.18; 95% CI, 0.99–1.40). In stratified analysis by incident CHD status, there was a 39% (HR, 1.39; 95% CI, 1.07–1.81) significantly higher risk of MCI for every 5-year increase in IEAA among women who developed CHD during follow-up. Other AgeAccel measures were not significantly associated with MCI or dementia. Conclusions IEAA was not significantly associated with cognitive impairment overall but was associated with impairment among women who developed CHD. Larger studies designed to examine associations of AgeAccel with cognitive impairment are needed, including exploration of whether associations are stronger in the setting of underlying vascular pathologies.

Magnetic resonance imaging data are being used in statistical models to predicted brain ageing (PBA) and as biomarkers for neurodegenerative diseases such as Alzheimers Disease. Despite their increasing application, the genetic and environmental etiology of global PBA indices is unknown. Likewise, the degree to which genetic influences in PBA are longitudinally stable and how PBA changes over time are also unknown. We analyzed data from 734 men from the Vietnam Era Twin Study of Aging with repeated MRI assessments between the ages 52 to 72 years. Biometrical genetic analyses twin models revealed significant and highly correlated estimates of additive genetic heritability ranging from 59% to 75%. Multivariate longitudinal modelling revealed that covariation between PBA at different timepoints could be explained by a single latent factor with 73% heritability. Our results suggest that genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and are largely explained by common genetic influences. HighlightsWe explored the genetic and environmental etiology of MRI-based predicted brain age (PBA) in a longitudinal sample of males starting in midlife. Genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and largely explained by common genetic influences.

Neuroimaging signatures based on composite scores of cortical thickness and hippocampal volume predict progression from mild cognitive impairment to Alzheimer’s disease. However, little is known about the ability of these signatures among cognitively normal adults to predict progression to mild cognitive impairment. Towards that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: (i) a validated MRI-derived Alzheimer’s disease signature based on cortical thickness and hippocampal volume in cognitively normal middle-aged adults would predict progression to mild cognitive impairment; and (ii) a novel grey matter mean diffusivity signature would be a better predictor than the thickness/volume signature. This cohort study was part of the Vietnam Era Twin Study of Aging. Concurrent analyses compared cognitively normal and mild cognitive impairment groups at each of three study waves (ns = 246–367). Predictive analyses included 169 cognitively normal men at baseline (age = 56.1, range = 51–60). Our previously published thickness/volume signature derived from independent data, a novel mean diffusivity signature using the same regions and weights as the thickness/volume signature, age, and an Alzheimer’s disease polygenic risk score were used to predict incident mild cognitive impairment an average of 12 years after baseline (follow-up age = 67.2, range = 61–71). Additional analyses adjusted for predicted brain age difference scores (chronological age minus predicted brain age) to determine if signatures were Alzheimer-related and not simply ageing-related. In concurrent analyses, individuals with mild cognitive impairment had higher (worse) mean diffusivity signature scores than cognitively normal participants, but thickness/volume signature scores did not differ between groups. In predictive analyses, age and polygenic risk score yielded an area under the curve of 0.74 (sensitivity = 80.00%; specificity = 65.10%). Prediction was significantly improved with addition of the mean diffusivity signature (area under the curve = 0.83; sensitivity = 85.00%; specificity = 77.85%; P = 0.007), but not with addition of the thickness/volume signature. A model including both signatures did not improve prediction over a model with only the mean diffusivity signature. Results held up after adjusting for predicted brain age difference scores. The novel mean diffusivity signature was limited by being yoked to the thickness/volume signature weightings. An independently derived mean diffusivity signature may thus provide even stronger prediction. The young age of the sample at baseline is particularly notable. Given that the brain signatures were examined when participants were only in their 50 s, our results suggest a promising step towards improving very early identification of Alzheimer’s disease risk and the potential value of mean diffusivity and/or multimodal brain signatures., Among cognitively normal adults in their 50 s, an Alzheimer’s brain signature based on grey matter mean diffusivity—but not cortical thickness—significantly improved prediction of progression to mild cognitive impairment 12 years later. Grey matter mean diffusivity signatures may be sensitive to Alzheimer-related changes as early as middle age., Graphical Abstract Graphical Abstract

Background Pathologic evidence of Alzheimer disease (AD) is detectable years before onset of clinical symptoms. Imaging-based identification of structural changes of the brain in people at genetic risk for early-onset AD may provide insights into how genes influence the pathologic cascade that leads to dementia. Purpose To assess structural connectivity differences in cortical networks between cognitively normal autosomal dominant Alzheimer disease (ADAD) mutation carriers versus noncarriers and to determine the cross-sectional relationship of structural connectivity and cortical amyloid burden with estimated years to symptom onset (EYO) of dementia in carriers. Materials and Methods In this exploratory analysis of a prospective trial, all participants enrolled in the Dominantly Inherited Alzheimer Network between January 2009 and July 2014 who had normal cognition at baseline, T1-weighted MRI scans, and diffusion tensor imaging (DTI) were analyzed. Amyloid PET imaging using Pittsburgh compound B was also analyzed for mutation carriers. Areas of the cerebral cortex were parcellated into three cortical networks: the default mode network, frontoparietal control network, and ventral attention network. The structural connectivity of the three networks was calculated from DTI. General linear models were used to examine differences in structural connectivity between mutation carriers and noncarriers and the relationship between structural connectivity, amyloid burden, and EYO in mutation carriers. Correlation network analysis was performed to identify clusters of related clinical and imaging markers. Results There were 30 mutation carriers (mean age ± standard deviation, 34 years ± 10; 17 women) and 38 noncarriers (mean age, 37 years ± 10; 20 women). There was lower structural connectivity in the frontoparietal control network in mutation carriers compared with noncarriers (estimated effect of mutation-positive status, -0.0266

Author(s): Elman, Jeremy A; Puckett, Olivia K; Beck, Asad; Fennema-Notestine, Christine; Cross, Latonya K; Dale, Anders M; Eglit, Graham ML; Eyler, Lisa T; Gillespie, Nathan A; Granholm, Eric L; Gustavson, Daniel E; Hagler, Donald J; Hatton, Sean N; Hauger, Richard; Jak, Amy J; Logue, Mark W; McEvoy, Linda K; McKenzie, Ruth E; Neale, Michael C; Panizzon, Matthew S; Reynolds, Chandra A; Sanderson-Cimino, Mark; Toomey, Rosemary; Tu, Xin M; Whitsel, Nathan; Williams, McKenna E; Xian, Hong; Lyons, Michael J; Franz, Carol E; Kremen, William S | Abstract: IntroductionThe locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression.MethodsParticipants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LCCNR ). We examined LCCNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction.ResultsHeritability of LCCNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction.DiscussionReduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.

Background: Estimated glomerular filtration rate (eGFR), albuminuria and serum uric acid (SUA) are markers of kidney function that have been associated with cognitive ability. However, whether these associations are causal is unclear. Methods: We performed one-sample Mendelian randomization (MR) to estimate the effects of kidney function markers on cognitive performance using data from 357,590 participants from the UK Biobank. Polygenic scores for serum uric acid (SUA), urine albumin to creatinine ratio (ACR), estimated glomerular filtration rate based on serum creatinine (eGFRcre) and serum cystatin-c (eGFRcys) were used as instruments, and cognitive function outcomes included a test of verbal-numeric reasoning and reaction time. Sensitivity analyses were carried out to address potential pleiotropy using MR-Egger and weighted median regression. Results: We found no evidence of a causal effect of genetically determined SUA, eGFRcre or eGFRcys on either cognitive function outcomes. There was no association between a polygenic score for ACR and verbal-numeric reasoning. However, there was suggestive evidence of a relationship between genetically increased ACR and slower reaction time (β (95% confidence interval [CI])) for 1 standard deviation log ACR = 4.93 (1.60 to 8.26), p=0.004). Pleiotropy adjusted estimates were directionally consistent with those of the principal analysis but overlapped with the null. Conclusions: This MR study does not support causal effects of SUA, eGFRcre or eGFRcys on cognitive performance. Genetically-increased ACR was associated with lower processing speed, but results need confirmation in independent samples.

BACKGROUND: Although physical activity has been associated with better cognitive function and reduced dementia risk, its association with cognitive decline in normal aging remains uncertain. OBJECTIVE: To determine whether physical activity in youth and older age are associated with age-related cognitive change. METHODS: Over a period of 27 years, 2,027 community-dwelling adults (mean age 73.5; 60% women) of the Rancho Bernardo Study of Healthy Aging completed up to seven cognitive assessments, including tests of global cognitive function, executive function, verbal fluency, and episodic memory. At each visit, participants reported concurrent physical activity. At baseline (1988–1992), participants additionally reported physical activity as a teenager and at age 30. For each age period, participants were classified as regularly active (3+ times/week) or inactive. RESULTS: Associations between concurrent physical activity and better cognitive function were stronger with advancing age on all tests, even after accounting for education, health, and lifestyle factors, as well as survival differences (ps < 0.05). Baseline physical activity did not predict rates of cognitive decline (ps > 0.40). Individuals who were physically active at age 30 and older age maintained the highest global cognitive function with advancing age (p = 0.002). CONCLUSION: Regular physical activity is associated with better cognitive function with advancing age. Physical activity in young adulthood may contribute to cognitive reserve, which together with physical activity in later years, may act to preserve cognitive function with age.

OBJECTIVE The aim of the study was to examine the association of pregnancy history with trajectories of cognitive function in older women. METHODS Participants were 1,025 women (mean age = 73.1 ± 9.6 y) enrolled in the Rancho Bernardo Study who attended a clinic visit between 1988 and 1992, when pregnancy history (ever pregnant, number of pregnancies, ages at first and last pregnancy) was recorded and cognitive function was assessed with a battery of four tests repeated up to 7 times through 2016. Linear mixed-effects regression models were used to examine the association between pregnancy history and longitudinal change in cognitive function. RESULTS Overall, 77% of women had at least one pregnancy; number of pregnancies ranged from 1 to 14 (mean = 2.9 ± 1.7). Ages at first and last pregnancy ranged from 16 to 44 years (mean = 24.9 ± 4.7) and 16 to 49 years (mean = 30.7 ± 5.5), respectively. Of 16 associations tested (4 pregnancy exposures by 4 cognitive tests), one was statistically significant without correction for multiple comparisons. Women who reported ever being pregnant recalled 0.12 fewer words on the Buschke Selective Reminding Test for every year increase in age than women who had never been pregnant (P = 0.05). No other significant associations of pregnancy history with cognitive decline were observed. CONCLUSIONS Our results show no clinically meaningful long-term influence of pregnancy history on age-related change in cognitive function. These reassuring findings suggest childbearing decisions and timing will not affect cognitive function in older age.

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer’s disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10−9), MINK1 (chromosome 17, meta-p = 1.98 × 10−7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10−7 and closest gene = MYBPC3, meta-p = 5.62 × 10−8). In a large ‘AD-by-proxy’ cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.