Cross-sectional and longitudinal interaction effects of physical activity and APOE-ε4 on white matter integrity in older adults: The MAPT study.

BACKGROUND: Physical activity (PA) has been shown to modulate the detrimental effect of carrying the apolipoprotein-E epsilon 4 (APOE-ɛ4) allele on brain structure. However, the current literature mainly provides cross-sectional data, and longitudinal studies investigating the interaction between genotype and PA on white matter (WM) integrity are lacking. OBJECTIVES: We investigated both the cross-sectional and the longitudinal interactive effects of APOE-ɛ4 and PA on WM integrity in older adults. METHODS: Fractional anisotropy, as well as axial, radial, and mean diffusivity, extracted from brain diffusion tensor imaging (DTI) were used to assess WM integrity in non-demented older adults. They were categorized according to their APOE-ɛ4 status (carriers vs. non-carriers), and their level of total (TPA), moderate to vigorous (MVPA) and light (LPA) PA were assessed using a questionnaire. Mixed model regressions were performed to test the interactive effects of APOE-ɛ4 status and PA on WM integrity at baseline and over a 3-year follow-up. RESULTS: 190 subjects with a mean age 74.5 years (SD = 3.9) were examined. Despite a lack of cross-sectional associations, sensitivity analyses revealed that, in the carrier group only, higher levels of LPA, but not MVPA, were mainly associated with higher axial and mean diffusivity values over time. CONCLUSIONS: This study partially confirms the previously reported interactive associations between PA, APOE-ɛ4 genotype and WM integrity, supporting the hypothesis that PA may protect against fiber loss in WM tracts containing crossing fibers. Future studies assessing sedentary behaviors in addition to PA could bring relevant contributions to the field. CLINICAL TRIAL REGISTRATION NUMBER FROM CLINICALTRIALS.GOV: NCT00672685.

APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis.

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field. METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4. RESULTS: Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. CONCLUSIONS: Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a 'Warburg like' endophenotype that is observable in young females decades prior to clinically manifest AD.

APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE-TR mice.

The impact of sex and menopausal status in Alzheimer's disease remains understudied despite increasing evidence of greater female risk, particularly in APOE4 carriers. Utilizing female APOE-TR mice maintained on a high-fat diet background we induced ovarian failure through repeated VCD injections, to mimic human menopause. At 12 months of age, recognition memory and spatial memory were assessed using object recognition, Y-maze spontaneous alternation, and Barnes maze. A VCD*genotype interaction reduced the recognition memory (P < .05), with APOE4 VCD-treated animals unable to distinguish between novel and familiar objects. APOE4 mice displayed an additional 37% and 12% reduction in Barnes (P < .01) and Y-maze (P < .01) performance, indicative of genotype-specific spatial memory impairment. Molecular analysis indicated both VCD and genotype-related deficits in synaptic plasticity with BDNF, Akt, mTOR, and ERK signaling compromised. Subsequent reductions in the transcription factors Creb1 and Atf4 were also evident. Furthermore, the VCD*genotype interaction specifically diminished Ephb2 expression, while Fos, and Cnr1 expression reduced as a consequence of APOE4 genotype. Brain DHA levels were 13% lower in VCD-treated animals independent of genotype. Consistent with this, we detected alterations in the expression of the DHA transporters Acsl6 and Fatp4. Our results indicate that the combination of ovarian failure and APOE4 leads to an exacerbation of cognitive and neurological deficits.

ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism.

Alzheimer's disease (AD) risk gene ApoE4 perturbs brain lipid homeostasis and energy transduction. However, the cell-type-specific mechanism of ApoE4 in modulating brain lipid metabolism is unclear. Here, we describe a detrimental role of ApoE4 in regulating fatty acid (FA) metabolism across neuron and astrocyte in tandem with their distinctive mitochondrial phenotypes. ApoE4 disrupts neuronal function by decreasing FA sequestering in lipid droplets (LDs). FAs in neuronal LDs are exported and internalized by astrocytes, with ApoE4 diminishing the transport efficiency. Further, ApoE4 lowers FA oxidation and leads to lipid accumulation in both astrocyte and the hippocampus. Importantly, diminished capacity of ApoE4 astrocytes in eliminating neuronal lipids and degrading FAs accounts for their compromised metabolic and synaptic support to neurons. Collectively, our findings reveal a mechanism of ApoE4 disruption to brain FA and bioenergetic homeostasis that could underlie the accelerated lipid dysregulation and energy deficits and increased AD risk for ApoE4 carriers.

Differential Effects of the Interaction Between the Education and APOE ε4 Allele on Amyloid-beta Retention and Memory Performances in Cognitively Normal Older Adults and Alzheimer's Disease Patients.

BACKGROUND: Despite the effect of education and APOE ε4 allele on amyloid-beta (Aß) retention and memory, previous studies have not dealt with an interaction between two factors on Aß deposition and memory function in the course of Alzheimer's disease (AD). OBJECTIVE: To evaluate education by APOE ε4 allele interactions for Aß retention and neuropsychological test scores in cognitively normal older adults without Aß deposition [CN(Aß-), n=45] and Alzheimer's disease patients with Aß retention [AD(Aß+), n=33]. METHODS: Multiple regression analyses (adjusted for age, gender) were conducted to examine the effects of education, APOE ε4 allele, and the interaction between the two factors on global, regional Aß load quantified using [18F]flutemetamol standardized uptake value ratio with the pons as a reference region, and on neuropsychological test scores in each group. RESULTS: The interaction between education and APOE ε4 allele had an effect on amyloid load in parietal lobes (uncorrected p<0.05) and striatum (Bonferroni corrected p<0.05) in each CN(Aß-) and AD(Aß+). There was also an interaction effect of education and APOE ε4 allele on the memory performance in each CN(Aß-) and AD(Aß+) (uncorrected p<0.05). APOE ε4 carriers of both groups showed opposing slopes with each other in the correlation between the education years and Aß load, memory performance. CONCLUSION: The current results suggest a possible explanation of the differential effects of education and APOE ε4 allele interactions on AD pathology and memory function at the beginning and end of AD progress. However, further study with a validating cohort is needed for confirming this explanation.

Effect of ApoE isoforms on mitochondria in Alzheimer disease.

OBJECTIVE: To test the hypothesis that ApoE isoforms affect mitochondrial structure and function that are related to cognitive impairment in Alzheimer disease (AD), we systematically investigated the effects of ApoE isoforms on mitochondrial biogenesis and dynamics, oxidative stress, synapses, and cognitive performance in AD. METHODS: We obtained postmortem human brain tissues and measured proteins that are responsible for mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1α [PGC-1α] and sirtuin 3 [SIRT3]), for mitochondrial dynamics (mitofusin 1 [MFN1], mitofusin 2 [MFN2], and dynamin-like protein 1 [DLP1]), for oxidative stress (superoxide dismutase 2 [SOD2] and forkhead-box protein O3a [Foxo3a]), and for synapses (postsynaptic density protein 95 [PSD95] and synapsin1 [Syn1]). A total of 46 cases were enrolled, including ApoE-ɛ4 carriers (n = 21) and noncarriers (n = 25). RESULTS: Levels of these proteins were compared between ApoE-ɛ4 carriers and noncarriers. ApoE-ɛ4 was associated with impaired mitochondrial structure and function, oxidative stress, and synaptic integrity in the human brain. Correlation analysis revealed that mitochondrial proteins and the synaptic protein were strongly associated with cognitive performance. CONCLUSION: ApoE isoforms influence mitochondrial structure and function, which likely leads to alteration in oxidative stress, synapses, and cognitive function. These mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.

Interaction Between Odor Identification Deficit and APOE4 Predicts 6-Year Cognitive Decline in Elderly Individuals.

Olfactory identification impairment might indicate future cognitive decline in elderly individuals. An unresolved question is to what extent this effect is dependent on the ApoE-ε4, a genotype associated with risk of Alzheimer's Disease (AD). Given the current concern about reproducibility in empirical research, we assessed this issue in a large sample (n = 1637) of older adults (60 - 96 years) from the population-based longitudinal Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). A hierarchical regression analysis was carried out to determine if a low score on an odor identification test, and the presence of ApoE-ε4, would predict the magnitude of a prospective 6-year change in the Mini-Mental State Examination (MMSE) after controlling for demographic, health-related, and cognitive variables. We found that overall, lower odor identification performance was predictive of cognitive decline, and, as hypothesized, we found that the effect was most pronounced among ApoE-ε4 carriers. Our results from this high-powered sample suggest that in elderly carriers of the ApoE-ε4 allele, odor identification impairment provides an indication of future cognitive decline, which has relevance for the prognosis of AD.

Apolipoprotein E4 Expression Causes Gain of Toxic Function in Isogenic Human Induced Pluripotent Stem Cell-Derived Endothelial Cells.

OBJECTIVE: The ApoE (apolipoprotein) allele epsilon 4 is a major genetic risk factor for Alzheimer disease, cardiovascular disorders, and stroke, indicating that it significantly impacts cerebral and vascular systems. However, very little is known about how APOE genotype affects brain endothelial cells, which form a network of tight junctions to regulate communication between the brain and circulating blood factors. Approach and Results: Here, we present a novel model of endothelial dysfunction using isogenic human induced pluripotent stem cell-derived cells harboring different alleles of the APOE gene, specifically ApoE 3/3, 3/4, and 4/4. We show for the first time that ApoE4 expression by endothelial cells is sufficient to cause a toxic gain of cellular dysfunction. Using RNAseq, we found significant effects of ApoE4 on signaling pathways involved in blood coagulation and barrier function. These changes were associated with altered cell function, including increased binding of platelets to ECs with the 3/4 or 4/4 genotype. ApoE4-positive cells exhibited a proinflammatory state and prothrombotic state, evidenced by higher secretion of Aß (amyloid-ß) 40 and 42, increased release of cytokines, and overexpression of the platelet-binding protein VWF (vonWillebrand factor). Immunohistochemistry of human brain Alzheimer disease brains also showed increased VWF expression with the ApoE4/4 genotype. Finally, pharmacological inhibition of inflammation in ECs by celastrol rescued overexpression of VWF in cells expressing ApoE4. CONCLUSIONS: These cells provide novel insight into ApoE4-mediated endothelial dysfunction and provide a new platform to test potential therapies for vascular disorders.

Altered SPMs and age-associated decrease in brain DHA in APOE4 female mice.

An apolipoprotein E (APOE) 4 genotype is the most important, common genetic determinant for Alzheimer disease (AD), and female APOE4 carriers present with an increased risk compared with males. The study quantified cortical and hippocampal fatty acid and phospholipid profiles along with select eicosapentaenoic acid (EPA)- and docosahexaenoic acid (DHA)-derived specialized proresolving mediators (SPMs) in 2-, 9-, and 18-mo-old APOE3 and APOE4 male and female mice. A 10% lower cortical DHA was evident in APOE4 females at 18 mo compared with 2 mo, with no significant decrease in APOE3 or APOE4 males. This decrease was associated with a reduction in DHA-phosphatidylethanolamine. Older APOE4 females had a 15% higher oleic acid content compared with young mice. Although no sex*APOE genotype interactions were observed for SPMs expressed as a ratio of their parent compound, higher cortical 18R/S-hydroxy-5Z,8Z,11Z,14Z,16E-EPA, resolvin D3, protectin D1, 10S,17S-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-DHA (10S,17S-diHDHA), maresin 1, 17S-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-DHA, and 14S-hydroxy-4Z,7Z,10Z,12E,16Z,19Z-DHA were evident in females, and lower cortical 17R-resolvin D1, 10S,17S-diHDHA, and 18-HEPE in APOE4. Our findings show a strong association between age, female sex, and an APOE4 genotype, with decreased cortical DHA and a number of SPMs, which together may contribute to the development of cognitive decline and AD pathology.-Martinsen, A., Tejera, N., Vauzour, D., Harden, G., Dick, J., Shinde, S., Barden, A., Mori, T. A., Minihane, A. M. Altered SPMs and age-associated decrease in brain DHA in APOE4 female mice.

Clinical and neuropathological differences between Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies - current issues and future directions.

Lewy body diseases share clinical, pathological, genetic and biochemical signatures, and are regarded as a highly heterogeneous group of neurodegenerative disorders. Inclusive of Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), controversy still exists as to whether they should be considered as separate disease entities or as part of the same disease continuum. Here we discuss emerging knowledge relating to both clinical, and neuropathological differences and consider current biomarker strategies as we try to improve our diagnostic capabilities and design of disease modifying therapeutics for this group of debilitating neurodegenerative disorders. This article is part of the Special Issue "Synuclein".

Lipidated apolipoprotein E4 structure and its receptor binding mechanism determined by a combined cross-linking coupled to mass spectrometry and molecular dynamics approach.

Apolipoprotein E (apoE) is a forefront actor in the transport of lipids and the maintenance of cholesterol homeostasis, and is also strongly implicated in Alzheimer's disease. Upon lipid-binding apoE adopts a conformational state that mediates the receptor-induced internalization of lipoproteins. Due to its inherent structural dynamics and the presence of lipids, the structure of the biologically active apoE remains so far poorly described. To address this issue, we developed an innovative hybrid method combining experimental data with molecular modeling and dynamics to generate comprehensive models of the lipidated apoE4 isoform. Chemical cross-linking combined with mass spectrometry provided distance restraints, characterizing the three-dimensional organization of apoE4 molecules at the surface of lipidic nanoparticles. The ensemble of spatial restraints was then rationalized in an original molecular modeling approach to generate monomeric models of apoE4 that advocated the existence of two alternative conformations. These two models point towards an activation mechanism of apoE4 relying on a regulation of the accessibility of its receptor binding region. Further, molecular dynamics simulations of the dimerized and lipidated apoE4 monomeric conformations revealed an elongation of the apoE N-terminal domain, whereby helix 4 is rearranged, together with Arg172, into a proper orientation essential for lipoprotein receptor association. Overall, our results show how apoE4 adapts its conformation for the recognition of the low density lipoprotein receptor and we propose a novel mechanism of activation for apoE4 that is based on accessibility and remodeling of the receptor binding region.

Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated.

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-ß, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-ß common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-ß (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-ß, α-synuclein and TDP-43.

Using event-related fMRI to examine sustained attention processes and effects of APOE ε4 in young adults.

In this study we investigated effects of the APOE ε4 allele (which confers an enhanced risk of poorer cognitive ageing, and Alzheimer's Disease) on sustained attention (vigilance) performance in young adults using the Rapid Visual Information Processing (RVIP) task and event-related fMRI. Previous fMRI work with this task has used block designs: this study is the first to image an extended (6-minute) RVIP task. Participants were 26 carriers of the APOE ε4 allele, and 26 non carriers (aged 18-28). Pupil diameter was measured throughout, as an index of cognitive effort. We compared activity to RVIP task hits to hits on a control task (with similar visual parameters and response requirements but no working memory load): this contrast showed activity in medial frontal, inferior and superior parietal, temporal and visual cortices, consistent with previous work, demonstrating that meaningful neural data can be extracted from the RVIP task over an extended interval and using an event-related design. Behavioural performance was not affected by genotype; however, a genotype by condition (experimental task/control task) interaction on pupil diameter suggested that ε4 carriers deployed more effort to the experimental compared to the control task. fMRI results showed a condition by genotype interaction in the right hippocampal formation: only ε4 carriers showed downregulation of this region to experimental task hits versus control task hits. Experimental task beta values were correlated against hit rate: parietal correlations were seen in ε4 carriers only, frontal correlations in non-carriers only. The data indicate that, in the absence of behavioural differences, young adult ε4 carriers already show a different linkage between functional brain activity and behaviour, as well as aberrant hippocampal recruitment patterns. This may have relevance for genotype differences in cognitive ageing trajectories.

Apolipoprotein E 4 triggers multiple pathway-mediated Ca2+ overload, causes CaMK II phosphorylation abnormity and aggravates oxidative stress caused cerebral cortical neuron damage.

OBJECTIVE: Apolipoprotein E (APOE) gene polymorphism is correlated closely with resistance to brain damage. This study aims to investigate the effects of APOE4 on oxidative stress damaged cerebral cortical neuron. MATERIALS AND METHODS: Primary cerebral cortical neurons were isolated from APOE gene knock-out mice (APOE-/- mice). Oxidative stress damaged APOE-/- mouse cerebral cortical neuron model was established. Three experimental designs (experiment 1, 2, 3) were conducted by employing several methods. Lactate dehydrogenase (LDH) and superoxide dismutase (SOD) analysis were employed for neurotoxicity assessment. Flow cytometry and transferase-mediated deoxyuridine-triphosphate-biotin nick end labeling (TUNEL) were used to examine neuron apoptosis. Immunohistochemistry and Nissl staining were used to identify neuron morphology. Western blot was used to detect phosphorylated CaMK II (p-CaMK II) and cleaved caspase 3 expression. Ca2+ levels in neurons were also examined by detecting fluorescence intensity. RESULTS: APOE4 treatment (Vehicle + APOE4) significantly aggravates oxidative stress damaged cerebral cortical neuron by increasing LDH levels and decreasing SOD activities, induces neuron apoptosis compared to Vehicle group (p < 0.05). APOE4 treatment significantly enhanced Ca2+ levels compared to Sham group (p < 0.05), MK801 treatment (Vehicle + APOE4 + MK801) significantly decreased Ca2+ levels compared to the Vehicle+APOE4 group at 12 h and 24 h (p < 0.05). APOE4 triggers CaMK II phosphorylation, caspase 3 activation and neurons apoptosis. Both of MK801 and KN93 inhibit CaMK II phosphorylation, decreases caspase 3 activation, and suppresses neurons apoptosis CONCLUSIONS: APOE triggers Ca2+ overload through NMDAR and CaMK II signaling pathway, both of which cause Ca2+ concentration increasing, CaMK II phosphorylation abnormity, and finally aggravate oxidative stress damaged neurons apoptosis.

Differential Aging Trajectories of Modulation of Activation to Cognitive Challenge in APOE ε4 Groups: Reduced Modulation Predicts Poorer Cognitive Performance.

The present study was designed to investigate the effect of a genetic risk factor for Alzheimer's disease (AD), ApolipoproteinE ε4 (APOEε4), on the ability of the brain to modulate activation in response to cognitive challenge in a lifespan sample of healthy human adults. A community-based sample of 181 cognitively intact, healthy adults were recruited from the Dallas-Fort Worth metroplex. Thirty-one APOEε4+ individuals (48% women), derived from the parent sample, were matched based on sex, age, and years of education to 31 individuals who were APOEε4-negative (APOEε4-). Ages ranged from 20 to 86 years of age. Blood oxygen level-dependent functional magnetic resonance imaging was collected during the performance of a visuospatial distance judgment task with three parametric levels of difficulty. Multiple regression was used in a whole-brain analysis with age, APOE group, and their interaction predicting functional brain modulation in response to difficulty. Results revealed an interaction between age and APOE in a large cluster localized primarily to the bilateral precuneus. APOEε4- individuals exhibited age-invariant modulation in response to task difficulty, whereas APOEε4+ individuals showed age-related reduction of modulation in response to increasing task difficulty compared with ε4- individuals. Decreased modulation in response to cognitive challenge was associated with reduced task accuracy as well as poorer name-face associative memory performance. Findings suggest that APOEε4 is associated with a reduction in the ability of the brain to dynamically modulate in response to cognitive challenge. Coupled with a significant genetic risk factor for AD, changes in modulation may provide additional information toward identifying individuals potentially at risk for cognitive decline associated with preclinical AD.SIGNIFICANCE STATEMENT Understanding how risk factors for Alzheimer's disease (AD) affect brain function and cognition in healthy adult samples may help to identify the biomarkers needed to detect nonsymptomatic, preclinical phases of the disease. Findings from the current study show that ApolipoproteinE ε4-positive (APOEε4+) individuals exhibit an altered lifespan trajectory in the ability of the brain to dynamically modulate function to cognitive challenge compared with APOEε4- individuals. This effect manifests in otherwise healthy individuals who are at increased risk for AD in the precuneus, a salient region for early AD changes. Notably, these functional alterations are detrimental to performance, and thus, the combination of a genetic risk factor and altered modulation may provide important information for identifying individuals who are at increased risk for AD.

Upregulation of Mineralocorticoid Receptor in the Hypothalamus Associated with a High Anxiety-like Level in Apolipoprotein E4 Transgenic Mice.

Anxiety symptoms occur in a large portion of Alzheimer's disease (AD) patients. ApolipoproteinE-4 (ApoE ε4 allele), a risk factor for AD, has been recognized as an important contributor to psychiatric disorders. In the present study, we aimed to investigate the corticosterone level in relation to anxiety-like behavior changes in transgenic male mice with different glial fibrillary acidic protein (GFAP)-ApoE isoforms. GFAP-ApoE4 transgenic mice aged 3 months showed higher anxiety-like behavior in open field, light-dark box and elevated plus maze tasks compared with that of age-matched GFAP-ApoE3 mice. However, corticotropin releasing factor levels in the hypothalamus and plasma corticosterone secretion were similar in GFAP-ApoE3 and GFAP-ApoE4 transgenic male mice. Additionally, increased expression of the mineralocorticoid receptor (MR) and unchanged expression of the glucocorticoid receptor were observed in the hypothalamus of GFAP-ApoE4 mice. However, no significant differences were found in the expression levels of the MR in GFAP-ApoE3 and GFAP-ApoE4 mice at postnatal day 2. In conclusion, we found that MR upregulation rather than corticosterone level changes in the early stage of adulthood was associated with the higher anxiety-like level measured in GFAP-ApoE4 mice.

Apolipoprotein E, carbon dioxide vasoreactivity, and cognition in older adults: effect of hypertension.

OBJECTIVES: To investigate the associations between the apolipoprotein E (APOE) ε4 allele, carbon dioxide (CO2 ) vasoreactivity, and cognitive performance and to explore the effect of CO2 vasoreactivity and hypertension on the associations between APOE and cognition. DESIGN: Observational. SETTING: Community. PARTICIPANTS: Older adults (N = 625) enrolled in the Maintenance of Balance, Independent Living, Intellect and Zest in the Elderly of Boston Study. MEASUREMENTS: Change in cerebral blood flow velocity in response to CO2 challenge (CO2 ), measured using transcranial Doppler ultrasonography, Trail-Making Test Part B - A (TMT), Hopkins Verbal Learning Test delayed recall (HVLT). RESULTS: APOE-ε4 was associated with lower CO2 vasoreactivity (P = .009) and poorer performance on the TMT (P < .001) and HVLT (P < .001). Having hypertension and APOE-ε4 was associated with worse cognitive and CO2 vasoreactivity measures than having neither or either alone (P < .001 for TMT and HVLT, P = .01 for CO2 vasoreactivity). The association between APOE-ε4 and cognition was only significant if it was present concurrent with low CO2 vasoreactivity, defined as below the median of the sample (APOE by CO2 vasoreactivity interaction: P = .04 for TMT, P = .04 for HVLT). In hypertension, the association between APOE-ε4 and executive function was also only significant in participants with lower CO2 vasoreactivity (P = .005 for APOE by CO2 vasoreactivity). CONCLUSION: Individuals at risk of Alzheimer's disease (AD) because they have APOE-ε4 may have lower CO2 vasoreactivity, which in turn may be contributing to the observed lower cognitive performance associated with this allele. The cognitive effect of APOE-ε4 is magnified in hypertension and low CO2 vasoreactivity. This study offers evidence that APOE-ε4 may be associated with microvascular brain injury even in the absence of clinical AD.

Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia.

Several lines of evidence support immune response in brain as a mechanism of injury in Alzheimer disease (AD). Moreover, immune activation is heightened in apolipoprotein E (APOE) ε4 carriers; inhibitors of prostaglandin (PG) synthesis show a partially protective effect on AD risk from APOE ε4; and genetic variants in triggering receptor expressed on myeloid cells 2 (TREM2) are a rare but potent risk for AD. We tested the hypothesis that APOE ε4 inheritance modulates both the PGE2 pathway and TREM2 expression using primary murine microglia from targeted replacement (TR) APOE3/3 and APOE4/4 mice. Microglial cyclooxygenase-2, microsomal PGE synthase, and PGE2 expression were increased 2- to 25-fold in both genotypes by TLR activators; however, this induction was significantly (P < 0.01) greater in TR APOE4/4 microglia with TLR3 and TLR4 activators. Microglial TREM2 expression was reduced approximately 85% by all TLR activators; this reduction was approximately one-third greater in microglia from TR APOE4/4 mice. Importantly, both receptor-associated protein and a nuclear factor κ-light-chain-enhancer inhibitor blocked TR APOE4/4-dependent effects on the PGE2 pathway but not on TREM2 expression. These data demonstrate complementary, but mechanistically distinct, regulation of pro- and anti-inflammatory mediators in TR APOE4/4 murine microglia that yields a more proinflammatory state than with TR APOE3/3.

Dietary fat composition and dementia risk.

This is a qualitative review of the evidence linking dietary fat composition to the risk of developing dementia. The review considers laboratory and animal studies that identify underlying mechanisms as well as prospective epidemiologic studies linking biochemical or dietary fatty acids to cognitive decline or incident dementia. Several lines of evidence provide support for the hypothesis that high saturated or trans fatty acids increase the risk of dementia and high polyunsaturated or monounsaturated fatty acids decrease risk. Dietary fat composition is an important factor in blood-brain barrier function and the blood cholesterol profile. Cholesterol and blood-brain barrier function are involved in the neuropathology of Alzheimer's disease, and the primary genetic risk factor for Alzheimer's disease, apolipoprotein E-ε4, is involved in cholesterol transport. The epidemiologic literature is seemingly inconsistent on this topic, but many studies are difficult to interpret because of analytical techniques that ignored negative confounding by other fatty acids, which likely resulted in null findings. The studies that appropriately adjust for confounding by other fats support the dietary fat composition hypothesis.

Interaction of APOE genotype and testosterone on episodic memory in middle-aged men.

Age-related changes in testosterone are believed to be a key component of the processes that contribute to cognitive aging in men. The APOE-ε4 allele may interact with testosterone and moderate the hormone's association with cognition. The goals of the present study were to examine the degree to which free testosterone is associated with episodic memory in a community-based sample of middle-aged men, and examine the potential interaction between free testosterone and the APOE-ε4 allele. Data were used from 717 participants in the Vietnam Era Twin Study of Aging. Average age was 55.4 years (standard deviation = 2.5). Significant positive associations were observed between free testosterone level and verbal episodic memory, as well as a significant interaction between free testosterone and APOE-ε4 status. In ε4 carriers free testosterone was positively associated with verbal episodic memory performance (story recall), whereas no association was observed in ε4 noncarriers. Results support the hypothesis that APOE-ε4 status increases susceptibility to other risk factors, such as low testosterone, which may ultimately contribute to cognitive decline or dementia.