Association between APOE-ε4 allele and cognitive function is mediated by Alzheimer's disease pathology: a population-based autopsy study in an admixed sample.

BACKGROUND: Apolipoprotein E ε4 allele (APOE-ε4) is the main genetic risk factor for late-onset Alzheimer's disease (AD) and may impact cognitive function also via other neuropathological lesions. However, there is limited evidence available from diverse populations, as APOE associations with dementia seem to differ by race. Therefore, we aimed to evaluate the pathways linking APOE-ε4 to cognitive abilities through AD and non-AD neuropathology in an autopsy study with an admixed sample. METHODS: Neuropathological lesions were evaluated following international criteria using immunohistochemistry. Participants were classified into APOE-ε4 carriers (at least one ε4 allele) and non-carriers. Cognitive abilities were evaluated by the Clinical Dementia Rating Scale sum of boxes. Mediation analyses were conducted to assess the indirect association of APOE-ε4 with cognition through AD-pathology, lacunar infarcts, hyaline arteriosclerosis, cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), and TAR DNA-binding protein 43 (TDP-43). RESULTS: We included 648 participants (mean age 75 ± 12 years old, mean education 4.4 ± 3.7 years, 52% women, 69% White, and 28% APOE-ε4 carriers). The association between APOE-ε4 and cognitive abilities was mediated by neurofibrillary tangles (ß = 0.88, 95% CI = 0.45; 1.38, p < 0.001) and neuritic plaques (ß = 1.36, 95% CI = 0.86; 1.96, p < 0.001). Lacunar infarcts, hyaline arteriosclerosis, CAA, LBD, and TDP-43 were not mediators in the pathway from APOE-ε4 to cognition. CONCLUSION: The association between APOE-ε4 and cognitive abilities was partially mediated by AD-pathology. On the other hand, cerebrovascular lesions and other neurodegenerative diseases did not mediate the association between APOE-ε4 and cognition.

Apolipoprotein E ε2 allele is associated with lower risk of carotid artery obstruction in a population-based autopsy study.

INTRODUCTION: Apolipoprotein E (APOE) ε4 allele has been associated with higher carotid atherosclerosis risk, while the APOE-ε2 seems to decrease this risk. Data from autopsy studies, where carotid arteries can be evaluated in their full extension, is scarce. Therefore, we investigated the association between APOE alleles and direct morphometric measurements of carotid atherosclerosis in an autopsy study with an admixed sample. METHODS: We measured the intima-media thickness (IMT) and stenosis of the common (CCA) and internal carotid (ICA) arteries. The APOE polymorphisms were determined by real-time polymerase chain reaction. Participants were classified into three groups according to the APOE alleles (ε2, ε3, and ε4). We evaluated the association between APOE groups and carotid atherosclerosis using adjusted regression models and included interaction terms of APOE alleles with age, sex, and race. RESULTS: We evaluated 1,850 carotid artery samples from 185 participants (mean age=75±12 years old, 55% female, and 71% White). The APOE-ε2 group (n=17) had a lower carotid obstruction and a lower number of severe stenoses (≥ 70%). Having at least one ε4 allele (n=51) was not associated with carotid atherosclerosis. APOE alleles were also not associated with carotid IMT. Age, sex, and race did not modify these relationships. CONCLUSION: APOE-ε2 carriers had a lower percentage of carotid obstruction and less severe stenosis. APOE-ε4 was not related to a higher risk of carotid atherosclerosis in this cross-sectional population-based autopsy study.

Computerized working memory training for hypertensive individuals with executive function impairment: a randomized clinical trial.

Background: Hypertension is associated with working memory (WM) impairment. However, the benefits of Cogmed WM training for the hypertensive population are unknown. Therefore, we aimed to evaluate Cogmed's effects on the WM performance of hypertensive individuals with executive function (EF) impairment. Methods: We included 40 hypertensive patients (aged 40-70 years, 68% female) with EF impairment. They were randomized in a 1:1 ratio to receive 10 weeks of adaptive Cogmed training or a non-adaptive control training based on online games. The primary outcome was the WM performance. The secondary outcomes were verbal memory, visuospatial ability, executive function, global cognition, and the neuronal activity measured using functional magnetic resonance imaging (fMRI) under two WM task conditions: low (memorization of 4 spatial locations) and high (memorization of 6 spatial locations). An intention-to-treat (ITT) and per-protocol (PP) analysis were performed. Results: Cogmed did not show a significant effect on WM or any other cognitive outcome post-training. However, under the WM-low load and WM-high load conditions of the fMRI, respectively, the Cogmed group had an activation decrease in the right superior parietal lobe (ITT and PP analyses) and left inferior frontal lobe (PP analysis) in comparison to the control group. Conclusion: The Cogmed showed no effects on the WM performance of hypertensive individuals with EF impairment. However, activation decreases were observed in frontoparietal areas related to the WM network, suggesting a more efficient neuronal activity after training.

Apolipoprotein E genotypes were not associated with intracranial atherosclerosis: a population-based autopsy study.

BACKGROUND: Apolipoprotein E gene (APOE) ε4 allele is associated with a higher risk of carotid atherosclerosis, but less is known about the association of APOE with intracranial atherosclerotic disease (IAD). We aimed to investigate the association of APOE alleles with IAD in a cross-sectional autopsy study. METHODS: We measured the stenosis in the 12 arteries of the Circle of Willis using postmortem morphometric measurements. The APOE polymorphism was determined by real-time polymerase chain reaction. We assessed the association between APOE polymorphism and IAD using regression models adjusted for sociodemographic and clinical variables. We also verified the modifier effect of age, sex, and race on this association. We stratified the analysis by age group to investigate the possibility of attrition bias. RESULTS: In 400 participants (mean age=73.2±12.3 years old, 51% female, and 64% White), IAD was evaluated in 4,504 artery segments. APOE-ε4 was not associated with IAD nor with the number of artery stenosis compared to non-APOE-ε4 carriers. Sociodemographic variables did not modify this relationship. Among participants older than 70 years, there was a trend towards an association between APOE allele ε4 and a lower stenosis index in the middle cerebral artery, suggesting attrition bias related to the APOE-ε4 effect on mortality. CONCLUSIONS: APOE alleles were not associated with IAD in this population-based autopsy study. Lower stenosis in older participants suggests the possibility of attrition bias.

Higher Perceived Stress as an Independent Predictor for Lower Use of Emotion-Focused Coping Strategies in Hypertensive Individuals.

Introduction: Individuals with high scores of perceived stress (PS) are more likely to develop arterial hypertension (AH) than those with low levels of stress. In addition to this, AH and stress are both independent risk factors for executive function (EF) impairment and worse quality of life (QoL). Therefore, strategies to control and cope with emotional stress are of paramount importance. However, less is known about the association of PS with EF, QoL, and coping in individuals with hypertension. This study aimed to evaluate the association of PS with EF performance, coping strategies use, and QoL in a sample of hypertensive patients. Methods: We assessed a group of 45 hypertensive individuals (mean age = 58.42 ± 8.9 years, 71.11% female). The EF evaluation was: Frontal Assessment Battery; Controlled Oral Word Association Test-FAS; Letter-Number Sequencing subtest from the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III); Digit Span subtest from the Wechsler Memory Scale-Revised (WMS-R) and Wisconsin Card Sorting Test. The type and frequency of coping strategies used were measured by the Brief Coping with Experienced Problems Scale (Brief-COPE). The World Health Organization Quality of Life Questionnaire Bref (WHOQOL-bref) was applied to measure QoL. The associations of the PS with EF performance, coping strategies, and QoL were investigated using univariate and multiple linear regression models adjusted for age, sex, education, systolic pressure, and depression symptoms. Results: In the multivariate analyses, higher PS was an independent predictor for a lower frequency of emotion-focused strategy use (ß = -0.23; p = 0.03). However, PS was not significantly related to EF and Qol in this sample. The lower the PS, the greater the use of emotion-focused coping. Conclusion: Hypertensive individuals with high PS use less frequently positive emotion-focused coping strategies.

Vasoactive intestinal peptide exerts an excitatory effect on hypothalamic kisspeptin neurons during estrogen negative feedback.

Hypothalamic kisspeptin neurons are the primary modulators of gonadotropin-releasing hormone (GnRH) neurons. It has been shown that circadian rhythms driven by the suprachiasmatic nucleus (SCN) contribute to GnRH secretion. Kisspeptin neurons are potential targets of SCN neurons due to reciprocal connections with the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeN) and the arcuate nucleus of the hypothalamus (ARH). Vasoactive intestinal peptide (VIP), a notable SCN neurotransmitter, modulates GnRH secretion depending on serum estradiol levels, aging or time of the day. Considering that kisspeptin neurons may act as interneurons and mediate VIP's effects on the reproductive axis, we investigated the effects of VIP on hypothalamic kisspeptin neurons in female mice during estrogen negative feedback. Our findings indicate that VIP induces a TTX-independent depolarization of approximately 30% of AVPV/PeN kisspeptin neurons in gonad-intact (diestrus) and ovariectomized (OVX) mice. In the ARH, the percentage of kisspeptin neurons that were depolarized by VIP was even higher (approximately 90%). An intracerebroventricular infusion of VIP leds to an increased percentage of kisspeptin neurons expressing the phosphoSer133 cAMP-response-element-binding protein (pCREB) in the AVPV/PeN. On the other hand, pCREB expression in ARH kisspeptin neurons was similar between saline- and VIP-injected mice. Thus, VIP can recruit different signaling pathways to modulate AVPV/PeN or ARH kisspeptin neurons, resulting in distinct cellular responses. The expression of VIP receptors (VPACR) was upregulated in the AVPV/PeN, but not in the ARH, of OVX mice compared to mice on diestrus and estradiol-primed OVX mice. Our findings indicate that VIP directly influences distinct cellular aspects of the AVPV/PeN and ARH kisspeptin neurons during estrogen negative feedback, possibly to influence pulsatile LH secretion.

Relation of a Socioeconomic Index with Cognitive Function and Neuroimaging in Hypertensive Individuals.

BACKGROUND: Socioeconomic factors are important contributors to brain health. However, data from developing countries (where social inequalities are the most prominent) are still scarce, particularly about hypertensive individuals. OBJECTIVE: To evaluate the relationship between socioeconomic index, cognitive function, and cortical brain volume, as well as determine whether white matter hyperintensities are mediators of the association of the socioeconomic index with cognitive function in hypertensive individuals. METHODS: We assessed 92 hypertensive participants (mean age = 58±8.6 years, 65.2%female). Cognitive evaluation and neuroimaging were performed and clinical and sociodemographic data were collected using questionnaires. A socioeconomic index was created using education, income, occupation (manual or non-manual work), and race. The associations of the socioeconomic index with cognitive performance and brain volume were investigated using linear regression models adjusted for age, sex, time of hypertension since diagnosis, and comorbidities. A causal mediation analysis was also conducted. RESULTS: Better socioeconomic status was associated with better visuospatial ability, executive function, and global cognition. We found associations between a better socioeconomic index and a higher parietal lobe volume. White matter hyperintensities were also not mediators in the relationship between the socioeconomic index and cognitive performance. CONCLUSION: Socioeconomic disadvantages are associated with worse cognitive performance and brain volume in individuals with hypertension.