APOE genotype, hippocampal volume, and cognitive reserve predict improvement by cognitive training in older adults without dementia: a randomized controlled trial.

Cognitive training (CT) programs aim to improve cognitive performance and impede its decline. Thus, defining the characteristics of individuals who can benefit from these interventions is essential. Our objectives were to assess if the cognitive reserve (CR), APOE genotype (e4 carriers/non-carriers) and/or hippocampal volume might predict the effectiveness of a CT program. Participants were older adults without dementia (n = 226), randomized into parallel experimental and control groups. The assessment consisted of a neuropsychological protocol and additional data regarding total intracranial, gray matter, left/right hippocampus volume; APOE genotype; and Cognitive Reserve (CR). The intervention involved multifactorial CT (30 sessions, 90 min each), with an evaluation pre- and post-training (at six months); the control group simply following the center's routine activities. The primary outcome measures were the change in cognitive performance and the predictors of change. The results show that APOE-e4 non-carriers (79.1%) with a larger left hippocampal volume achieved better gains in semantic verbal fluency (R2 = .19). Subjects with a larger CR and a greater gray matter volume better improved their processing speed (R2 = .18). Age was correlated with the improvement in executive functions, such that older age predicts less improvement (R2 = .07). Subjects with a larger left hippocampal volume achieved more significant gains in general cognitive performance (R2 = .087). In conclusion, besides the program itself, the effectiveness of CT depends on age, biological factors like genotype and brain volume, and CR. Thus, to achieve better results through a CT, it is essential to consider the different characteristics of the participants, including genetic factors.Trial registration: Trial retrospectively registered on January 29th, 2020-(ClinicalTrials.gov -NCT04245579).

Oxidative Stress, Lipid Peroxidation and Ferroptosis Are Major Pathophysiological Signatures in the Placental Tissue of Women with Late-Onset Preeclampsia.

Preeclampsia, a serious and potentially life-threatening medical complication occurring during pregnancy, is characterized by hypertension and often accompanied by proteinuria and multiorgan dysfunction. It is classified into two subtypes based on the timing of diagnosis: early-onset (EO-PE) and late-onset preeclampsia (LO-PE). Despite being less severe and exhibiting distinct pathophysiological characteristics, LO-PE is more prevalent than EO-PE, although both conditions have a significant impact on placental health. Previous research indicates that different pathophysiological events within the placenta may contribute to the development of preeclampsia across multiple pathways. In our experimental study, we investigated markers of oxidative stress, ferroptosis, and lipid peroxidation pathways in placental tissue samples obtained from women with LO-PE (n = 68) compared to healthy control pregnant women (HC, n = 43). Through a comprehensive analysis, we observed an upregulation of specific molecules associated with these pathways, including NADPH oxidase 1 (NOX-1), NADPH oxidase 2 (NOX-2), transferrin receptor protein 1 (TFRC), arachidonate 5-lipoxygenase (ALOX-5), acyl-CoA synthetase long-chain family member 4 (ACSL-4), glutathione peroxidase 4 (GPX4) and malondialdehyde (MDA) in women with LO-PE. Furthermore, increased ferric tissue deposition (Fe3+) was observed in placenta samples stained with Perls' Prussian blue. The assessment involved gene and protein expression analyses conducted through RT-qPCR experiments and immunohistochemistry assays. Our findings underscore the heightened activation of inflammatory pathways in LO-PE compared to HC, highlighting the pathological mechanisms underlying this pregnancy disorder.

Sex differences in the progression to Alzheimer's disease: a combination of functional and structural markers.

Mild cognitive impairment (MCI) has been frequently interpreted as a transitional phase between healthy cognitive aging and dementia, particularly of the Alzheimer's disease (AD) type. Of note, few studies explored that transition from a multifactorial perspective, taking into consideration the effect of basic factors such as biological sex. In the present study 96 subjects with MCI (37 males and 59 females) were followed-up and divided into two subgroups according to their clinical outcome: "progressive" MCI (pMCI = 41), if they fulfilled the diagnostic criteria for AD at the end of follow-up; and "stable" MCI (sMCI = 55), if they remained with the initial diagnosis. Different markers were combined to characterize sex differences between groups, including magnetoencephalography recordings, cognitive performance, and brain volumes derived from magnetic resonance imaging. Results indicated that the pMCI group exhibited higher low-frequency activity, lower scores in neuropsychological tests and reduced brain volumes than the sMCI group, being these measures significantly correlated. When sex was considered, results revealed that this pattern was mainly due to the influence of the females' sample. Overall, females exhibited lower cognitive scores and reduced brain volumes. More interestingly, females in the pMCI group showed an increased theta activity that correlated with a more abrupt reduction of cognitive and volumetric scores as compared with females in the sMCI group and with males in the pMCI group. These findings suggest that females' brains might be more vulnerable to the effects of AD pathology, since regardless of age, they showed signs of more pronounced deterioration than males.

Understanding the Episodic Memory and Executive Functioning Axis Impairment in MCI Patients: A Multicenter Study in Comparison with CSF Biomarkers.

BACKGROUND: This study aimed to explore the association between a verbal learning task that evaluates the potential mutual dependency between memory and executive functions (i.e., the Test of Memory Strategies, TMS) and cerebrospinal fluid (CSF) Alzheimer's Disease (AD) biomarkers. METHODS: A sample of 47 mild cognitive impairment (MCI) participants from Poland and Spain were classified according to the Erlangen Score Diagnostic Algorithm (ESA) into CSF- (n = 16) and CSF+ (n = 31) groups. Correlation analyses between TMS word-list conditions and CSF biomarkers were conducted. Additionally, an analysis of covariance was performed to define the effect on ESA classification in the sample, using as a covariable the country of origin of the participants. RESULTS: Significant associations between the TMS-3 condition and Aß42, t-tau, and p-tau were observed for the whole sample. In addition, the CSF- participants obtained higher cognitive performance in TMS-3 compared to the CSF+ group. This outcome persisted if the groups were based on Aß42 scores, but not t-tau or p-tau values. CONCLUSIONS: These findings could indicate that poor performance on verbal learning tests may be affected by executive dysfunctions. Therefore, future intervention plans focused on training executive functions would be of interest to improve the ability of MCI patients to encode and organize information.

Association between Mineral Intake and Cognition Evaluated by Montreal Cognitive Assessment (MoCA): A Cross-Sectional Study.

BACKGROUND: Mineral intake may protect against cognitive impairment (CI) and all-cause dementia, which affects a large number of adults worldwide. The aim of this study was to investigate the association between mineral intake and Montreal Cognitive Assessment (MoCA), which is a sensitive and specific test. METHODS: In total, 201 adults were included in a cross-sectional study. They completed a three-day dietary record to estimate their average daily intake of minerals. Contributions to dietary reference intakes (DRIs) were also calculated. The participants were divided into tertiles according to their mineral intake. CI classifications were determined via the MoCA (score < 26). Apolipoprotein E (APOE) genotyping was carried out, and the patients' anthropometric measurements and physical activity, health and personal data were collected. RESULTS: The prevalence of CI in this selective sample was 54.2% (34.3% females and 19.9% males). In women, being in the third tertiles of iron and manganese intake was associated with lower odds of having CI (OR [95% CI]: 0.32 [0.11 ± 0.93]; 0.33 [0.12 ± 0.93], p < 0.05). No significant differences were observed for any of the nutrients studied in men. CONCLUSIONS: These findings suggest that a low mineral intake, especially low iron and manganese intake in women, is associated with a worse cognition as assessed by MoCA.

The role of life satisfaction in the association between problematic technology use and anxiety in children and adolescents during the COVID-19 pandemic.

The main aim of this study is to explore problematic technology use among adolescents (Internet, video games, mobiles, and television) and its association with anxiety symptoms. Furthermore, we also analysed the possible moderating role of life satisfaction in this relationship during the COVID-19 pandemic in Spain. A cross-sectional survey of 4025 children and adolescents (52% females and 48% males) between 12 and 18 years old was carried out to explore problematic technology use and its correlation with anxiety and life satisfaction after pandemic lockdown. Four multivariate regressions containing the independent variable (problematic technology use), the moderator (life satisfaction), and their interaction were entered to predict the outcome (anxiety). The moderated models were examined using SPSS PROCESS macro software (Model 1). Analyses showed significant positive correlations with anxiety and negative correlations with life satisfaction regarding problematic technology use (mobile phone, television, and internet). Both gender and age had a significant direct effect on anxiety (showing that women and older participants had the greatest anxiety). In the moderation analysis, when life satisfaction was higher, the presence of anxiety symptoms depended to a greater extent on the problematic use of technology. Our results confirm that problematic technology use is related to higher levels of anxiety in adolescents, with differences by age and gender. The results also showed that life satisfaction mediated the relationship between technology abuse and anxiety, such that when life satisfaction was higher, the presence of anxiety symptoms was more dependent on problematic technology use. These findings have implications for health and education professionals.

Sex specific EEG signatures associated with cerebrospinal fluid biomarkers in mild cognitive impairment.

OBJECTIVE: The use of the electroencephalography (EEG) technique in Alzheimer's disease (AD) diagnosis is scarce due to a lack of validation of its neurophysiological information with current biomarkers. Therefore, our goal was to assess correlations between brain spectral power signatures and cerebrospinal fluid markers (CSF) such as amyloid-ß 42 load (Aß-42), total tau (t-tau), and phosphorylated tau (p-tau) in a mild cognitive impairment (MCI) population. Furthermore, given the AD sex-dependent vulnerability related to CSF biomarkers, we went a little forward looking for different electrophysiological correlations for males and females independently. METHODS: A data-driven approach was employed to determine bidimensional spectral power signatures (space-frequency) that correlated (Spearman) significantly with any of the three CSF markers in 27 patients with MCI in any of the two sex-dependent subsamples (i.e., 12 females and 15 males). RESULTS: Our main significant outcomes evidenced 1) a negative correlation of Aß-42 load with central-posterior theta power and a negative correlation of t-tau with widespread alpha power within the male subsample, and 2) a significant negative correlation between t-tau and widespread beta power in the female subgroup. CONCLUSIONS: There is a distinctive profile of correlations between resting-state electrophysiological signatures and CSF markers in male and female individuals. SIGNIFICANCE: The combination of these two measures would be pointing out the need of a more personalized approach to promote early AD diagnosis.

Modification of Alpha Brain Oscillatory Activity in Fibromyalgia After Very Low Intensity Transcranial Magnetic Stimulation.

BACKGROUND: Fibromyalgia (FM) is a chronic disease, with no effective treatments for this disorder. The origin is suspected to be a misprocessing of signals in the central nervous system. One of the experimental treatments is very low intensity transcranial magnetic stimulation (LITMS) used to perform central neuromodulation. OBJECTIVES: The main objective was to characterize the differences in oscillatory brain processing before and after LITMS in FM and compare the results with healthy controls. STUDY DESIGN: This is an interventional study with control group, which shows how the treatment with LITMS could modify brain oscillatory activity and be useful for the improvement of symptoms in FM patients. METHODS: Thirty-three women with FM and 14 healthy controls are studied using magnetoencephalography recording, and mechanical stimuli are applied before and after treatment with transcranial magnetic stimulation. Changes in different brain areas and a specific brain frequency are studied, and the results are analyzed within and between patients, before and after treatment. RESULTS: In the FM group, an increase in alpha brain oscillatory activity was observed mainly in the dorsolateral prefrontal cortex (DLPFS), and more pronounced in the left hemisphere (P = 0.03). In addition, there was a significant improvement in the FM impact questionnaire in the patients (P < 0.01). When comparing patients with controls, it is observed that the differences in alpha frequency in this brain area disappear between groups. LIMITATIONS: Age difference between patients and controls. Replicating the long-term results. CONCLUSIONS: This treatment improves the patients' symptomatology, and also produces statistical changes in alpha brain activity in the DLPFS. Furthermore, a normalization was observed in this frequency and in this area, similar to that of the controls.

Age and APOE genotype affect the relationship between objectively measured physical activity and power in the alpha band, a marker of brain disease.

BACKGROUND: Electrophysiological studies show that reductions in power within the alpha band are associated with the Alzheimer's disease (AD) continuum. Physical activity (PA) is a protective factor that has proved to reduce AD risk and pathological brain burden. Previous research has confirmed that exercise increases power in the alpha range. However, little is known regarding whether other non-modifiable risk factors for AD, such as increased age or APOE ε4 carriage, alter the association between PA and power in the alpha band. METHODS: The relationship between PA and alpha band power was examined in a sample of 113 healthy adults using magnetoencephalography. Additionally, we explored whether ε4 carriage and age modulate this association. The correlations between alpha power and gray matter volumes and cognition were also investigated. RESULTS: We detected a parieto-occipital cluster in which PA positively correlated with alpha power. The association between PA and alpha power remained following stratification of the cohort by genotype. Younger and older adults were investigated separately, and only younger adults exhibited a positive relationship between PA and alpha power. Interestingly, when four groups were created based on age (younger-older adult) and APOE (E3/E3-E3/E4), only younger E3/E3 (least predicted risk) and older E3/E4 (greatest predicted risk) had associations between greater alpha power and higher PA. Among older E3/E4, greater alpha power in these regions was associated with improved memory and preserved brain structure. CONCLUSION: PA could protect against the slowing of brain activity that characterizes the AD continuum, where it is of benefit for all individuals, especially E3/E4 older adults.

A multivariate model of time to conversion from mild cognitive impairment to Alzheimer's disease.

The present study was aimed at determining which combination of demographic, genetic, cognitive, neurophysiological, and neuroanatomical factors may predict differences in time to progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). To this end, a sample of 121 MCIs was followed up during a 5-year period. According to their clinical outcome, MCIs were divided into two subgroups: (i) the "progressive" MCI group (n = 46; mean time to progression 17 ± 9.73 months) and (ii) the "stable" MCI group (n = 75; mean time of follow-up 31.37 ± 14.58 months). Kaplan-Meier survival analyses were applied to explore each variable's relationship with the progression to AD. Once potential predictors were detected, Cox regression analyses were utilized to calculate a parsimonious model to estimate differences in time to progression. The final model included three variables (in order of relevance): left parahippocampal volume (corrected by intracranial volume, LP_ ICV), delayed recall (DR), and left inferior occipital lobe individual alpha peak frequency (LIOL_IAPF). Those MCIs with LP_ICV volume, DR score, and LIOL_IAPF value lower than the defined cutoff had 6 times, 5.5 times, and 3 times higher risk of progression to AD, respectively. Besides, when the categories of the three variables were "unfavorable" (i.e., values below the cutoff), 100% of cases progressed to AD at the end of follow-up. Our results highlighted the relevance of neurophysiological markers as predictors of conversion (LIOL_IAPF) and the importance of multivariate models that combine markers of different nature to predict time to progression from MCI to dementia.

The relationship between physical activity, apolipoprotein E ε4 carriage, and brain health.

BACKGROUND: Neuronal hyperexcitability and hypersynchrony have been described as key features of neurophysiological dysfunctions in the Alzheimer's disease (AD) continuum. Conversely, physical activity (PA) has been associated with improved brain health and reduced AD risk. However, there is controversy regarding whether AD genetic risk (in terms of APOE ε4 carriage) modulates these relationships. The utilization of multiple outcome measures within one sample may strengthen our understanding of this complex phenomenon. METHOD: The relationship between PA and functional connectivity (FC) was examined in a sample of 107 healthy older adults using magnetoencephalography. Additionally, we explored whether ε4 carriage modulates this association. The correlation between FC and brain structural integrity, cognition, and mood was also investigated. RESULTS: A relationship between higher PA and decreased FC (hyposynchrony) in the left temporal lobe was observed among all individuals (across the whole sample, in ε4 carriers, and in ε4 non-carriers), but its effects manifest differently according to genetic risk. In ε4 carriers, we report an association between this region-specific FC profile and preserved brain structure (greater gray matter volumes and higher integrity of white matter tracts). In this group, decreased FC also correlated with reduced anxiety levels. In ε4 non-carriers, this profile is associated with improved cognition (working and episodic memory). CONCLUSIONS: PA could mitigate the increase in FC (hypersynchronization) that characterizes preclinical AD, being beneficial for all individuals, especially ε4 carriers.

How cognitive reserve influences older adults' cognitive state, executive functions and language comprehension: A structural equation model.

Cognitive reserve has been defined as the individuals' ability to tolerate age-related and neurodegenerative changes in the brain without developing clinical symptoms or signs of disease. Formal education, occupational attainment, and knowledge of other languages have been assessed as the most relevant factors determining cognitive reserve. The main objective of this study was to develop a structural equation model that reflects the direct influence of cognitive reserve on old adults' general cognitive status and executive functioning, and indirectly on sentence comprehension performance through executive functions mediation. One hundred and fifty eight Spanish-speaking older adults, cognitively intact, were assessed to obtain cognitive reserve data, general cognitive status, executive functioning (inhibitory control, working memory and cognitive flexibility), and sentence comprehension measures. High indicators of adjustment of the proposed model were obtained. The most related factors to cognitive reserve were education and occupational attainment. As we hypothesize, cognitive reserve had a higher direct significant relation to cognitive status and, in a lesser extent, to executive functioning. Participants' general cognitive status and executive function were high and directly related. Furthermore, cognitive reserve has an indirect positive relation to sentence comprehension via executive functions' mediation.

BDNF Val66Met Polymorphism and Gamma Band Disruption in Resting State Brain Functional Connectivity: A Magnetoencephalography Study in Cognitively Intact Older Females.

The pathophysiological processes undermining brain functioning decades before the onset of the clinical symptoms associated with dementia are still not well understood. Several heritability studies have reported that the Brain Derived Neurotrophic Factor (BDNF) Val66Met genetic polymorphism could contribute to the acceleration of cognitive decline in aging. This mutation may affect brain functional connectivity (FC), especially in those who are carriers of the BDNF Met allele. The aim of this work was to explore the influence of the BDNF Val66Met polymorphism in whole brain eyes-closed, resting-state magnetoencephalography (MEG) FC in a sample of 36 cognitively intact (CI) older females. All of them were ε3ε3 homozygotes for the apolipoprotein E (APOE) gene and were divided into two subgroups according to the presence of the Met allele: Val/Met group (n = 16) and Val/Val group (n = 20). They did not differ in age, years of education, Mini-Mental State Examination scores, or normalized hippocampal volumes. Our results showed reduced antero-posterior gamma band FC within the Val/Met genetic risk group, which may be caused by a GABAergic network impairment. Despite the lack of cognitive decline, these results might suggest a selective brain network vulnerability due to the carriage of the BDNF Met allele, which is linked to a potential progression to dementia. This neurophysiological signature, as tracked with MEG FC, indicates that age-related brain functioning changes could be mediated by the influence of particular genetic risk factors.

Factors Explaining Language Performance After Training in Elders With and Without Subjective Cognitive Decline.

The present study explores if cognitive reserve, executive functions, and working memory capacity are predictive of performance in the language domain (specifically in sentence comprehension and naming) after a cognitive training intervention. Sixty-six Spanish older adults voluntarily participated in the study, classified either as older adults with subjective cognitive decline according to Jessen et al.'s (2014) criteria (n = 35; 70.94 ± 4.16 years old) or cognitively intact (n = 31; 71.34 ± 4.96 years old). Written sentence comprehension and visual confrontation naming were assessed both immediately after recruitment (at the baseline), and then 6 months later, once each participant had completed his/her cognitive training (a well-known program in Spain, called UMAM; English translation: Madrid City Council Memory Unit Program). Cognitive reserve, executive functions (cognitive flexibility and controlled interference efficiency), and working memory capacity were measured for all participants at the baseline. Results pointed out that the subjective cognitive decline group presented greater benefits in the language domain than cognitively intact participants. We also observed that lower executive functioning and working memory capacity at the baseline predicted larger benefits in language performance after training, but only in the group of cognitively intact older adults. However, selected predictors hardly explained subjective cognitive decline participants' results in language performance after training.

Physical activity effects on the individual alpha peak frequency of older adults with and without genetic risk factors for Alzheimer's Disease: A MEG study.

OBJECTIVE: Since a cure for Alzheimer's Disease (AD) is yet to be discovered, attention has shifted towards prevention. Physical activity (PA) emerged as a notorious lifestyle factor that could influence brain structure and function. The individual alpha peak frequency (IAPF) is a measure that summarizes the spectral content of brain signals and has been proven to be sensitive to both AD pathology and PA interventions. Therefore, our goal was to unravel whether chronic PA modulates IAPF and if APOE ɛ4 carriage moderates this relationship. METHODS: We analyzed 4-minutes of resting-state magnetoencephalographic recordings from 100 healthy elders that provided self-reported measures of PA, and the IAPF was calculated. RESULTS: We found that IAPF was negatively influenced by age and APOE and positively influenced by PA. The effect of PA on IAPF only remained significant for the ɛ4 non-carriers group. CONCLUSIONS: PA is positively associated to higher IAPF in healthy older adults and could potentially act as a protective factor against cognitive decline. Nevertheless, such effect is non-significant among elders who are more vulnerable to developing AD due to their genetic carriage. SIGNIFICANCE: This investigation offers the first neurophysiological evidences on the combined effects of APOE genotype and PA in healthy elders.

Young alcohol binge drinkers have elevated blood endotoxin, peripheral inflammation and low cortisol levels: neuropsychological correlations in women.

Alcohol binge drinking is a pattern of heavy alcohol consumption that is increasingly practiced by adolescents and young adults. Evidence indicates that alcohol binges induce peripheral inflammation and an exacerbated neuroimmune response that may participate in alcohol-induced cognitive/behavioral dysfunctions. Here, we recruited 20-year-old male and female university students who were identified as binge drinkers for at least 2 years. Compared with controls, young alcohol binge drinkers had elevated levels of blood endotoxin and upregulated markers of the toll-like receptor 4/NF-κB inflammatory pathway in peripheral blood mononuclear cells, together with pro-inflammatory cytokine/chemokine release, oxidative stress and lipid peroxidation. These changes positively correlate with the estimated blood alcohol levels achieved during alcohol binge intoxication and negatively correlate with the time elapsed from the last alcohol consumption. The immune/inflammatory changes were more prominent in female drinkers, who showed elevated levels of alcohol danger-associated molecules, such as high mobility group box 1, indicating that there are sex-related differences in the peripheral inflammatory response to alcohol. In contrast, cortisol levels were decreased in alcohol binge drinkers. Finally, higher levels of inflammatory markers, mainly monocyte chemoattractant protein-1, as well as LPS, high mobility group box 1, toll-like receptor 4, IL-6 and ciclooxygenase-2, correlated with worse scores on episodic memory and executive functioning tasks in female binge drinkers but not in male binge drinkers. These results emphasize possible risky consequences of alcohol use in binge episodes during young adulthood and call attention to sex-related differences in the alcohol-induced immune/inflammatory and neurocognitive responses.

Increased plasma oleoylethanolamide and palmitoleoylethanolamide levels correlate with inflammatory changes in alcohol binge drinkers: the case of HMGB1 in women.

Alcohol binge drinking is a heavy pattern of alcohol consumption increasingly used by young people. In a previous study, we reported that young drinkers with a 2-year history of binge alcohol consumption had an overactivation of the innate immune system and peripheral inflammation when compared with controls. In the present study, we measured several biolipids that are fatty acid derivatives belonging to the acylethanolamide or 2-acylglycerol families in the plasma of the same subjects (n = 42; 20 men and 22 women). We found that during abstinence, alcohol binge drinkers had elevated plasma levels of oleoylethanolamide, palmitoleoylethanolamide, arachidonoylethanolamide, dihomo-γ-linolenoyl ethanolamide and linoleoyl ethanolamide, which positively correlated with changes in the mRNA expression of key inflammatory markers in peripheral blood mononuclear cells, such as toll-like receptors (TLR4), pro-inflammatory cytokines/chemokines interleukin-1 beta, interleukin-6 and monocyte chemoattractant protein-1, and cyclooxygenase-2. Additionally, plasma oleoylethanolamide positively correlated with plasma levels of high mobility group box-1, which is a danger-associated molecular pattern and an endogenous TLR4 agonist, specifically in female alcohol binge drinkers. No changes were observed in 2-acylglycerols in alcohol binge drinkers, although sex-related differences in these bioactive lipids as well as in palmitoleoylethanolamide and docosatetraenoylethanolamide levels were detected. These results extend the previous clinical findings observed in patients diagnosed with long-term alcohol use disorder to young users and suggest a prominent role for these lipids in the response to acute alcohol exposure.

APOE ε4 Modulation of Training Outcomes in Several Cognitive Domains in a Sample of Cognitively Intact Older Adults.

BACKGROUND: Most research points to the ɛ4 allele of the apolipoprotein E (APOE) gene as the most recognizable genetic risk factor associated with Alzheimer's disease pathogenesis. It has been also suggested that the APOEɛ4 allele has a negative influence on cognitive functioning, which begins long before cognitive impairment becomes manifest. However, still, little is known about the APOEɛ4 interaction with cognitive intervention programs. OBJECTIVE: The main goal of this study was to explore whether there was a differential APOE genotype modulation effect after cognitive training in different domains, such as language comprehension, executive functions, and memory. Contrary to other studies, hippocampal volume was controlled for. METHODS: Fifty older adults (65+ years; 30 women and 20 men) participated in a multi-domain cognitive training that involved 30 sessions taking place over 12 weeks. Half of the participants were APOEɛ4 carriers. The control group was matched in age, gender, normalized hippocampal volume, cognitive reserve, Mini-Mental State Examination score, and Geriatric Depression Scale-Short Version. RESULTS: The study revealed that there were consistent treatment benefits in complex sentence comprehension (noncanonical sentences and sentences with two propositions), a domain that was not directly trained, but only in the A POEɛ4 noncarrier group. CONCLUSION: Genetic profile modulates training outcomes in sentence comprehension.

APOE ε4 Genotype and Cognitive Reserve Effects on the Cognitive Functioning of Healthy Elders.

AIM: To test the association between cognitive performance and APOE genotype, and to assess potential modifications of this association by sociodemographic and neuroanatomical factors in a sample of 74 healthy elders. METHODS: Firstly, we explored the isolated role of the APOE ɛ4 genotype (i.e., APOE4) in different neuropsychological tests, and then the effects of its interaction with sociodemographic (i.e., age, gender, and educational level) and neuroanatomical (i.e., hippocampal volumes) variables. Subsequently, we performed the same analyses after dividing the sample into two subgroups according to their Mini-Mental State Examination scores (control-high group ≥29 and control-low group < 29). RESULTS: In the whole group, APOE4 carriers exhibited a significantly poorer execution in several cognitive domains including global cognitive functioning, episodic memory, verbal fluency, and naming. This effect was more noticeable in older and less educated subjects. The separated analyses revealed that APOE4 carriers in the control-low group exhibited lower scores in global cognitive functioning and episodic memory, while no effects were observed in the control-high group. Neither gender nor hippocampal volumes showed a significant interaction effect with APOE genotype. CONCLUSIONS: Current results point out that APOE4 genotype influences healthy aged cognition, although factors such age or educational attainment seem to modulate its effects.