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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 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-β 42 load (Aβ-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.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).Our main significant outcomes evidenced 1) a negative correlation of Aβ-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.There is a distinctive profile of correlations between resting-state electrophysiological signatures and CSF markers in male and female individuals.The combination of these two measures would be pointing out the need of a more personalized approach to promote early AD diagnosis.

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.

Alzheimer’s disease (AD) studies on animal models, and humans showed a tendency of the brain tissue to become hyperexcitable and hypersynchronized, causing neurodegeneration. However, we know little about either the onset of this phenomenon or its early effects on functional brain networks. We studied functional connectivity (FC) on 127 participants (92 middle-age relatives of AD patients and 35 age-matched nonrelatives) using magnetoencephalography. FC was estimated in the alpha band in areas known both for early amyloid accumulation and disrupted FC in MCI converters to AD. We found a frontoparietal network (anterior cingulate cortex, dorsal frontal, and precuneus) where relatives of AD patients showed hypersynchronization in high alpha (not modulated by APOE-ε4 genotype) in comparison to age-matched nonrelatives. These results represent the first evidence of neurophysiological events causing early network disruption in humans, opening a new perspective for intervention on the excitation/inhibition unbalance.

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., This study was funded by the Spanish Ministry of Economy and Competitiveness under the Grant PSI2015-68793-C3-1-R [D601] and by the project B2017/BMD-3760 from NEUROCENTRO. Complimentary, it was supported by a predoctoral fellowship from La Caixa Foundation to JFL, a postdoctoral fellowship from the Spanish Ministry of Economy and Competitiveness to PC (FJCI-2015-26755), a grant from the Spanish Ministry of Science, Innovation and Universities to JVR (FJCI-2017-33396), and a predoctoral grant by the Spanish Ministry of Economy (BES-2016-076869) to FRT.

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.

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.

Background: Most research points to the ϵ4 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 APOE ϵ4 allele has a negative influence on cognitive functioning, which begins long before cognitive impairment becomes manifest. However, still, little is known about the APOE ϵ4 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 APOE ϵ4 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 POE ϵ4 noncarrier group. Conclusion: Genetic profile modulates training outcomes in sentence comprehension.

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.

Working memory (WM) is a crucial cognitive process and its disruption is among the earliest symptoms of Alzheimer’s disease. While alterations of the neuronal processes underlying WM have been evidenced in mild cognitive impairment (MCI), scarce literature is available in subjective cognitive decline (SCD). We used magnetoencephalography during a WM task performed by MCI [Formula: see text], SCD [Formula: see text] and healthy elders [Formula: see text] to examine group differences during the maintenance period (0–4000[Formula: see text]ms). Data were analyzed using time–frequency analysis and significant oscillatory differences were localized at the source level. Our results indicated significant differences between groups, mainly during the early maintenance (250–1250[Formula: see text]ms) in the theta, alpha and beta bands and in the late maintenance (2750–3750[Formula: see text]ms) in the theta band. MCI showed lower local synchronization in fronto-temporal cortical regions in the early theta–alpha window relative to controls [Formula: see text] and SCD [Formula: see text], and in the late theta window relative to controls [Formula: see text] and SCD [Formula: see text]. Early theta–alpha power was significantly correlated with memory scores [Formula: see text] and late theta power was correlated with task performance [Formula: see text] and functional activity scores [Formula: see text]. In the early beta window, MCI showed reduced power in temporo-posterior regions relative to controls [Formula: see text] and SCD [Formula: see text]. Our results may suggest that these alterations would reflect that memory-related networks are damaged.

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.

The role of colour in object recognition is controversial; in this study, a critical review of previous studies, as well as a longitudinal study, was conducted. We examined whether colour benefits the ability of Alzheimer’s disease (AD) patients and normal controls (NC) when naming items differing in colour diagnosticity: living things (LT) versus nonliving things (NLT). Eleven AD patients were evaluated twice with a temporal interval of 3 years; 26 NC were tested once. The participants performed a naming task (colour and greyscale photographs); the impact of nuisance variables (NVs) and potential ceiling effects were also controlled. Our results showed that (i) colour slightly favoured processing of items with higher colour diagnosticity (i.e., LT) in both groups; (ii) AD patients used colour information similarly to NC, retaining this ability over time; (iii) NVs played a significant role as naming predictors in all the participants, relegating domain to a minor plane; and (iv) category effects (better processing of NLT) were present in both groups. Finally, although patients underwent semantic longitudinal impairment, this was independent of colour deterioration. This finding provides better support to the view that colour is effective at the visual rather than at the semantic level of object processing.

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.

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.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 group29).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.Current results point out that APOE4 genotype influences healthy aged cognition, although factors such age or educational attainment seem to modulate its effects.

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.

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.

The consideration of Subjective Cognitive Decline (SCD) as a preclinical stage of AD remains still a matter of debate. Alpha band alterations represent one of the most significant changes in the electrophysiological profile of AD. In particular, AD patients exhibit reduced alpha relative power and frequency. We used alpha band activity measured with MEG to study whether SCD and MCI elders present these electrophysiological changes characteristic of AD, and to determine the evolution of the observed alterations across AD spectrum. The total sample consisted of 131 participants: 39 elders without SCD, 41 elders with SCD and 51 MCI patients. All of them underwent MEG and MRI scans and neuropsychological assessment. SCD and MCI patients exhibited a similar reduction in alpha band activity compared with the no SCD group. However, only MCI patients showed a slowing in their alpha peak frequency compared with both SCD and no SCD. These changes in alpha band were related to worse cognition. Our results suggest that AD-related alterations may start in the SCD stage, with a reduction in alpha relative power. It is later, in the MCI stage, where the slowing of the spectral profile takes place, giving rise to objective deficits in cognitive functioning.

In this study, the Nombela 2.0 semantic battery is presented. This is a new version of its earlier precedent: the battery Nombela (I), in an attempt to improve it (dealing with ceiling effects) and reducing the application time by decreasing the number of tasks. The battery is constructed on a common set of 98 stimuli, including both living and nonliving semantic domains. It consists of five tasks designed to explore category specificity by tapping semantic production and comprehension, using both visual and verbal input. All of the items were rated according to Spanish norms, as stated in a previous study of our group, and all of the tasks were matched across domain on six nuisance variables. The present study has two goals: (i) to make available the updated version (2.0) of the Nombela semantic memory battery and (ii) to characterize and compare the neuropsychological profiles of two different patient groups: mild cognitive impairment and Alzheimer disease, with regard to normal controls.

This article presents a new corpus of 820 words pertaining to 14 semantic categories, 7 natural (animals, body parts, insects, flowers, fruits, trees, and vegetables) and 7 man-made (buildings, clothing, furniture, kitchen utensils, musical instruments, tools, and vehicles); each word in the database was collected empirically in a previous exemplar generation study. In the present study, 152 Spanish speakers provided data for four psycholinguistic variables known to affect lexical-semantic processing in both neurologically intact and brain-damaged participants: age of acquisition, familiarity, manipulability, and typicality. Furthermore, we collected lexical frequency data derived from Internet search hits, plus three additional Spanish lexical frequency indexes. Word length, number of syllables, and the proportion of respondents citing the exemplar as a category member-which can be useful as an additional measure of typicality-are also provided. Reliability and validity indexes showed that our items display characteristics similar to those of other corpora. Overall, this new corpus of words provides a useful tool for scientists engaged in cognitive- and neuroscience-based research focused on examining language, memory, and object processing. The full set of norms can be downloaded from www.psychonomic.org/archive.