Planum temporale asymmetry in newborn monkeys predicts the future development of gestural communication's handedness.

The planum temporale (PT), a key language area, is specialized in the left hemisphere in prelinguistic infants and considered as a marker of the pre-wired language-ready brain. However, studies have reported a similar structural PT left-asymmetry not only in various adult non-human primates, but also in newborn baboons. Its shared functional links with language are not fully understood. Here we demonstrate using previously obtained MRI data that early detection of PT left-asymmetry among 27 newborn baboons (Papio anubis, age range of 4 days to 2 months) predicts the future development of right-hand preference for communicative gestures but not for non-communicative actions. Specifically, only newborns with a larger left-than-right PT were more likely to develop a right-handed communication once juvenile, a contralateral brain-gesture link which is maintained in a group of 70 mature baboons. This finding suggests that early PT asymmetry may be a common inherited prewiring of the primate brain for the ontogeny of ancient lateralised properties shared between monkey gesture and human language.

Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer's disease.

Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer's Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.

Tau propagation in the brain olfactory circuits is associated with smell perception changes in aging.

The direct access of olfactory afferents to memory-related cortical systems has inspired theories about the role of the olfactory pathways in the development of cortical neurodegeneration in Alzheimer's disease (AD). In this study, we used baseline olfactory identification measures with longitudinal flortaucipir and PiB PET, diffusion MRI of 89 cognitively normal older adults (73.82 ± 8.44 years; 56% females), and a transcriptomic data atlas to investigate the spatiotemporal spreading and genetic vulnerabilities of AD-related pathology aggregates in the olfactory system. We find that odor identification deficits are predominantly associated with tau accumulation in key areas of the olfactory pathway, with a particularly strong predictive power for longitudinal tau progression. We observe that tau spreads from the medial temporal lobe structures toward the olfactory system, not the reverse. Moreover, we observed a genetic background of odor perception-related genes that might confer vulnerability to tau accumulation along the olfactory system.

[The association between frontotemporal connecting fibers and seizure severity in patients with temporal lobe epilepsy].

The patients with temporal lobe epilepsy (TLE) admitted in the Department of Neurology, Zhongshan Hospital, Fudan University from June 2009 to February 2012 were prospectively enrolled. The diffusion tensor imaing was performed on the patients at the time of enrollment and 3 years later. The fractional anisotropy (FA) values of the white matter connecting fibers(bilateral hooked, arcuate, cingulate, and superior longitudinal tracts), the connecting fibers of both hemispheres(anterior union, anterior callosal forceps, posterior forceps, and bilateral fornix), and fibers of perirhinal cortices system(bilateral radiating crown and anterior limb of the internal capsule) were measured by the region of interest method. The severity of epilepsy was evaluated using the Veterans Administration Seizure Type and Frequency Rating Scale(VA-2) and National Hospital Seizure Severity Scale (NHS3). A total of 51 patients with TLE were screened, with 27 patients completing the 3-year follow-up. There were 13 males and 14 females with an age of (32±11) years and a follow-up duration of (39.1±1.1) months. During the follow-up, 6 patients had increased/unchanged NHS3 or VA-2 scores, while 21 patients had decreased scores. Three years later, the FA values of the bilateral arcuate fasciculus, the right superior longitudinal fasciculus, the right radial coronal and corpus callosum anterior forceps in TLE patients decreased compared to baseline(P<0.05). However, compared to the patients with decreased VA-2 scores during the follow-up, the degree of increase in FA values (ΔFA, follow-up FA value-baseline FA value) of the ipsilateral hook bundle caused by epilepsy was more significant in the group with increased/unchanged VA-2 scores (decreased score group vs increased/unchanged score group:-0.032±0.063 vs 0.018±0.043, t=2.305, P=0.035). The value of ΔFA in epileptic patients with increased/unchanged NHS3 scores (0.075±0.113) was higher compared to those with decreased scores (-0.079±0.099, t=2.804, P=0.010). Correlation analysis also showed the changes in FA values of epileptic lateral fasciculus (r=0.503, P=0.009) and arcuate fasciculus (r=0.602, P=0.001)were positively correlated with the changes in VA-2 and HNS3 scores, respectively. The seizure severity in patients with TLE was closely associated with the microstructure changes in the frontal and temporal white matter, especially the arcuate and uncinate tracts, on the same side that caused seizures, which may indicate the white matter remodeling and abnormal network reformation associated with seizures.

Hypertension is associated with reduced resting-state medial temporal lobe dynamic network flexibility in older African Americans.

Hypertension disproportionately affects African Americans and is a risk factor for Alzheimer's disease (AD). We investigated the relationship of blood pressure (BP) with medial temporal lobe (MTL) dynamic network flexibility (a novel AD biomarker) and cognitive generalization in older African Americans. In a cross-sectional study, 37 normotensive (systolic BP <130 mmHg, 82.5% F, 64.4 ± 4.9 years; 14.3 ± 2.1 years of education) versus 79 hypertensive (systolic BP ≥130 mmHg, 79.5% F, 66.8 ± 4.1 years; 14.0 ± 0.2 years of education) participants were enrolled. All participants completed a 10-min resting-state functional magnetic resonance imaging scan to assess MTL dynamic network flexibility and two generalization tasks to assess cognition. Anthropometrics and aerobic fitness (via 6-min walk test) were also determined. There was no difference in BMI (29.7 ± 6.4 vs. 31.9 ± 6.3 kg/m2, p = 0.083) or aerobic fitness (15.5 ± 2.6 vs. 15.1 ± 2.6 mL/kg/min; p = 0.445) between normotensive and hypertensive groups. However, normotensive participants had higher MTL dynamic network flexibility compared to hypertensive participants (0.42 ± 0.23 vs. 0.32 ± 0.25 mL, p = 0.040), and this was associated with higher mean arterial blood pressure (r = -0.21, p = 0.036). Therefore, hypertensive older African Americans demonstrated lower MTL dynamic network flexibility compared to their normotensive counterparts independent of BMI and aerobic fitness. Further studies are required to determine how blood pressure mediates AD risk in African Americans.

Phase-dependent word perception emerges from region-specific sensitivity to the statistics of language.

Neural oscillations reflect fluctuations in excitability, which biases the percept of ambiguous sensory input. Why this bias occurs is still not fully understood. We hypothesized that neural populations representing likely events are more sensitive, and thereby become active on earlier oscillatory phases, when the ensemble itself is less excitable. Perception of ambiguous input presented during less-excitable phases should therefore be biased toward frequent or predictable stimuli that have lower activation thresholds. Here, we show such a frequency bias in spoken word recognition using psychophysics, magnetoencephalography (MEG), and computational modelling. With MEG, we found a double dissociation, where the phase of oscillations in the superior temporal gyrus and medial temporal gyrus biased word-identification behavior based on phoneme and lexical frequencies, respectively. This finding was reproduced in a computational model. These results demonstrate that oscillations provide a temporal ordering of neural activity based on the sensitivity of separable neural populations.

Orienting role of the putative human posterior infero-temporal area in visual attention.

The dorsal attention network (DAN) is a network of brain regions essential for attentional orienting, which includes the lateral intraparietal area (LIP) and frontal eye field (FEF). Recently, the putative human dorsal posterior infero-temporal area (phPITd) has been identified as a new node of the DAN. However, its functional relationship with other areas of the DAN and its specific role in visual attention remained unclear. In this study, we analyzed a large publicly available neuroimaging dataset to investigate the intrinsic functional connectivities (FCs) of the phPITd with other brain areas. The results showed that the intrinsic FCs of the phPITd with the areas of the visual network and the DAN were significantly stronger than those with the ventral attention network (VAN) areas and areas of other networks. We further conducted individual difference analyses with a sample size of 295 participants and a series of attentional tasks to investigate which attentional components each phPITd-based DAN edge predicts. Our findings revealed that the intrinsic FC of the left phPITd with the LIPv could predict individual ability in attentional orienting, but not in alerting, executive control, and distractor suppression. Our results not only provide direct evidence of the phPITd's functional relationship with the LIPv, but also offer a comprehensive understanding of its specific role in visual attention.

Cognition in children with arachnoid cysts - A five-year follow-up after microneurosurgical fenestration.

BACKGROUND AND PURPOSE: In recent years there has been a re-evaluation regarding the clinical implications of temporal lobe arachnoid cysts (temporal arachnoid cysts) in children. These cysts have often been considered asymptomatic, or if symptomatic, only causing focal neurological symptoms or signs of increased intracranial pressure. However, several studies have more recently reported on cognitive symptoms improving after surgery. This study aimed to evaluate if reported cognitive improvement after surgery of temporal arachnoid cysts were stable after five years. METHOD: Ten consecutive children (m = 14.65; range 12.1-19.415 were assessed cognitively five years after micro-neurosurgical fenestration of a temporal arachnoid cyst. Results were compared to results from their pre- and post-surgical evaluations. Evaluations included the Wechsler-scales, Boston Naming Test (BNT), Rey Auditory Verbal Learning Test (RAVLT), verbal fluency test (FAS) and Rey Complex Figure Test (RCFT). RESULTS: The analysis revealed significant postsurgical improvement compared to baseline on the Wechsler-scales measures of general intelligence (FSIQ), verbal abilities (VCI) and processing speed (PSI). Mean differences after surgery were 8.3 for FSIQ, (p = 0.026), 8.5 for VI (p = < .01) and 9.9 for PSI (p = 0.03). There were no significant differences in mean test results when comparing postsurgical scores with scores five years after surgery, indicating long-term stability of improvements. CONCLUSION: The results indicate that affected cognitive functions in children with temporal arachnoid cysts improve after surgery and that the improvements remain stable five years later. The improvements and long term stability were also consistent with the experience of both parents and children. The findings provide a strong argument for neurosurgical fenestration of temporal arachnoid cysts in children.

Switching off: disruptive TMS reveals distinct contributions of the posterior middle temporal gyrus and angular gyrus to bilingual speech production.

The role of the left temporoparietal cortex in speech production has been extensively studied during native language processing, proving crucial in controlled lexico-semantic retrieval under varying cognitive demands. Yet, its role in bilinguals, fluent in both native and second languages, remains poorly understood. Here, we employed continuous theta burst stimulation to disrupt neural activity in the left posterior middle-temporal gyrus (pMTG) and angular gyrus (AG) while Italian-Friulian bilinguals performed a cued picture-naming task. The task involved between-language (naming objects in Italian or Friulian) and within-language blocks (naming objects ["knife"] or associated actions ["cut"] in a single language) in which participants could either maintain (non-switch) or change (switch) instructions based on cues. During within-language blocks, cTBS over the pMTG entailed faster naming for high-demanding switch trials, while cTBS to the AG elicited slower latencies in low-demanding non-switch trials. No cTBS effects were observed in the between-language block. Our findings suggest a causal involvement of the left pMTG and AG in lexico-semantic processing across languages, with distinct contributions to controlled vs. "automatic" retrieval, respectively. However, they do not support the existence of shared control mechanisms within and between language(s) production. Altogether, these results inform neurobiological models of semantic control in bilinguals.

Role of the left posterior middle temporal gyrus in shape recognition and its reconstruction during drawing: A study combining transcranial magnetic stimulation and functional near infrared spectroscopy.

There are numerous reports of enhanced or emerged visual arts abilities in patients with semantic impairment. These reports led to the theory that a loss of function on the language side of the brain can result in changes of ability to draw and/or to paint. Further, the left posterior middle temporal gyrus (l-pMTG) has been revealed to contribute to the higher control semantic mechanisms with objects recognition and integration of visual information, within a widely distributed network of the left hemisphere. Nevertheless, the theory has not been fully studied in neural bases. The aim of this study is to examine role of the l-pMTG on shape recognition and its reconstruction within drawing behavior, by using a combining method of the repetitive transcranial magnetic stimulation (rTMS) and functional near-infrared spectroscopy (fNIRS). Eighteen healthy participants received a low frequency inhibitory rTMS to their l-pMTG during the drawing task of the Benton Visual Retention Test (BVRT). There was a significant decrease of the mean accuracy of reproductions in the Complex designs of the BVRT, compared to the Simple and Medium designs. The fNIRS data showed strong negative correlations with the results of the BVRT. Though our hypothesis had a contradiction that rTMS would have inhibited the brain activity in the stimulated site, the results suggest that shape recognition and its reconstruction such as the BVRT require neural activations of the l-TL as well as that of the l-pMTG.

Age-related enhancement of the association between episodic memory and gray matter volume in medial temporal and frontal lobes.

BACKGROUND: Episodic memory (EM) deteriorates as a result of normal aging as well as Alzheimer's disease. The neural underpinnings of such age-related memory impairments in older individuals are not well-understood. Although previous research has unveiled the association between gray matter volume (GMV) and EM in the elderly population, such findings exhibit variances across distinct age cohorts. Consequently, an investigation into the dynamic evolution of this relationship with advancing age is imperative. RESULT: The present study utilized a sliding window approach to examine how the correlation between EM and GMV varied with age in a cross-sectional sample of 926 Chinese older adults. We found that both verbal EM (VEM) and spatial EM (SEM) exhibited positive correlations with GMV in extensive areas primarily in the temporal and frontal lobes and that these correlations typically became stronger with older age. Moreover, there were variations in the strength of the correlation between EM and GMV with age, which differed based on sex and the specific type of EM. Specifically, the association between VEM and GMVs in the insula and parietal regions became stronger with age for females but not for males, whereas the association between SEM and GMVs in the parietal and occipital regions became stronger for males but not for females. At the brain system level, there is a significant age-related increase in the correlations between both types of EM and the GMV of both the anterior temporal (AT) system and the posterior medial (PM) system in male group. In females, both types of EM show stronger age-related correlations with the GMV of the AT system compared to males. CONCLUSIONS: Our study revealed a significant positive correlation between GMV in most regions associated with EM and age, particularly in the frontal and temporal lobes. This discovery offers new insights into the connection between brain structure and the diminishing episodic memory function among older individuals.

A petavoxel fragment of human cerebral cortex reconstructed at nanoscale resolution.

To fully understand how the human brain works, knowledge of its structure at high resolution is needed. Presented here is a computationally intensive reconstruction of the ultrastructure of a cubic millimeter of human temporal cortex that was surgically removed to gain access to an underlying epileptic focus. It contains about 57,000 cells, about 230 millimeters of blood vessels, and about 150 million synapses and comprises 1.4 petabytes. Our analysis showed that glia outnumber neurons 2:1, oligodendrocytes were the most common cell, deep layer excitatory neurons could be classified on the basis of dendritic orientation, and among thousands of weak connections to each neuron, there exist rare powerful axonal inputs of up to 50 synapses. Further studies using this resource may bring valuable insights into the mysteries of the human brain.

The hippocampus supports precise memory for public events regardless of their remoteness.

The necessity of the human hippocampus and surrounding medial temporal lobe structures to semantic memory remains contentious. Impaired semantic memory following hippocampal lesions could arise either due to partially intertwined episodic memories and/or retrograde/anterograde effects. In this study, we tested amnesic individuals with lesions in hippocampus and surrounding medial temporal lobe (n = 7) and age-matched controls (n = 14) on their ability to precisely recall the dates of famous public events that occurred either before (i.e., pre-lifetime) or after participants' birth date (lifetime). We show that deficits in dating precision are greatest for recent lifetime events, consistent with the notion that recent event memory may be particularly intertwined with episodic memory. At the same time, individuals with medial temporal lobe lesions showed more subtle impairments in their ability to date pre-birth and remote lifetime events precisely. Together, these findings suggest that the hippocampus and surrounding medial temporal lobe structures are important for representational precision of semantic memories regardless of their remoteness.

Temporal multiplexing of perception and memory codes in IT cortex.

A central assumption of neuroscience is that long-term memories are represented by the same brain areas that encode sensory stimuli1. Neurons in inferotemporal (IT) cortex represent the sensory percept of visual objects using a distributed axis code2-4. Whether and how the same IT neural population represents the long-term memory of visual objects remains unclear. Here we examined how familiar faces are encoded in the IT anterior medial face patch (AM), perirhinal face patch (PR) and temporal pole face patch (TP). In AM and PR we observed that the encoding axis for familiar faces is rotated relative to that for unfamiliar faces at long latency; in TP this memory-related rotation was much weaker. Contrary to previous claims, the relative response magnitude to familiar versus unfamiliar faces was not a stable indicator of familiarity in any patch5-11. The mechanism underlying the memory-related axis change is likely intrinsic to IT cortex, because inactivation of PR did not affect axis change dynamics in AM. Overall, our results suggest that memories of familiar faces are represented in AM and perirhinal cortex by a distinct long-latency code, explaining how the same cell population can encode both the percept and memory of faces.

Cerebellum function: The chronometry of social perception.

The posterior cerebellum is emerging as a key structure for social cognition. A new study causally demonstrates its early involvement during emotion perception and functional connectivity with the posterior superior temporal sulcus, a cortical hub of the social brain.

A multimodal interface for speech perception: the role of the left superior temporal sulcus in social cognition and autism.

Multimodal integration is crucial for human interaction, in particular for social communication, which relies on integrating information from various sensory modalities. Recently a third visual pathway specialized in social perception was proposed, which includes the right superior temporal sulcus (STS) playing a key role in processing socially relevant cues and high-level social perception. Importantly, it has also recently been proposed that the left STS contributes to audiovisual integration of speech processing. In this article, we propose that brain areas along the right STS that support multimodal integration for social perception and cognition can be considered homologs to those in the left, language-dominant hemisphere, sustaining multimodal integration of speech and semantic concepts fundamental for social communication. Emphasizing the significance of the left STS in multimodal integration and associated processes such as multimodal attention to socially relevant stimuli, we underscore its potential relevance in comprehending neurodevelopmental conditions characterized by challenges in social communication such as autism spectrum disorder (ASD). Further research into this left lateral processing stream holds the promise of enhancing our understanding of social communication in both typical development and ASD, which may lead to more effective interventions that could improve the quality of life for individuals with atypical neurodevelopment.

Neural mechanisms underlying improved new-word learning with high-density transcranial direct current stimulation.

Neurobehavioral studies have provided evidence for the effectiveness of anodal tDCS on language production, by stimulation of the left Inferior Frontal Gyrus (IFG) or of left Temporo-Parietal Junction (TPJ). However, tDCS is currently not used in clinical practice outside of trials, because behavioral effects have been inconsistent and underlying neural effects unclear. Here, we propose to elucidate the neural correlates of verb and noun learning and to determine if they can be modulated with anodal high-definition (HD) tDCS stimulation. Thirty-six neurotypical participants were randomly allocated to anodal HD-tDCS over either the left IFG, the left TPJ, or sham stimulation. On day one, participants performed a naming task (pre-test). On day two, participants underwent a new-word learning task with rare nouns and verbs concurrently to HD-tDCS for 20 min. The third day consisted of a post-test of naming performance. EEG was recorded at rest and during naming on each day. Verb learning was significantly facilitated by left IFG stimulation. HD-tDCS over the left IFG enhanced functional connectivity between the left IFG and TPJ and this correlated with improved learning. HD-tDCS over the left TPJ enabled stronger local activation of the stimulated area (as indexed by greater alpha and beta-band power decrease) during naming, but this did not translate into better learning. Thus, tDCS can induce local activation or modulation of network interactions. Only the enhancement of network interactions, but not the increase in local activation, leads to robust improvement of word learning. This emphasizes the need to develop new neuromodulation methods influencing network interactions. Our study suggests that this may be achieved through behavioral activation of one area and concomitant activation of another area with HD-tDCS.

Associations Between Self and Study Partner Report of Cognitive Decline With Regional Tau in a Multicohort Study.

BACKGROUND AND OBJECTIVES: Self-reported cognitive decline is an early behavioral manifestation of Alzheimer disease (AD) at the preclinical stage, often believed to precede concerns reported by a study partner. Previous work shows cross-sectional associations with ß-amyloid (Aß) status and self-reported and study partner-reported cognitive decline, but less is known about their associations with tau deposition, particularly among those with preclinical AD. METHODS: This cross-sectional study included participants from the Anti-Amyloid Treatment in Asymptomatic AD/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies (N = 444) and the Harvard Aging Brain Study and affiliated studies (N = 231), which resulted in a cognitively unimpaired (CU) sample of individuals with both nonelevated (Aß-) and elevated Aß (Aß+). All participants and study partners completed the Cognitive Function Index (CFI). Two regional tau composites were derived by averaging flortaucipir PET uptake in the medial temporal lobe (MTL) and neocortex (NEO). Global Aß PET was measured in Centiloids (CLs) with Aß+ >26 CL. We conducted multiple linear regression analyses to test associations between tau PET and CFI, covarying for amyloid, age, sex, education, and cohort. We also controlled for objective cognitive performance, measured using the Preclinical Alzheimer Cognitive Composite (PACC). RESULTS: Across 675 CU participants (age = 72.3 ± 6.6 years, female = 59%, Aß+ = 60%), greater tau was associated with greater self-CFI (MTL: ß = 0.28 [0.12, 0.44], p < 0.001, and NEO: ß = 0.26 [0.09, 0.42], p = 0.002) and study partner CFI (MTL: ß = 0.28 [0.14, 0.41], p < 0.001, and NEO: ß = 0.31 [0.17, 0.44], p < 0.001). Significant associations between both CFI measures and MTL/NEO tau PET were driven by Aß+. Continuous Aß showed an independent effect on CFI in addition to MTL and NEO tau for both self-CFI and study partner CFI. Self-CFI (ß = 0.01 [0.001, 0.02], p = 0.03), study partner CFI (ß = 0.01 [0.003, 0.02], p = 0.01), and the PACC (ß = -0.02 [-0.03, -0.01], p < 0.001) were independently associated with MTL tau, but for NEO tau, PACC (ß = -0.02 [-0.03, -0.01], p < 0.001) and study partner report (ß = 0.01 [0.004, 0.02], p = 0.002) were associated, but not self-CFI (ß = 0.01 [-0.001, 0.02], p = 0.10). DISCUSSION: Both self-report and study partner report showed associations with tau in addition to Aß. Additionally, self-report and study partner report were associated with tau above and beyond performance on a neuropsychological composite. Stratification analyses by Aß status indicate that associations between self-reported and study partner-reported cognitive concerns with regional tau are driven by those at the preclinical stage of AD, suggesting that both are useful to collect on the early AD continuum.

Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly.

BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma. Here, we aimed to (i) assess differences in blood and imaging biomarkers used to evaluate neurodegeneration among cognitively unimpaired APOE ε4 homozygotes, heterozygotes, and non-carriers with varying risk for sporadic AD, and (ii) to determine how different cerebral pathologies (i.e., Aß deposition, medial temporal atrophy, and cerebrovascular pathology) contribute to blood biomarker concentrations in this sample. METHODS: Sixty APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) ranging from 60 to 75 years, were recruited in collaboration with Auria biobank (Turku, Finland). Participants underwent Aß-PET ([11C]PiB), structural brain MRI including T1-weighted and T2-FLAIR sequences, and blood sampling for measuring serum neurofilament light chain (NfL), plasma total tau (t-tau), plasma N-terminal tau fragments (NTA-tau) and plasma glial fibrillary acidic protein (GFAP). [11C]PiB standardized uptake value ratio was calculated for regions typical for Aß accumulation in AD. MRI images were analysed for regional volumes, atrophy scores, and volumes of white matter hyperintensities. Differences in biomarker levels and associations between blood and imaging biomarkers were tested using uni- and multivariable linear models (unadjusted and adjusted for age and sex). RESULTS: Serum NfL concentration was increased in APOE ε4 homozygotes compared with non-carriers (mean 21.4 pg/ml (SD 9.5) vs. 15.5 pg/ml (3.8), p = 0.013), whereas other blood biomarkers did not differ between the groups (p > 0.077 for all). From imaging biomarkers, hippocampal volume was significantly decreased in APOE ε4 homozygotes compared with non-carriers (6.71 ml (0.86) vs. 7.2 ml (0.7), p = 0.029). In the whole sample, blood biomarker levels were differently predicted by the three measured cerebral pathologies; serum NfL concentration was associated with cerebrovascular pathology and medial temporal atrophy, while plasma NTA-tau associated with medial temporal atrophy. Plasma GFAP showed significant association with both medial temporal atrophy and Aß pathology. Plasma t-tau concentration did not associate with any of the measured pathologies. CONCLUSIONS: Only increased serum NfL concentrations and decreased hippocampal volume was observed in cognitively unimpaired APOEε4 homozygotes compared to non-carriers. In the whole population the concentrations of blood biomarkers were affected in distinct ways by different pathologies.