Differences in cognitive function at 18 y of age explain the association between low education and early dementia risk.

Major initiatives attempt to prevent dementia by targeting modifiable risk factors. Low education is frequently pointed to, due to its relationship with dementia. Impact of education is difficult to assess, however, because of associations with multiple other factors, requiring large population-representative samples to tease the relationships apart. We studied 207,814 Norwegian men born between 1950 and 1959 who underwent compulsory cognitive testing during military conscription as young adults, to systematically test associations of education, cognition, and other important factors. Participants were grouped into five education levels and seven cognitive levels. A total of 1,521 were diagnosed with dementia between ages 60 and 69 y. While having compulsory education only was associated with increased risk (Hazard ratio [HR] = 1.37, CI: 1.17 to 1.60), this association was markedly attenuated when controlling for cognitive test scores (HR = 1.08, CI: 0.91 to 1.28). In contrast, low cognitive score was associated with double risk of later diagnosis, even when controlling for education (HR = 2.00, CI: 1.65 to 2.42). This relationship survived controlling for early-life socioeconomic status and replicated within pairs of brothers. This suggests that genetic and environmental factors shared within families, e.g., common genetics, parental education, socioeconomic status, or other shared experiences, cannot account for the association. Rather, independent, nonfamilial factors are more important. In contrast, within-family factors accounted for the relationship between low education and diagnosis risk. In conclusion, implementing measures to increase cognitive function in childhood and adolescence appears to be a more promising strategy for reducing dementia burden.

Recalled through this day but forgotten next week?-retrieval activity predicts durability of partly consolidated memories.

Even partly consolidated memories can be forgotten given sufficient time, but the brain activity associated with durability of episodic memory at different time scales remains unclear. Here, we aimed to identify brain activity associated with retrieval of partly consolidated episodic memories that continued to be remembered in the future. Forty-nine younger (20 to 38 years; 25 females) and 43 older adults (60 to 80 years, 25 females) were scanned with functional magnetic resonance imaging during associative memory retrieval 12 h post-encoding. Twelve hours is sufficient to allow short-term synaptic consolidation as well as early post-encoding replay to initiate memory consolidation. Successful memory trials were classified into durable and transient source memories based on responses from a memory test ~6 d post-encoding. Results demonstrated that successful retrieval of future durable vs. transient memories was supported by increased activity in a medial prefrontal and ventral parietal area. Individual differences in activation as well as the subjective vividness of memories during encoding were positively related to individual differences in memory performance after 6 d. The results point to a unique and novel aspect of brain activity supporting long-term memory, in that activity during retrieval of memories even after 12 h of consolidation contains information about potential for long-term durability.

Is Short Sleep Bad for the Brain? Brain Structure and Cognitive Function in Short Sleepers.

Many sleep less than recommended without experiencing daytime sleepiness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this using a cross-sectional and longitudinal sample of 47,029 participants of both sexes (20-89 years) from the Lifebrain consortium, Human Connectome project (HCP) and UK Biobank (UKB), with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. A total of 740 participants who reported to sleep <6 h did not experience daytime sleepiness or sleep problems/disturbances interfering with falling or staying asleep. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime sleepiness and sleep problems (n = 1742) and participants sleeping the recommended 7-8 h (n = 3886). However, both groups of short sleepers showed slightly lower general cognitive function (GCA), 0.16 and 0.19 SDs, respectively. Analyses using accelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income, and education. The results suggest that some people can cope with less sleep without obvious negative associations with brain morphometry and that sleepiness and sleep problems may be more related to brain structural differences than duration. However, the slightly lower performance on tests of general cognitive abilities warrants closer examination in natural settings.SIGNIFICANCE STATEMENT Short habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here, we show that daytime sleepiness and sleep problems are more strongly related to regional brain volumes than sleep duration. However, participants sleeping ≤6 h had slightly lower scores on tests of general cognitive function (GCA). This indicates that sleep need is individual and that sleep duration per se is very weakly if at all related brain health, while daytime sleepiness and sleep problems may show somewhat stronger associations. The association between habitual short sleep and lower scores on tests of general cognitive abilities must be further scrutinized in natural settings.

Sustained upregulation of widespread hippocampal-neocortical coupling following memory encoding.

Systems consolidation of new experiences into lasting episodic memories involves hippocampal-neocortical interactions. Evidence of this process is already observed during early post-encoding rest periods, both as increased hippocampal coupling with task-relevant perceptual regions and reactivation of stimulus-specific patterns following intensive encoding tasks. We investigate the spatial and temporal characteristics of these hippocampally anchored post-encoding neocortical modulations. Eighty-nine adults participated in an experiment consisting of interleaved memory task- and resting-state periods. We observed increased post-encoding functional connectivity between hippocampus and individually localized neocortical regions responsive to stimuli encountered during memory encoding. Post-encoding modulations were manifested as a nearly system-wide upregulation in hippocampal coupling with all major functional networks. The configuration of these extensive modulations resembled hippocampal-neocortical interaction patterns estimated from active encoding operations, suggesting hippocampal post-encoding involvement exceeds perceptual aspects. Reinstatement of encoding patterns was not observed in resting-state scans collected 12 h later, nor when using other candidate seed regions. The similarity in hippocampal functional coupling between online memory encoding and offline post-encoding rest suggests reactivation in humans involves a spectrum of cognitive processes engaged during the experience of an event. There were no age effects, suggesting that upregulation of hippocampal-neocortical connectivity represents a general phenomenon seen across the adult lifespan.

Individual differences in brain aging: heterogeneity in cortico-hippocampal but not caudate atrophy rates.

It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.

Educational attainment does not influence brain aging.

Education has been related to various advantageous lifetime outcomes. Here, using longitudinal structural MRI data (4,422 observations), we tested the influential hypothesis that higher education translates into slower rates of brain aging. Cross-sectionally, education was modestly associated with regional cortical volume. However, despite marked mean atrophy in the cortex and hippocampus, education did not influence rates of change. The results were replicated across two independent samples. Our findings challenge the view that higher education slows brain aging.

Hippocampal-cortical functional connectivity during memory encoding and retrieval.

Memory encoding and retrieval are critical sub-processes of episodic memory. While the hippocampus is involved in both, less is known about its connectivity with the neocortex during memory processing in humans. This is partially due to variations in demands in common memory tasks, which inevitably recruit cognitive processes other than episodic memory. Conjunctive analysis of data from different tasks with the same core elements of encoding and retrieval can reduce the intrusion of patterns related to subsidiary perceptual and cognitive processing. Leveraging data from two large-scale functional resonance imaging studies with different episodic memory tasks (514 and 237 participants), we identified hippocampal-cortical networks active during memory tasks. Whole-brain functional connectivity maps were similar during resting state, encoding, and retrieval. Anterior and posterior hippocampus had distinct connectivity profiles, which were also stable across resting state and memory tasks. When contrasting encoding and retrieval connectivity, conjunctive encoding-related connectivity was sparse. During retrieval hippocampal connectivity was increased with areas known to be active during recollection, including medial prefrontal, inferior parietal, and parahippocampal cortices. This indicates that the stable functional connectivity of the hippocampus along its longitudinal axis is superposed by increased functional connectivity with the recollection network during retrieval, while auxiliary encoding connectivity likely reflects contextual factors.

Whole-brain connectivity during encoding: age-related differences and associations with cognitive and brain structural decline.

There is a limited understanding of age differences in functional connectivity during memory encoding. In the present study, a sample of cognitively healthy adult participants (n = 488, 18-81 years), a subsample of whom had longitudinal cognitive and brain structural data spanning on average 8 years back, underwent functional magnetic resonance imaging while performing an associative memory encoding task. We investigated (1) age-related differences in whole-brain connectivity during memory encoding; (2) whether encoding connectivity patterns overlapped with the activity signatures of specific cognitive processes, and (3) whether connectivity associated with memory encoding related to longitudinal brain structural and cognitive changes. Age was associated with lower intranetwork connectivity among cortical networks and higher internetwork connectivity between networks supporting higher level cognitive functions and unimodal and attentional areas during encoding. Task-connectivity between mediotemporal and posterior parietal regions-which overlapped with areas involved in mental imagery-was related to better memory performance only in older age. The connectivity patterns supporting memory performance in older age reflected preservation of thickness of the medial temporal cortex. The results are more in accordance with a maintenance rather than a compensation account.

Reduced Hippocampal-Striatal Interactions during Formation of Durable Episodic Memories in Aging.

Encoding of durable episodic memories requires cross-talk between the hippocampus and multiple brain regions. Changes in these hippocampal interactions could contribute to age-related declines in the ability to form memories that can be retrieved after extended time intervals. Here we tested whether hippocampal-neocortical- and subcortical functional connectivity (FC) observed during encoding of durable episodic memories differed between younger and older adults. About 48 younger (20-38 years; 25 females) and 43 older (60-80 years; 25 females) adults were scanned with fMRI while performing an associative memory encoding task. Source memory was tested ~20 min and ~6 days postencoding. Associations recalled after 20 min but later forgotten were classified as transient, whereas memories retained after long delays were classified as durable. Results demonstrated that older adults showed a reduced ability to form durable memories and reduced hippocampal-caudate FC during encoding of durable memories. There was also a positive relationship between hippocampal-caudate FC and higher memory performance among the older adults. No reliable age group differences in durable memory-encoding activity or hippocampal-neocortical connectivity were observed. These results support the classic theory of striatal alterations as one cause of cognitive decline in aging and highlight that age-related changes in episodic memory extend beyond hippocampal-neocortical connections.

Education and Income Show Heterogeneous Relationships to Lifespan Brain and Cognitive Differences Across European and US Cohorts.

Higher socio-economic status (SES) has been proposed to have facilitating and protective effects on brain and cognition. We ask whether relationships between SES, brain volumes and cognitive ability differ across cohorts, by age and national origin. European and US cohorts covering the lifespan were studied (4-97 years, N = 500 000; 54 000 w/brain imaging). There was substantial heterogeneity across cohorts for all associations. Education was positively related to intracranial (ICV) and total gray matter (GM) volume. Income was related to ICV, but not GM. We did not observe reliable differences in associations as a function of age. SES was more strongly related to brain and cognition in US than European cohorts. Sample representativity varies, and this study cannot identify mechanisms underlying differences in associations across cohorts. Differences in neuroanatomical volumes partially explained SES-cognition relationships. SES was more strongly related to ICV than to GM, implying that SES-cognition relations in adulthood are less likely grounded in neuroprotective effects on GM volume in aging. The relatively stronger SES-ICV associations rather are compatible with SES-brain volume relationships being established early in life, as ICV stabilizes in childhood. The findings underscore that SES has no uniform association with, or impact on, brain and cognition.

Stakeholder engagement in European brain research: Experiences of the Lifebrain consortium.

INTRODUCTION: Stakeholder engagement remains scarce in basic brain research. However, it can greatly improve the relevance of investigations and accelerate the translation of study findings to policy. The Lifebrain consortium investigated risk and protective factors influencing brain health using cognition, lifestyle and imaging data from European cohorts. Stakeholder activities of Lifebrain-organized in a separate work package-included organizing stakeholder events, investigating public perceptions of brain health and dissemination. Here, we describe the experiences of researchers and stakeholders regarding stakeholder engagement in the Lifebrain project. METHODS: Stakeholder engagement in Lifebrain was evaluated through surveys among researchers and stakeholders and stakeholders' feedback at stakeholder events through evaluation forms. Survey data were analysed using a simple content analysis approach, and results from evaluation forms were summarized after reviewing the frequency of responses. RESULTS: Consortium researchers and stakeholders experienced the engagement activities as meaningful and relevant. Researchers highlighted that it made the research and research processes more visible and contributed to new networks, optimized data collection on brain health perceptions and the production of papers and provided insights into stakeholder views. Stakeholders found research activities conducted in the stakeholder engagement work package to be within their field of interest and research results relevant to their work. Researchers identified barriers to stakeholder engagement, including lack of time, difficulties in identifying relevant stakeholders, and challenges in communicating complex scientific issues in lay language and maintaining relationships with stakeholders over time. Stakeholders identified barriers such as lack of budget, limited resources in their organization, time constraints and insufficient communication between researchers and stakeholders. CONCLUSION: Stakeholder engagement in basic brain research can greatly benefit researchers and stakeholders alike. Its success is conditional on dedicated human and financial resources, clear communication, transparent mutual expectations and clear roles and responsibilities. PUBLIC CONTRIBUTION: Patient organizations, research networks, policymakers and members of the general public were involved in engagement and research activities throughout the project duration.

Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer's disease in healthy samples across the lifespan.

The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer's disease (AD). Paradoxically, APOE ε4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan. Here, we examine associations of blood CRP levels, APOE ε4, and biomarkers for AD in a cognitively healthy lifespan cohort (N up to 749; 20-81 years of age) and replicate the findings in UK Biobank (N = 304 322; 37-72 years of age), the developmental ABCD study (N = 10 283; 9-11 years of age), and a middle-aged sample (N = 339; 40-65 years of age). Hippocampal volume, brain amyloid-ß (Aß) plaque levels, cerebrospinal fluid (CSF) levels of Aß and tau species, and neurofilament protein light protein (NFL) were used as AD biomarkers in subsamples. In addition, we examined the genetic contribution to the variation of CRP levels over different CRP ranges using polygenic scores for CRP (PGS-CRP). Our results show APOE ε4 consistently associates with low blood CRP levels across all age groups (p < 0.05). Strikingly, both ε4 and PGS-CRP associated mainly with blood CRP levels within the low range (<5mg/L). We then show both APOE ε4 and high CRP levels associate with smaller hippocampus volumes across the lifespan (p < 0.025). APOE ε4 was associated with high Aß plaque levels in the brain (FDR-corrected p = 8.69x10-4), low levels of CSF Aß42 (FDR-corrected p = 6.9x10-2), and lower ratios of Aß42 to Aß40 (FDR-corrected p = 5.08x10-5). Blood CRP levels were weakly correlated with higher ratio of CSF Aß42 to Aß40 (p = 0.03, FDR-corrected p = 0.4). APOE ε4 did not correlate with blood concentrations of another 9 inflammatory cytokines, and none of these cytokines correlated with AD biomarkers. CONCLUSION: The inverse correlation between APOEε 4 and blood CRP levels existed before any pathological AD biomarker was observed, and only in the low CRP level range. Thus, we suggest to investigate whether APOEε 4 can confer risk by being associated with a lower inflammatory response to daily exposures, possibly leading to greater accumulation of low-grade inflammatory stress throughout life. A lifespan perspective is needed to understand this relationship concerning risk of developing AD.

The Functional Foundations of Episodic Memory Remain Stable Throughout the Lifespan.

It has been suggested that specific forms of cognition in older age rely largely on late-life specific mechanisms. Here instead, we tested using task-fMRI (n = 540, age 6-82 years) whether the functional foundations of successful episodic memory encoding adhere to a principle of lifespan continuity, shaped by developmental, structural, and evolutionary influences. We clustered regions of the cerebral cortex according to the shape of the lifespan trajectory of memory activity in each region so that regions showing the same pattern were clustered together. The results revealed that lifespan trajectories of memory encoding function showed a continuity through life but no evidence of age-specific mechanisms such as compensatory patterns. Encoding activity was related to general cognitive abilities and variations of grey matter as captured by a multi-modal independent component analysis, variables reflecting core aspects of cognitive and structural change throughout the lifespan. Furthermore, memory encoding activity aligned to fundamental aspects of brain organization, such as large-scale connectivity and evolutionary cortical expansion gradients. Altogether, we provide novel support for a perspective on memory aging in which maintenance and decay of episodic memory in older age needs to be understood from a comprehensive life-long perspective rather than as a late-life phenomenon only.

Poor Self-Reported Sleep is Related to Regional Cortical Thinning in Aging but not Memory Decline-Results From the Lifebrain Consortium.

We examined whether sleep quality and quantity are associated with cortical and memory changes in cognitively healthy participants across the adult lifespan. Associations between self-reported sleep parameters (Pittsburgh Sleep Quality Index, PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n = 2205, 4363 MRIs, 18-92 years). In additional analyses, we tested coherence with cell-specific gene expression maps from the Allen Human Brain Atlas, and relations to changes in memory performance. "PSQI # 1 Subjective sleep quality" and "PSQI #5 Sleep disturbances" were related to thinning of the right lateral temporal cortex, with lower quality and more disturbances being associated with faster thinning. The association with "PSQI #5 Sleep disturbances" emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. None of the sleep scales were related to a longitudinal change in episodic memory function, suggesting that sleep-related cortical changes were independent of cognitive decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults.

A recipe for accurate estimation of lifespan brain trajectories, distinguishing longitudinal and cohort effects.

We address the problem of estimating how different parts of the brain develop and change throughout the lifespan, and how these trajectories are affected by genetic and environmental factors. Estimation of these lifespan trajectories is statistically challenging, since their shapes are typically highly nonlinear, and although true change can only be quantified by longitudinal examinations, as follow-up intervals in neuroimaging studies typically cover less than 10% of the lifespan, use of cross-sectional information is necessary. Linear mixed models (LMMs) and structural equation models (SEMs) commonly used in longitudinal analysis rely on assumptions which are typically not met with lifespan data, in particular when the data consist of observations combined from multiple studies. While LMMs require a priori specification of a polynomial functional form, SEMs do not easily handle data with unstructured time intervals between measurements. Generalized additive mixed models (GAMMs) offer an attractive alternative, and in this paper we propose various ways of formulating GAMMs for estimation of lifespan trajectories of 12 brain regions, using a large longitudinal dataset and realistic simulation experiments. We show that GAMMs are able to more accurately fit lifespan trajectories, distinguish longitudinal and cross-sectional effects, and estimate effects of genetic and environmental exposures. Finally, we discuss and contrast questions related to lifespan research which strictly require repeated measures data and questions which can be answered with a single measurement per participant, and in the latter case, which simplifying assumptions that need to be made. The examples are accompanied with R code, providing a tutorial for researchers interested in using GAMMs.

Reliability and sensitivity of two whole-brain segmentation approaches included in FreeSurfer - ASEG and SAMSEG.

Accurate and reliable whole-brain segmentation is critical to longitudinal neuroimaging studies. We undertake a comparative analysis of two subcortical segmentation methods, Automatic Segmentation (ASEG) and Sequence Adaptive Multimodal Segmentation (SAMSEG), recently provided in the open-source neuroimaging package FreeSurfer 7.1, with regard to reliability, bias, sensitivity to detect longitudinal change, and diagnostic sensitivity to Alzheimer's disease. First, we assess intra- and inter-scanner reliability for eight bilateral subcortical structures: amygdala, caudate, hippocampus, lateral ventricles, nucleus accumbens, pallidum, putamen and thalamus. For intra-scanner analysis we use a large sample of participants (n = 1629) distributed across the lifespan (age range = 4-93 years) and acquired on a 1.5T Siemens Avanto (n = 774) and a 3T Siemens Skyra (n = 855) scanners. For inter-scanner analysis we use a sample of 24 participants scanned on the day with three models of Siemens scanners: 1.5T Avanto, 3T Skyra and 3T Prisma. Second, we test how each method detects volumetric age change using longitudinal follow up scans (n = 491 for Avanto and n = 245 for Skyra; interscan interval = 1-10 years). Finally, we test sensitivity to clinically relevant change. We compare annual rate of hippocampal atrophy in cognitively normal older adults (n = 20), patients with mild cognitive impairment (n = 20) and Alzheimer's disease (n = 20). We find that both ASEG and SAMSEG are reliable and lead to the detection of within-person longitudinal change, although with notable differences between age-trajectories for most structures, including hippocampus and amygdala. In summary, SAMSEG yields significantly lower differences between repeated measures for intra- and inter-scanner analysis without compromising sensitivity to changes and demonstrating ability to detect clinically relevant longitudinal changes.

Age-Related Differences in Functional Asymmetry During Memory Retrieval Revisited: No Evidence for Contralateral Overactivation or Compensation.

Brain asymmetry is inherent to cognitive processing and seems to reflect processing efficiency. Lower frontal asymmetry is often observed in older adults during memory retrieval, yet it is unclear whether lower asymmetry implies an age-related increase in contralateral recruitment, whether less asymmetry reflects compensation, is limited to frontal regions, or predicts neurocognitive stability or decline. We assessed age-related differences in asymmetry across the entire cerebral cortex, using functional magnetic resonance imaging data from 89 young and 76 older adults during successful retrieval, and surface-based methods allowing direct homotopic comparison of activity between cortical hemispheres . An extensive left-asymmetric network facilitated retrieval in both young and older adults, whereas diverse frontal and parietal regions exhibited lower asymmetry in older adults. However, lower asymmetry was not associated with age-related increases in contralateral recruitment but primarily reflected either less deactivation in contralateral regions reliably signaling retrieval failure in the young or lower recruitment of the dominant hemisphere-suggesting that functional deficits may drive lower asymmetry in older brains, not compensatory activity. Lower asymmetry predicted neither current memory performance nor the extent of memory change across the preceding ~ 8 years in older adults. Together, these findings are inconsistent with a compensation account for lower asymmetry during retrieval and aging.

Self-reported Sleep Problems Related to Amyloid Deposition in Cortical Regions with High HOMER1 Gene Expression.

Sleep problems are related to the elevated levels of the Alzheimer's disease (AD) biomarker ß-amyloid (Aß). Hypotheses about the causes of this relationship can be generated from molecular markers of sleep problems identified in rodents. A major marker of sleep deprivation is Homer1a, a neural protein coded by the HOMER1 gene, which has also been implicated in brain Aß accumulation. Here, we tested whether the relationship between cortical Aß accumulation and self-reported sleep quality, as well as changes in sleep quality over 3 years, was stronger in cortical regions with high HOMER1 mRNA expression levels. In a sample of 154 cognitively healthy older adults, Aß correlated with poorer sleep quality cross-sectionally and longitudinally (n = 62), but more strongly in the younger than in older individuals. Effects were mainly found in regions with high expression of HOMER1. The anatomical distribution of the sleep-Aß relationship followed closely the Aß accumulation pattern in 69 patients with mild cognitive impairment or AD. Thus, the results indicate that the relationship between sleep problems and Aß accumulation may involve Homer1 activity in the cortical regions, where harbor Aß deposits in AD. The findings may advance our understanding of the relationship between sleep problems and AD risk.

CSF sTREM2 and Tau Work Together in Predicting Increased Temporal Lobe Atrophy in Older Adults.

Neuroinflammation may be a key factor in brain atrophy in aging and age-related neurodegenerative disease. The objective of this study was to test the association between microglial expression of soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2), as a measure of neuroinflammation, and brain atrophy in cognitively unimpaired older adults. Brain magnetic resonance imagings (MRIs) and cerebrospinal fluid (CSF) sTREM2, total tau (t-tau), phosphorylated181 tau (p-tau), and Aß42 were analyzed in 115 cognitively unimpaired older adults, classified according to the A/T/(N)-framework. MRIs were repeated after 2 (n = 95) and 4 (n = 62) years. High baseline sTREM2 was associated with accelerated cortical thinning in the temporal cortex of the left hemisphere, as well as bilateral hippocampal atrophy, independently of age, Aß42, and tau. sTREM2-related atrophy only marginally increased with biomarker positivity across the AD continuum (A-T- #x2292; A+T- #x2292; A+T+) but was significantly stronger in participants with a high level of p-tau (T+). sTREM2-related cortical thinning correlated significantly with areas of high microglial-specific gene expression in the Allen Human Brain Atlas. In conclusion, increased CSF sTREM2 was associated with accelerated cortical and hippocampal atrophy in cognitively unimpaired older participants, particularly in individuals with tau pathology. This suggests a link between neuroinflammation, neurodegeneration, and amyloid-independent tauopathy.

Corticosteroids and Regional Variations in Thickness of the Human Cerebral Cortex across the Lifespan.

Exposures to life stressors accumulate across the lifespan, with possible impact on brain health. Little is known, however, about the mechanisms mediating age-related changes in brain structure. We use a lifespan sample of participants (n = 21 251; 4-97 years) to investigate the relationship between the thickness of cerebral cortex and the expression of the glucocorticoid- and the mineralocorticoid-receptor genes (NR3C1 and NR3C2, respectively), obtained from the Allen Human Brain Atlas. In all participants, cortical thickness correlated negatively with the expression of both NR3C1 and NR3C2 across 34 cortical regions. The magnitude of this correlation varied across the lifespan. From childhood through early adulthood, the profile similarity (between NR3C1/NR3C2 expression and thickness) increased with age. Conversely, both profile similarities decreased with age in late life. These variations do not reflect age-related changes in NR3C1 and NR3C2 expression, as observed in 5 databases of gene expression in the human cerebral cortex (502 donors). Based on the co-expression of NR3C1 (and NR3C2) with genes specific to neural cell types, we determine the potential involvement of microglia, astrocytes, and CA1 pyramidal cells in mediating the relationship between corticosteroid exposure and cortical thickness. Therefore, corticosteroids may influence brain structure to a variable degree throughout life.