Background/Aims: Early dementia diagnosis is a considerable challenge. The present study examined the predictive value of cognitive performance for a future clinical diagnosis of late-onset Alzheimer's disease or vascular dementia in a random population sample. Methods: Cognitive performance was retrospectively compared between three groups of participants from the Betula longitudinal cohort. Group 1 developed dementia 11-22 years after baseline testing (n = 111) and group 2 after 1-10 years (n = 280); group 3 showed no deterioration towards dementia during the study period (n = 2,855). Multinomial logistic regression analysis was used to investigate the predictive value of tests reflecting episodic memory performance, semantic memory performance, visuospatial ability, and prospective memory performance. Results: Age-and education-corrected performance on two free recall episodic memory tests significantly predicted dementia 10 years prior to clinical diagnosis. Free recall performance also predicted dementia 11-22 years prior to diagnosis when controlling for education, but not when age was added to the model. Conclusion: The present results support the suggestion that two free recall-based tests of episodic memory function may be useful for detecting individuals at risk of developing dementia 10 years prior to clinical diagnosis.

As regulators of gene expression, microRNAs (miRNAs) are likely to play an important role in the development of disease. In this study we present a large-scale strategy to identify miRNAs with a role in the regulation of neuronal processes. Thereby we found variant rs7861254 located near the MIR204 gene to be significantly associated with schizophrenia. This variant resulted in reduced expression of miR-204 in neuronal-like SH-SY5Y cells. Analysis of the consequences of the altered miR-204 expression on the transcriptome of these cells uncovered a new mode of action for miR-204, being the regulation of noncoding RNAs (ncRNAs), including several miRNAs, such as MIR296. Furthermore, pathway analysis showed downstream effects of miR-204 on neurotransmitter and ion channel related gene sets, potentially mediated by miRNAs regulated through miR-204.

Objectives: Dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most consistent findings in the pathophysiology of mood disorders. The potential role of genes related to HPA axis function has been investigated extensively in major depression. However, in bipolar disorder (BPD) such studies are scarce. We performed a systematic HapMap-based association study of six genes crucial for HPA axis function in relation to BPD.

Methods: Haplotype tagging single nucleotide polymorphisms (htSNPs) were selected in order to identify all haplotypes with a frequency of more than 1% in the genes encoding the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), corticotrophin releasing hormone receptor 1 (CRH-R1) and 2 (CRH-R2), CRH binding protein (CRH-BP), and FK binding protein 5 (FKBP5). This resulted in a total selection of 225 SNPs that were genotyped and analyzed in 309 BPD patients and 364 matched control individuals all originating from an isolated northern Swedish population.

Results: Consistent evidence for an association with BPD was found for NR3C1, the gene encoding GR. Almost all SNPs in two adjacent haplotype blocks contributed to the positive signal, comprised of significant single marker, sliding window, and haplotype-specific p-values. All these results point to a moderately frequent (10-15%) susceptibility haplotype covering the entire coding region and 3 > untranslated region (UTR) of NR3C1.

Conclusions: This study contributes to the growing evidence for a role of the glucocorticoid receptor gene (NR3C1) in vulnerability to mood disorders, and BPD in particular, and warrants further in vitro investigation of the at-risk haplotypes with respect to disease etiology. However, this association might be restricted to this specific population, as it is observed in a rather small sample from an isolated population without replication, and data from large meta-analyses for genome-wide association studies in BPD do not show the GR as a very strong candidate.

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.

Epigenetic alterations during aging have been proposed to contribute to decline in physical and cognitive functions, and accelerated epigenetic aging has been associated with disease and all-cause mortality later in life. In this study, we estimated epigenetic age dynamics in groups with different memory trajectories (maintained high performance, average decline, and accelerated decline) over a 15-year period. Epigenetic (DNA-methylation [DNAm]) age was assessed, and delta age (DNAm age - chronological age) was calculated in blood samples at baseline (age: 55-65 years) and 15 years later in 52 age- and gender-matched individuals from the Betula study in Sweden. A lower delta DNAm age was observed for those with maintained memory functions compared with those with average (p = 0.035) or accelerated decline (p = 0.037). Moreover, separate analyses revealed that DNAm age at follow-up, but not chronologic age, was a significant predictor of dementia (p = 0.019). Our findings suggest that young epigenetic age contributes to maintained memory in aging.

The biological underpinnings and the pathological lesions of psychiatric disorders are centuries-old questions that have yet to be understood. Recent studies suggest that schizophrenia and related disorders likely have their origins in perturbed neurodevelopment and can result from a large number of common genetic variants or multiple, individually rare genetic alterations. It is thus conceivable that key neurodevelopmental pathways underline the various genetic changes and the still unknown pathological lesions in schizophrenia. Here, we report that mice defective of the nicastrin subunit of gamma-secretase in oligodendrocytes have hypomyelination in the central nervous system. These mice have altered dopamine signaling and display profound abnormal phenotypes reminiscent of schizophrenia. In addition, we identify an association of the nicastrin gene with a human schizophrenia cohort. These observations implicate gamma-secretase and its mediated neurodevelopmental pathways in schizophrenia and provide support for the "myelination hypothesis" of the disease. Moreover, by showing that schizophrenia and obsessive-compulsive symptoms could be modeled in animals wherein a single genetic factor is altered, our work provides a biological basis that schizophrenia with obsessive-compulsive disorder is a distinct subtype of schizophrenia.

Objectives: To determine whether dementia could explain the association between poor olfactory performance and mortality risk within a decade-long follow-up period. Design: Prospective cohort study. SettingBetula Study, Umea, Sweden. ParticipantsA population-based sample of adult participants without dementia at baseline aged 40 to 90 (N = 1,774). Measurements: Olfactory performance using the Scandinavian Odor-Identification Test (SOIT) and self-reported olfactory function; several social, cognitive, and medical risk factors at baseline; and incident dementia during the following decade. Results: Within the 10-year follow-up, 411 of 1,774 (23.2%) participants had died. In a Cox model, the association between higher SOIT score and lower mortality was significant (hazard ratio (HR) = 0.74 per point interval, 95% confidence interval (CI) = 0.71-0.77, P < .001). The effect was attenuated, but remained significant, after controlling for age, sex, education, and health-related and cognitive variables (HR = 0.92, 95% CI = 0.87-0.97, P = .001). The association between SOIT score and mortality was retained after controlling for dementia conversion before death (HR = 0.92, 95% CI = 0.87-0.97, P = .001). Similar results were obtained for self-reported olfactory dysfunction. Conclusion: Poor odor identification and poor self-reported olfactory function are associated with greater likelihood of future mortality. Dementia does not attenuate the association between olfactory loss and mortality, suggesting that olfactory loss might mark deteriorating health, irrespective of dementia.

There is a great need for diagnostic biomarkers of impending dementia. Metabolite markers in blood have been investigated in several studies, but inconclusive findings encourage further investigation, particularly in the pre-diagnostic phase. In the present study, the serum metabolomes of 110 dementia or pre-diagnostic dementia individuals and 201 healthy individuals matched for age, gender, and education were analyzed by nuclear magnetic resonance spectroscopy in combination with multivariate data analysis. 58 metabolites were quantified in each of the 311 samples. Individuals with dementia were discriminated from controls using a panel of seven metabolites, while the pre-diagnostic dementia subjects were distinguished from controls using a separate set of seven metabolites, where threonine was a common significant metabolite in both panels. Metabolite and pathway alterations specific for dementia and pre-diagnostic dementia were identified, in particular a disturbed threonine catabolism at the pre-diagnostic stage that extends to several threonine-linked pathways at the dementia stage.

Saliva is a biofluid that is sensitive to metabolic changes and is straightforward to collect in a non-invasive manner, but it is seldom used for metabolite analysis when studying neurodegenerative disorders. We present a procedure for both an untargeted and targeted analysis of the saliva metabolome in which nuclear magnetic resonance (NMR) spectroscopy is used in combination with multivariate data analysis. The applicability of this approach is demonstrated on saliva samples selected from the 25 year prospective Betula study, including samples from dementia subjects with either Alzheimer's disease (AD) or vascular dementia at the time of sampling or who developed it by the next sampling/assessment occasion five years later, and age-, gender-, and education-matched control individuals without dementia. Statistically significant multivariate models were obtained that separated patients with dementia from controls and revealed seven discriminatory metabolites. Dementia patients showed significantly increased concentrations of acetic acid (fold change (fc) = 1.25, p = 2 x 10(-5)), histamine (fc = 1.26, p = 0.019), and propionate (fc = 1.35, p = 0.002), while significantly decreased levels were observed for dimethyl sulfone (fc = 0.81, p = 0.005), glycerol (fc = 0.79, p = 0.04), taurine (fc = 0.70, p = 0.007), and succinate (fc = 0.62, p = 0.008). Histamine, succinate, and taurine are known to be important in AD, and acetic acid and glycerol are involved in related pathways. Dimethyl sulfone and propionate originate from the diet and bacterial flora and might reflect poorer periodontal status in the dementia patients. For these seven metabolites, a weak but statistically significant pre-diagnostic value was observed. Taken together, we present a robust and general NMR analysis approach for studying the saliva metabolome that has potential use for screening and early detection of dementia.

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N = 17 052; mean age = 59.2 +/- 8.8 years) provided results for associations between qPCR-measuredTL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (beta = 0.051 per s. d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P = 0.0002), and MMSE (beta = 0.025; 95% CI: 0.002, 0.047; P = 0.03), and faster STROOP (beta = -0.053; 95% CI: -0.087, -0.018; P = 0.003). Effects for DSST were stronger in APOE epsilon 4 non-carriers (beta = 0.081; 95% CI: 0.045, 0.117; P = 1.0 x 10(-5)), whereas carriers performed better in STROOP (beta = -0.074; 95% CI: -0.140, -0.009; P = 0.03). Causal associations were found for STROOP only (beta = -0.598 per s. d.-increase of TL; 95% CI: -1.125, -0.072; P = 0.026), with a larger effect in epsilon 4-carriers (beta = -0.699; 95% CI: -1.330, -0.069; P = 0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE epsilon 4-carriers might be at differential risk.

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.

Robust statistical, genetic and functional evidence supports a role for DISC1 in the aetiology of major mental illness. Furthermore, many of its protein-binding partners show evidence for involvement in the pathophysiology of a range of neurodevelopmental and psychiatric disorders. Copy number variants (CNVs) are suspected to play an important causal role in these disorders. In this study, CNV analysis of DISC1 and its binding partners PAFAH1B1, NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B in Scottish and Northern Swedish population-based samples was carried out using multiplex amplicon quantification. Here, we report the finding of rare CNVs in DISC1, NDE1 (together with adjacent genes within the 16p13.11 duplication), NDEL1 (including the overlapping MYH10 gene) and CIT. Our findings provide further evidence for involvement of DISC1 and its interaction partners in neuropsychiatric disorders and also for a role of structural variants in the aetiology of these devastating diseases.

Objectives: Prospective studies suggest that memory deficits are detectable decades before clinical symptoms of dementia emerge. However, individual differences in long-term memory trajectories prior to diagnosis need to be further elucidated. The aim of the current study was to investigate long-term dementia and mortality risk for individuals with different memory trajectory profiles in a well-characterized population-based sample.

Methods: 1062 adults (aged 45–80 years) who were non-demented at baseline were followed over 23–28 years. Dementia and mortality risk were studied for three previously classified episodic memory trajectory groups: maintained high performance (Maintainers; 26%), average decline (Averages; 64%), and accelerated decline (Decliners; 12%), using multistate modeling to characterize individuals’ transitions from an initial non-demented state, possibly to a state of dementia and/or death.

Results: The memory groups showed considerable intergroup variability in memory profiles, starting 10–15 years prior to dementia diagnosis, and prior to death. A strong relationship between memory trajectory group and dementia risk was found. Specifically, Decliners had more than a fourfold risk of developing dementia compared to Averages. In contrast, Maintainers had a 2.6 times decreased dementia risk compared to Averages, and in addition showed no detectable memory decline prior to dementia diagnosis. A similar pattern of association was found for the memory groups and mortality risk, although only among non-demented.

Conclusion: There was a strong relationship between accelerated memory decline and dementia, further supporting the prognostic value of memory decline. The intergroup differences, however, suggest that mechanisms involved in successful memory aging may delay symptom onset.

Most people's cognitive abilities decline with age, with significant and partly genetically driven, individual differences in rate of change. Although APOE 4 and genetic scores for late-onset Alzheimer's disease (LOAD) have been related to cognitive decline during preclinical stages of dementia, there is limited knowledge concerning genetic factors implied in normal cognitive aging. In the present study, we examined three potential genetic predictors of age-related cognitive decline as follows: (1) the APOE 4 allele, (2) a polygenic score for general cognitive ability (PGS-cog), and (3) a polygenic risk score for late-onset AD (PRS-LOAD). We examined up to six time points of cognitive measurements in the longitudinal population-based Betula study, covering a 25-year follow-up period. Only participants that remained alive and non-demented until the most recent dementia screening (1-3 years after the last test occasion) were included (n=1087). Individual differences in rate of cognitive change (composite score) were predicted by the PRS-LOAD and APOE 4, but not by PGS-cog. To control for the possibility that the results reflected a preclinical state of Alzheimer's disease in some participants, we re-ran the analyses excluding cognitive data from the last test occasion to model cognitive change up-until a minimum of 6 years before potential onset of clinical Alzheimers. Strikingly, the association of PRS-LOAD, but not APOE 4, with cognitive change remained. The results indicate that PRS-LOAD predicts individual difference in rate of cognitive decline in normal aging, but it remains to be determined to what extent this reflects preclinical Alzheimer's disease brain pathophysiology and subsequent risk to develop the disease.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 10(-5)). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence - both genetic and functional - indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P = 0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P = 0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that similar to 90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology.

Aims: This study compared serum metabolites of demented patients (Alzheimer's disease and vascular dementia) and controls, and explored serum metabolite profiles of nondemented individuals 5 years preceding the diagnosis. Methods: Cognitively healthy participants were followed up for 5-20 years. Cognitive assessment, serum sampling, and diagnosis were completed every 5 years. Multivariate analyses were conducted on the metabolite profiles generated by gas chromatography/time-of-flight mass spectrometry. Results: A significant group separation was found between demented patients and controls, and between incident cases and controls. Metabolites that contributed in both analyses were 3,4-dihydroxybutanoic acid, docosapentaenoic acid, and uric acid. Conclusions: Serum metabolite profiles are altered in demented patients, and detectable up to 5 years preceding the diagnosis. Blood sampling can make an important contribution to the early prediction of conversion to dementia.

Importance: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored.

Objective: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis.

Design, Setting, and Participants: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018.

Exposures: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium.

Main Outcomes and Measures: The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency).

Results: Of 34 573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (β = -.07; SE = .02; P = .002).

Conclusions and Relevance: Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.

Individual differences in cognitive performance increase with advancing age, reflecting marked cognitive changes in some individuals along with little or no change in others. Genetic and lifestyle factors are assumed to influence cognitive performance in ageing by affecting the magnitude and extent of age-related brain changes (i.e., brain maintenance or atrophy), as well as the ability to recruit compensatory processes. The purpose of this review is to present findings from the Betula study and other longitudinal studies, with a focus on clarifying the role of key biological and environmental factors assumed to underlie individual differences in brain and cognitive ageing. We discuss the vital importance of sampling, analytic methods, consideration of non-ignorable dropout, and related issues for valid conclusions on factors that influence healthy neurocognitive ageing.

Introduction: We investigated neurofilament light (NFL) accumulation in normal aging as well as in preclinical and clinical Alzheimer's disease (AD) and assessed individual differences in NFL load in relation to cognition and brain white-matter integrity.

Methods: We analyzed longitudinal data covering 30 years (1988-2017). Cognitive testing was done up to six times. Plasma NFL was quantified for controls and 142 cases who developed AD over time, and longitudinal changes in NFL were quantified for 100 individuals with three brain-imaging sessions.

Results: Longitudinal analyses revealed age-related NFL increases with marked variability. AD cases had elevated NFL levels, while no significant group differences were seen in the preclinical phase. Variability in NFL levels showed non-significant correlations with cognition but was associated with brain white matter.

Discussion: Our findings suggest that elevated blood NFL, likely reflecting brain white-matter alterations, characterizes clinical AD, while NFL levels do not predict age-related cognitive impairment or impending AD.

The ɛ4 allele of the Apolipoprotein E gene is a genetic risk factor for late-onset dementia of the Alzheimers' type (DAT), which is characterized by loss of both episodic memory and olfactory functions. Little is known about the possible role of ɛ4 in the association between ongoing episodic memory decline and olfactory deficits in the general population, but such information is relevant in determining the relevance of olfaction as a marker of DAT risk. The present study was based on a large, population-based sample (n=1087, aged 45-90 years, of which 324 were ɛ4-carriers). Episodic memory change rates were established using data collected every 5 years for a 10-20 year interval leading up to an olfactory assessment using the Scandinavian Odor Identification Test at the last wave of data collection. Participants were classified according to whether or not their episodic memory ability declined more rapidly than the age-typical norm (by > 1SD). Our main result is that only in ɛ4-carriers was episodic memory decline associated with odor identification impairment. In individuals without ɛ4, odor identification was unrelated to episodic memory decline status. Follow-up analyses indicated that this moderation by ɛ4 was due to the olfactory nature of the identification test, and that the effect was not caused by 63 individuals with dementia. Our results suggest that the ɛ4 determines the functional association between ongoing episodic memory decline and olfaction. These findings are consistent with the notion that ɛ4-carriers with DAT, compared to non-carriers, display a cortical atrophy pattern that is more focused on mediotemporal lobe regions supporting olfactory and episodic memory functions. Olfactory and memory assessments might provide complementary information on mediotemporal atrophy prior to clinical dementia onset, but the ɛ4 should be considered when using olfactory assessment as an early-stage indicator.

It is widely known that the apolipoprotein E (APOE) ε4 allele imposes a higher risk for Alzheimer's disease (AD). Recent evidence suggests that exposure to air pollution is also a risk factor for AD, and results from a few studies indicate that the effect of air pollution on cognitive function and dementia is stronger in APOE ε4 carriers than in non-carriers. Air pollution and interaction with APOE ε4 on AD risk thus merits further attention. We studied dementia incidence over a 15-year period from the longitudinal Betula study in Northern Sweden. As a marker for long-term exposure to traffic-related air pollution, we used modelled annual mean nitrogen oxide levels at the residential address of the participants at start of follow-up. Nitrogen oxide correlate well with fine particulate air pollution levels in the study area. We had full data on air pollution, incidence of AD and vascular dementia (VaD), APOE ε4 carrier status, and relevant confounding factors for 1,567 participants. As expected, air pollution was rather clearly associated with dementia incidence. However, there was no evidence for a modifying effect by APOE ε4 on the association (p-value for interaction > 0.30 for both total dementia (AD+VaD) and AD). The results from this study do not imply that adverse effects of air pollution on dementia incidence is limited to, or stronger in, APOE ε4 carriers than in the total population.

It is widely known that the apolipoprotein E (APOE) ɛ4 allele imposes a higher risk for Alzheimer’s disease (AD). Recent evidence suggests that exposure to air pollution is also a risk factor for AD, and results from a few studies indicate that the effect of air pollution on cognitive function and dementia is stronger in APOE ɛ4 carriers than in non-carriers. Air pollution and interaction with APOE ɛ4 on AD risk thus merits further attention. We studied dementia incidence over a 15-year period from the longitudinal Betula study in Northern Sweden. As a marker for long-term exposure to traffic-related air pollution, we used modelled annual mean nitrogen oxide levels at the residential address of the participants at start of follow-up. Nitrogen oxide correlate well with fine particulate air pollution levels in the study area. We had full data on air pollution, incidence of AD and vascular dementia (VaD), APOE ɛ4 carrier status, and relevant confounding factors for 1,567 participants. As expected, air pollution was rather clearly associated with dementia incidence. However, there was no evidence for a modifying effect by APOE ɛ4 on the association (p-value for interaction > 0.30 for both total dementia (AD+VaD) and AD). The results from this study do not imply that adverse effects of air pollution on dementia incidence is limited to, or stronger in, APOE ɛ4 carriers than in the total population.

BACKGROUND: Exposure to ambient air pollution is suspected to cause cognitive effects, but a prospective cohort is needed to study exposure to air pollution at the home address and the incidence of dementia.

OBJECTIVES: We aimed to assess the association between long-term exposure to traffic-related air pollution and dementia incidence in a major city in northern Sweden.

METHODS: Data on dementia incidence over a 15-year period were obtained from the longitudinal Betula study. Traffic air pollution exposure was assessed with a Land Use Regression Model with a spatial resolution of 50 m x 50 m. Annual mean nitrogen oxide levels at the residential address of the participants at baseline (the start of follow-up) was used as a marker for long-term exposure to air pollution.

RESULTS: Out of 1806 participants at baseline, 191 were diagnosed with Alzheimer's disease during follow-up, and 111 were diagnosed with vascular dementia. Participants in the highest exposure group were more likely to be diagnosed with dementia (Alzheimer's disease or vascular dementia), with a Hazard Ratio (HR) of 1.43 (95% Confidence Interval (CI): 0.998, 2.05 for the highest versus lowest quartile). The estimates were similar for Alzheimer's disease (HR 1.38) and vascular dementia (HR 1.47). The HR for dementia associated for the third quartile versus the lowest quartile was 1.48 (95% CI: 1.03, 2.11). A sub-analysis that excluded a younger sample that had been re-tested after only 5 years of follow-up suggested stronger associations with exposure than in the full cohort (HR = 1.71; 95% CI: 1.08, 2.73 for the highest versus lowest quartile).

CONCLUSIONS: If the associations we observed are causal, then air pollution from traffic might be an important risk factor for vascular dementia and Alzheimer's disease.

Leukocyte telomere length (LTL) is a proposed biomarker for aging-related disorders, including cognitive decline and dementia. Long-term longitudinal studies measuring intra-individual changes in both LTL and cognitive outcomes are scarce, precluding strong conclusions about a potential aging-related relationship between LTL shortening and cognitive decline. This study investigated associations between baseline levels and longitudinal changes in LTL and memory performance across an up to 20-year follow-up in 880 dementia-free participants from a population-based study (mean baseline age: 56.8 years, range: 40–80; 52% female). Shorter baseline LTL significantly predicted subsequent memory decline (r = .34, 95% confidence interval: 0.06, 0.82), controlling for age, sex, and other relevant covariates. No significant associations were however observed between intra-individual changes in LTL and memory, neither concurrently nor with a 5-year time-lag between LTL shortening and memory decline. These results support the notion of short LTL as a predictive factor for aging-related memory decline, but suggest that LTL dynamics in adulthood and older age may be less informative of cognitive outcomes in aging. Furthermore, the results highlight the importance of long-term longitudinal evaluation of outcomes in biomarker research.

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

BACKGROUND: The Apolipoprotein E (APOE) ɛ4 allele has been linked to increased tau phosphorylation and tangle formation. APOE ɛ4 carriers with elevated tau might be at the higher risk for Alzheimer's disease (AD) progression. Previous studies showed that tau pathology begins early in areas of the medial temporal lobe. Similarly, APOE ɛ4 carriers showed altered hippocampal functional integrity. However, it remains unknown whether the influence of elevated tau accumulation on hippocampal functional changes would be more pronounced for APOE ɛ4 carriers.

OBJECTIVE: We related ɛ4 carriage to levels of plasma phosphorylated tau (p-tau181) up to 15 years prior to AD onset. Furthermore, elevated p-tau181 was explored in relation to longitudinal changes in hippocampal function and connectivity.

METHODS: Plasma p-tau181 was analyzed in 142 clinically defined AD cases and 126 matched controls. The longitudinal analysis involved 87 non-demented individuals (from population-based study) with two waves of plasma samples and three waves of functional magnetic resonance imaging during rest and memory encoding.

RESULTS: Increased p-tau181 was observed for both ɛ4 carriers and non-carriers close to AD onset, but exclusively for ɛ4 carriers in the early preclinical groups (7- and 13-years pre-AD). In ɛ4 carriers, longitudinal p-tau181 increase was paralleled by elevated local hippocampal connectivity at rest and subsequent reduction of hippocampus encoding-related activity.

CONCLUSION: Our findings support an association of APOE ɛ4 and p-tau181 with preclinical AD and hippocampus functioning.

Background: Leukocyte telomere length (LTL) has been shown to predict Alzheimer’s disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor.

Methods: We analyzed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards.

Results: After follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1–24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404–7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947–2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD.

Conclusions: Our findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.

Background: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, hasshown promise for Alzheimer’s disease (AD) prediction.Objective: Testing long-term predictive ability (>15 years) of existing DNAm-based epigenetic age acceleration (EAA)measures and identifying novel early blood-based DNAm AD-prediction biomarkers.

Methods: EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models(LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16years before clinical onset, and post-onset follow-up. NovelDNAmbiomarkers were generated with epigenome-wide LMMs,and Sparse Partial Least Squares Discriminant Analysis applied at pre- (10–16 years), and post-AD-onset time-points.

Results: EAA did not differentiate cases from controls during the follow-up time (p > 0.05). Three new DNA biomarkersshowed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions(p-values: 0.022-<0.00001). Our longitudinally-derived panel replicated nominally (p = 0.012) in an external cohort (n = 146cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOE 4-carriership(OR = 1.38 per 1 SD DNAmscore increase versus OR= 13.58 for 4-allele carriage; AUCs = 77.2% versus 87.0%). Literaturereview showed low overlap (n = 4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with ouridentified CpGs.

Conclusion: The limited predictive value of EAA for AD extends prior findings by considering a longer follow-up time, andwith appropriate control for age, sex, APOE, and blood-cell proportions. Results also highlight challenges with replicatingdiscriminatory or predictive CpGs across studies.

BACKGROUND: Bipolar disorder type I (BP-I) belongs to a spectrum of affective disorders that are expressed in many different ways and therefore can be difficult to distinguish from other conditions, especially unipolar depression, schizoaffective disorder, schizophrenia (SZ), but also anxiety and personality disorders. Since early diagnosis and treatment have shown to improve the long-term prognosis, complementary specific biomarkers are of great value. The auditory brainstem response (ABR) has previously been applied successfully to identify specific abnormal ABR patterns in SZ and Asperger syndrome.

METHODS: The current study investigated the early auditory processing of complex sound stimuli e.g. forward masking, in BP-I compared to SZ patients. The ABR curves of BP-I patients (n=23) and SZ patients (n=20) were analyzed in terms of peak amplitudes and correlation with an ABR norm curve based on a non-psychiatric control group (n=20).

RESULTS: BP-I patients had significantly higher wave III (p=0.0062) and wave VII (p=0.0472) amplitudes compared with SZ patients. Furthermore, BP-I patients, and to a lesser extent SZ patients, showed low correlation with the norm ABR curve in the part of the curve comprising waves VI-VII.

LIMITATIONS: Sample size was relatively small and study groups were not matched for age and gender.

CONCLUSIONS: BP-I patients showed specific aberrances, specifically in the latter part of the ABR curve, implicating abnormalities in thalamocortical circuitry. The abnormal ABR wave patterns significantly separated BP-I patients from SZ patients suggesting that ABR might serve as a biomarker for BP-I.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10^-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10^-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

Objective: Elevated cortisol levels with aging have been associated with atrophy of the hippocampus and prefrontal cortex (PFC), as well as with impaired cognitive functions in men. However, coexisting diseases have confounded many studies examining these relationships. Studies in women are lacking. Our objective was to test whether salivary cortisol levels were related to morphology of the hippocampus and the PFC, and to cognitive performance. Design: A cross-sectional study including 200 elderly (55-80 years old) men and women. Method: We used magnetic resonance imaging, tests of episodic-, semantic-, and working memory, visuospatial ability, and cortisol levels in four saliva samples collected during 1 day. Results: Area under the curve (AUC) for cortisol levels was negatively related to cortical surface area of the left anterior cingulate gyrus (caudal P < 0.001; rostral P = 0.006), right lateral orbitofrontal cortex (P = 0.004), and right rostral middle frontal gyrus (P = 0.003). In women, there was also a negative relationship with cortical surface area in the left rostral middle frontal gyrus (P = 0.006). No relationship was found between cortisol levels and hippocampal volume. Conclusion: This study suggests that the structure of the medial PFC is related to cortisol levels in both elderly women and men.

Sequence analysis of 13 microRNA (miRNA) genes expressed in the human brain and located in genomic regions associated with schizophrenia and/or bipolar disorder, in a northern Swedish patient/control population, resulted in the discovery of two functional variants in the MIR137 gene. On the basis of their location and the allele frequency differences between patients and controls, we explored the hypothesis that the discovered variants impact the expression of the mature miRNA and consequently influence global mRNA expression affecting normal brain functioning. Using neuronal-like SH-SY5Y cells, we demonstrated significantly reduced mature miR-137 levels in the cells expressing the variant miRNA gene. Subsequent transcriptome analysis showed that the reduction in miR-137 expression led to the deregulation of gene sets involved in synaptogenesis and neuronal transmission, all implicated in psychiatric disorders. Our functional findings add to the growing data, which implicate that miR-137 has an important role in the etiology of psychiatric disorders and emphasizes its involvement in nervous system development and proper synaptic function.

Objectives: To examine the effect of perceived loneliness on the development of dementia (all-cause), Alzheimer's disease (AD), and vascular dementia (VaD).

Method: The study comprised 1,905 nondemented participants at baseline, drawn from the longitudinal Betula study in Sweden, with a follow-up time of up to 20 years (mean 11.1 years). Loneliness was measured with a single question: "Do you often feel lonely?".

Results: During the follow-up, 428 developed dementia; 221 had AD, 157 had VaD, and 50 had dementia of other subtypes. The entire dementia group is denoted "all-cause dementia". Cox regression models, adjusted for age, gender, and a baseline report of perceived loneliness, showed increased risk of all-cause dementia (hazard ratio [HR] = 1.46, 95% confidence interval [CI] 1.14–1.89), and AD (HR = 1.69, 95% CI 1.20–2.37), but not VaD (HR = 1.34, 95% CI 0.87–2.08). After adjusting for a range of potential confounders, and excluding participants with dementia onset within the first 5 years of baseline (to consider the possibility of reverse causality), the increased risk for the development of all-cause dementia and AD still remained significant (HR = 1.51, 95% CI 1.01–2.25 for all-cause dementia; HR = 2.50, 95% CI 1.44–4.36 for AD).

Discussion: The results suggest that perceived loneliness is an important risk factor for all-cause dementia and especially for AD, but not for VaD. These results underscore the importance of paying attention to subjective reports of loneliness among the elderly adults and identifying potential intervention strategies that can reduce loneliness.

We searched for genetic causes of major psychiatric disorders (bipolar disorder, schizoaffective disorder, and schizophrenia) in a large, densely affected pedigree from Northern Sweden that originated with three pairs of founders born around 1650. We applied a systematic genomic approach to the pedigree via karyotyping (N = 9), genome-wide SNP arrays (N = 418), whole-exome sequencing (N = 26), and whole-genome sequencing (N = 10). Comprehensive analysis did not identify plausible variants of strong effect. Rather, pedigree cases had significantly higher genetic risk scores compared to pedigree and community controls.

From a number of genome-wide association studies it was shown that de novo and/or rare copy number variants (CNVs) are found at an increased frequency in neuropsychiatric diseases. In this study we examined the prevalence of CNVs in six genomic regions (1q21.1, 2p16.3, 3q29, 15q11.2, 15q13.3, and 16p11.2) previously implicated in neuropsychiatric diseases. Hereto, a cohort of four neuropsychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, and intellectual disability) and control individuals from three different populations was used in combination with Multilpex Amplicon Quantifiaction (MAQ) assays, capable of high resolution (kb range) and custom-tailored CNV detection. Our results confirm the etiological candidacy of the six selected CNV regions for neuropsychiatric diseases. It is possible that CNVs in these regions can result in disturbed brain development and in this way lead to an increased susceptibility for different neuropsychiatric disorders, dependent on additional genetic and environmental factors. Our results also suggest that the neurodevelopmental component is larger in the etiology of schizophrenia and intellectual disability than in mood disorders. Finally, our data suggest that deletions are in general more pathogenic than duplications. Given the high frequency of the examined CNVs (12%) in patients of different neuropsychiatric disorders, screening of large cohorts with an affordable and feasible method like the MAQ assays used in this study is likely to result in important progress in unraveling the genetic factors leading to an increased susceptibility for several psychiatric disorders.

The GWAS-based association of CACNA1C with bipolar disorder (BPD) is one of the strongest genetic findings to date. CACNA1C belongs to the family of CACN genes encoding voltage-dependent calcium channels (VDCCs). VDCCs are involved in brain circuits and cognitive processes implicated in BPD and schizophrenia (SZ). Recently, it was shown that rare copy number variations (CNVs) are found at an increased frequency in SZ and to a lesser extent also in BPD, suggesting the involvement of CNVs in the causation of these diseases. We hypothesize that CNVs in CACN genes can influence the susceptibility to BPD, SZ, and/or schizoaffective disorder (SZA). A search for CNVs in eight CACN genes in a patient-control sample of European decent was performed. A total of 709 BP patients, 645 SZ patients, 189 SZA patients, and 1,470 control individuals were screened using the Multiplex Amplicon Quantification (MAQ) method. We found a rare, partial deletion of 35.7?kb in CACNA2D4 in two unrelated late onset bipolar I patients and in one control individual. All three deletions shared the same breakpoints removing exons 1726 of CACNA2D4, comprising part of the CACHE domain. Based on the data we cannot claim causality to BPD of the identified CACNA2D4 deletion but nevertheless this deletion can be important in unraveling the underlying processes leading to psychiatric diseases in general and BPD in particular.

Background: leukocyte telomere length (TL) is considered a marker of biological aging. Several studies have investigated the link between leukocyte TL and aging-associated functional attributes of the brain, but no prior study has investigated whether TL can be linked to brain atrophy and white matter hyperintensities (WMHs); two prominent structural manifestations of brain aging. Methods: we investigated whether leukocyte TL was related to brain atrophy and WMHs in a sample of 102 non-demented individuals aged 64-75 years. Results: shorter TL was related to greater degree of subcortical atrophy (beta = -0.217, P = 0.034), but not to cortical atrophy. Furthermore, TL was 371 bp shorter (P = 0.041) in participants exhibiting subcortical WMHs, and 552 bp shorter (P = 0.009) in older participants exhibiting periventricular WMHs. Conclusion: this study provides the first evidence of leukocyte TL being associated with cerebral subcortical atrophy and WMHs, lending further support to the concept of TL as a marker of biological aging, and in particular that of the aging brain.