Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling.

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder, and phobias) are highly prevalent, often onset early, persist throughout life, and cause substantial global disability. Although distinct in their clinical presentations, they likely represent differential expressions of a dysregulated threat-response system. Here we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant ANX risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 of the 58 associated variants were replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism, and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism underlying ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

Temporal changes in personal activity intelligence and the risk of incident dementia and dementia related mortality: A prospective cohort study (HUNT).

Background: The Personal Activity Intelligence (PAI) translates heart rate during daily activity into a weekly score. Obtaining a weekly PAI score ≥100 is associated with reduced risk of premature morbidity and mortality from cardiovascular diseases. Here, we determined whether changes in PAI score are associated with changes in risk of incident dementia and dementia-related mortality. Methods: We conducted a prospective cohort study of 29,826 healthy individuals. Using data from the Trøndelag Health-Study (HUNT), PAI was estimated 10 years apart (HUNT1 1984-86 and HUNT2 1995-97). Adjusted hazard-ratios (aHR) and 95%-confidence intervals (CI) for incidence of and death from dementia were related to changes in PAI using Cox regression analyses. Findings: During a median follow-up time of 24.5 years (interquartile range [IQR]: 24.1-25.0) for dementia incidence and 23.6 years (IQR: 20.8-24.2) for dementia-related mortality, there were 1998 incident cases and 1033 dementia-related deaths. Individuals who increased their PAI score over time or maintained a high PAI score at both assessments had reduced risk of dementia incidence and dementia-related mortality. Compared with persistently inactive individuals (0 weekly PAI) at both time points, the aHRs for those with a PAI score ≥100 at both occasions were 0.75 (95% CI: 0.58-0.97) for incident dementia, and 0.62 (95% CI: 0.43-0.91) for dementia-related mortality. Using PAI score <100 at both assessments as the reference cohort, those who increased from <100 at HUNT1 to ≥100 at HUNT2 had aHR of 0.83 (95% CI: 0.72-0.96) for incident dementia, and gained 2.8 (95% CI: 1.3-4.2, P<0.0001) dementia-free years. For dementia-related mortality, the corresponding aHR was 0.74 (95% CI: 0.59-0.92) and years of life gained were 2.4 (95% CI: 1.0-3.8, P=0.001). Interpretation: Maintaining a high weekly PAI score and increases in PAI scores over time were associated with a reduced risk of incident dementia and dementia-related mortality. Our findings extend the scientific evidence regarding the protective role of PA for dementia prevention, and suggest that PAI may be a valuable tool in guiding research-based PA recommendations. Funding: The Norwegian Research Council, the Liaison Committee between the Central Norway Regional Health Authority and Norwegian University of Science and Technology (NTNU), Trondheim, Norway.

Using Polygenic Hazard Scores to Predict Age at Onset of Alzheimer's Disease in Nordic Populations.

BACKGROUND: Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer's disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. OBJECTIVE: The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. METHODS: We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian DemGene cohort (n = 2,772). We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (n = 7,643) and The Copenhagen General Population Study (CGPS) cohort (n = 10,886). RESULTS: We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. CONCLUSION: PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations.

Processing speed and working memory are predicted by components of successful aging: a HUNT study.

BACKGROUND: Research has demonstrated that cognitive heterogeneity occurs with aging both within and between individuals. The purpose of this study was to explore whether the cognitive heterogeneity in aging was related to the subgroups of successful and usual aging. METHOD: Participants were a representative sample of normal older adults (n = 65, age range 70-89 years). All subjects had participated in the third phase of the Nord-Trøndelag Health Survey (HUNT3) and completed all subtests in the Wechsler Memory Scale (WMS-III) and Wechsler Adult Intelligence Scale (WAIS-III). Successful aging was defined in four ways in the study: as (1) absence of disease, (2) high functioning, (3) active engagement with life, or (4) all three components combined. Five domains of memory and intelligence functions were investigated using linear regression analysis, with group membership (successful versus usual aging) as predictors and age, sex and education as correlates. RESULTS: Processing speed performance was correlated with the successful aging component absence of disease, younger age and being of the female sex, while working memory performance was correlated with the successful aging component absence of disease and more years of education. Performance in other domains (verbal, visuospatial, and episodic memory) were not related to any successful aging definition. Age had a consistent negative effect on the processing speed domain for all successful aging definitions. Education was positively linked to cognitive performance on the verbal and working memory domains. Being female was positively linked to processing speed and episodic memory. CONCLUSIONS: Processing speed and working memory were linked to successful aging when it was defined as absence of disease, but not by other components of successful aging, i.e. domain-specific. In contrast, other cognitive domains were not related to any components of successful aging.

Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease.

Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

Characteristics associated with later self-harm hospitalization and/or suicide: A follow-up study of the HUNT-2 cohort, Norway.

BACKGROUND: To improve suicide and self-harm prevention in adults, better knowledge on preexisting characteristics and risk factors is of great importance. METHODS: This is a population-based case-control study; baseline measures were collected in the second wave of the North-Trøndelag Health Study (HUNT-2, 1995-1997) in Norway, and outcomes were observed for up to 19 years. Average follow up time was 4.9 years for self-harm and 6.8 years for suicides. Out of 93,898 eligible adult inhabitants aged 20 and above, a total of 65,229 (70%) participated in the study. The data were linked to the National Mortality Registry and hospital patient records in the three hospitals covering the HUNT-2 catchment area. RESULTS: Among the participants, 332 patients (68% women) were hospitalized because of self-harm (HSH), and 91 patients (32% women) were died by suicide (SU). A total of 10% of those who died by SU had previously been HSH. People in the HSH and SU groups were younger, reported more depression and anxiety symptoms, sleeping problems, higher use of alcohol and tobacco, poorer social network and more economic problems, compared to the rest of the HUNT-2 population. In addition, the HSH group reported more somatic health problems, higher use of health services, higher sick leave, and lower work participation than the SU group. LIMITATIONS: Younger adults (20-40 years) were under-represented in HUNT-2. Younger adults (20-40 years) were constituted 31.7% in HUNT-2, 50% in HSH and 33% in SU. Further, we did not identify less severe self-harm, not requiring hospitalization. Life changes, adverse events, and other possible triggers to self-harming behavior were not recorded. CONCLUSION: Psychological problems were long-term predictors of both HSH and SU. Somatic health problems and lower functional performance were more present in HSH-group compared to the SU-group.

Subjective working memory predicts objective memory in cognitively normal aging: a HUNT study.

BACKGROUND: Recent studies have shown that subjective memory is multi-, rather than uni-dimensional, in line with the results of objective memory tests. The purpose of this study was to investigate whether there is an association between aspects of memory measured by the subjective Meta-Memory Questionnaire (MMQ) and aspects of memory measured by the objective Wechsler Memory Scale-III (WMS-III) and Wechsler Adult Intelligence Scale-III (WAIS-III) tests in cognitively normal older adults. METHOD: The study subjects (n = 106) were cognitively normal, were aged 57-89 years and had participated in the third wave of the North-Trøndelag Health survey (HUNT3). All subjects had completed the MMQ, the WMS-III and the WAIS-III. Previous results from the MMQ (measured as the total MMQ score; the Component I score, related to long-term explicit declarative memory; and the Component II score, related to working/short-term memory) were compared with objective results from WMS-III (Logical Memory) and WAIS-III (Vocabulary and Letter-Number Sequencing) subtests. We conducted linear regression analyses with each objective memory test result as the dependent variable, and subjective memory measures and demographics as independent variables, as well as analyses of MMQ items vs. objective memory. RESULTS: Subjective working memory impairment (Component II) was significant related to poor performance in objective episodic memory, according to correlation and regression analyses with demographic covariates. In contrast, ratings of impaired subjective declarative memory (Component I) were not related to poor objective memory performance. CONCLUSIONS: Specific aspects of subjective memory related differentially to performance in specific objective memory tests. Clinicians and researchers might consider targeting working memory aspects of subjective memory tests, when seeking an estimate of objective memory performance.

Author Correction: Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Examining the association between genetic liability for schizophrenia and psychotic symptoms in Alzheimer's disease.

Psychosis (delusions or hallucinations) in Alzheimer's disease (AD + P) occurs in up to 50% of individuals and is associated with significantly worse clinical outcomes. Atypical antipsychotics, first developed for schizophrenia, are commonly used in AD + P, suggesting shared mechanisms. Despite this implication, little empirical research has been conducted to examine whether there are mechanistic similarities between AD + P and schizophrenia. In this study, we tested whether polygenic risk score (PRS) for schizophrenia was associated with AD + P. Schizophrenia PRS was calculated using Psychiatric Genomics Consortium data at ten GWAS p value thresholds (PT) in 3111 AD cases from 11 cohort studies characterized for psychosis using validated, standardized tools. Association between PRS and AD + P status was tested by logistic regression in each cohort individually and the results meta-analyzed. The schizophrenia PRS was associated with AD + P at an optimum PT of 0.01. The strongest association was for delusions where a one standard deviation increase in PRS was associated with a 1.18-fold increased risk (95% CI: 1.06-1.3; p = 0.001). These new findings point towards psychosis in AD-and particularly delusions-sharing some genetic liability with schizophrenia and support a transdiagnostic view of psychotic symptoms across the lifespan.

Lifestyle predictors of successful aging: A 20-year prospective HUNT study.

BACKGROUND: Lifestyle factors predicting successful aging as a unified concept or as separate components of successful aging are important for understanding healthy aging, interventions and preventions. The main objective was to investigate the effect of midlife predictors on subsequent successful aging 20 years later. MATERIALS AND METHODS: Data were from a population-based health survey, the Nord-Trøndelag Health Study (HUNT), with an average follow-up of 22.6 years. Individuals free of major disease at baseline in 1984-86 with complete datasets for the successful aging components in HUNT3 in 2006-08, were included (n = 4497; mean age at baseline 52.7, range 45-59, years). Successful aging was defined either as a unified category or as three components: being free of nine specified diseases and depression, having no physical or cognitive impairment, and being actively engaged with life. The midlife predictors (smoking, physical activity, alcohol consumption, obesity and social support) were analysed both as separate predictors and combined into a lifestyle index controlling for sociodemographic variables, using multivariable regression analysis. RESULTS: Successful aging as a unified concept was related to all the lifestyle factors in the unadjusted analyses, and all except alcohol consumption in the adjusted analyses. The individual components of successful aging were differently associated with the lifestyle factors; engagement with life was less associated with the lifestyle factors. Non- smoking and good social support were the most powerful predictors for successful aging as a unified concept. When the lifestyle factors were summed into a lifestyle index, there was a trend for more positive lifestyle to be related to higher odds for successful aging. CONCLUSIONS: Lifestyle factors predicted an overall measure of SA, as well as the individual components, more than 20 years later. Modifiable risk factors in midlife, exemplified by social support, may be used for interventions to promote overall health and specific aspects of health in aging.

GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study.

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10-8). One additional genetic locus previously linked to psychosis in Alzheimer's disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10-6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

Subjective working and declarative memory in dementia and normal aging.

OBJECTIVE: Subjective memory complaints are common in both elderly individuals and patients with dementia. This study investigated the power of subjective memory, divided into declarative and working memory, to differentiate between patients with dementia and normal elderly individuals. METHOD: Two groups of participants, patients with dementia (n = 117) and normal elderly individuals (n = 117), individually matched with regard to age, gender, and education. All subjects had participated in the third wave of the HUNT population health survey in Nord-Trøndelag County in Norway and completed the Meta-Memory Questionnaire (MMQ) in the HUNT study. The MMQ was subdivided into two components, one associated with declarative memory (episodic and semantic) and the other with working memory. RESULTS: Patients with dementia reported significantly more subjective memory concerns than normal elderly individuals. The difference between working and declarative memory components was significantly greater in patients with dementia than in normal elderly individuals. This finding made it possible to differentiate patients with dementia from the normal elderly individuals. Mental and somatic health conditions did not significantly add power to differentiating the two groups. CONCLUSION: In clinical and research applications, subjective memory components could contribute to differentiation of patients with dementia and normal elderly individuals by using self-reported impairment in working memory, rather than declarative memory.

Smoking and Obesity as Risk Factors in Frontotemporal Dementia and Alzheimer's Disease: The HUNT Study.

BACKGROUND: Few studies have assessed smoking and obesity together as risk factors for frontotemporal dementia (FTD) and Alzheimer's disease (AD). OBJECTIVE: To study smoking and obesity as risk factors for FTD and AD. METHODS: Ninety patients with FTD and 654 patients with AD were compared with 116 cognitively healthy elderly individuals in a longitudinal design with 15-31 years between measurements of risk factors before the dementia diagnosis. RESULTS: There were no associations between smoking and FTD (p = 0.218; odds ratio [OR]: 0.990; 95% confidence interval [CI]: 0.975-1.006). There were significant associations between obesity and FTD (p = 0.049; OR: 2.629; 95% CI: 1.003-6.894). There were significant associations between both smoking (p = 0.014; OR: 0.987; 95% CI: 0.977-0.997) and obesity (p = 0.015; OR: 2.679; 95% CI: 1.211-5.928) and AD. CONCLUSION: Our findings suggest that obesity is a shared risk factor for FTD and AD, while smoking plays various roles as a risk factor for FTD and AD.

Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.