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.

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.

Family caregivers experiences of the pre-diagnostic stage in frontotemporal dementia.

Frontotemporal dementia (FTD) is a neurodegenerative disease with symptoms that differs from other dementias. Commonly early symptoms in FTD are changes in personality and behavior, which can be interpreted as psychiatric disease. The delay in FTD diagnosis contributes to the burden of family caregivers. Therefore, it is important to have more knowledge about the pre-diagnostic stage. In this qualitative interview study, we explored fourteen family caregiver's experiences of the pre-diagnostic stage of frontotemporal dementia (FTD). Our findings suggest that the family caregivers experienced the pre-diagnostic stage of FTD as changes in the interpersonal relationship with their loved one. These changes were often subtle and difficult for family caregivers to explain to others. The findings from our study illuminate the importance of medical staff paying attention when a next of kin is concerned about subtle changes in a loved one. The findings also illuminate that awareness of FTD should be raised.

Risk factors for frontotemporal dementia. / Risikofaktorer for frontotemporal demens.

BAKGRUNN: Risikofaktorer for frontotemporal demens er lite kartlagt. Formålet med denne artikkelen var å gi en oppdatert oversikt over modifiserbare risikofaktorer for frontotemporal demens og vurdere kunnskapsgrunnlaget for kliniske anbefalinger for å redusere risiko for sykdommen. KUNNSKAPSGRUNNLAG: Det ble utført søk i basene PsychInfo, Embase, PubMed og Cochrane i perioden mai 2016-april 2017. Søket ga totalt 137 artikler. 101 artikler ble ekskludert fordi de kun omhandlet genetiske aspekter ved frontotemporal demens og ikke modifiserbare risikofaktorer. Etter å ha lest 36 artikler i fulltekst inkluderte vi 12 artikler som enten var oversiktsartikler eller originalstudier. RESULTATER: Enkelte studier viste sammenheng mellom modifiserbare risikofaktorer og utvikling av frontotemporal demens. I én studie fant man at diabetes ga økt risiko. Tre studier viste at hodetraume kan gi økt risiko for frontotemporal demens og at forekomsten av traumatisk hodeskade var signifikant høyere hos pasienter med frontotemporal demens enn andre former for demens. Autoimmun sykdom kan være forbundet med økt risiko for primær progressiv afasi, en undergruppe av frontotemporal demens. FORTOLKNING: Litteraturen indikerte sammenheng mellom diabetes, hodetraume, autoimmun sykdom og frontotemporal demens. Det finnes per i dag ikke tilstrekkelig kunnskap for å fremme anbefalinger om livsstilsendringer for å forebygge frontotemporal demens på befolkningsnivå.

Prevalence and correlates of successful aging in a population-based sample of older adults: the HUNT study.

BACKGROUND: The factors influencing successful aging (SA) are of great interest in an aging society. The aims of this study were to investigate the prevalence of SA, the relative importance across age of the three components used to define it (absence of disease and disability, high cognitive and physical function, and active engagement with life), and its correlates. METHODS: Data were extracted from the population-based cross-sectional Nord-Trøndelag Health Study (HUNT3 2006-2008). Individuals aged 70-89 years with complete datasets for the three components were included (N = 5773 of 8,040, 71.8%). Of the respondents, 54.6% were women. Univariate and multivariate regression analyses were used to analyze possible correlates of SA. RESULTS: Overall, 35.6% of the sample met one of the three criteria, 34.1% met combinations, and 14.5% met all of the three criteria. The most demanding criterion was high function, closely followed by absence of disease, while approximately two-thirds were actively engaged in life. The relative change with age was largest for the high cognitive and physical function component and smallest for active engagement with life. The significant correlates of SA were younger age, female gender, higher education, weekly exercise, more satisfaction with life, non-smoking, and alcohol consumption, whereas marital status was not related to SA. CONCLUSIONS: The prevalence of SA in this study (14.5%) is comparable to previous studies. It may be possible to increase the prevalence by intervention directed toward more exercise, non-smoking, and better satisfaction with life.

Alcohol consumption and risk of dementia up to 27 years later in a large, population-based sample: the HUNT study, Norway.

The relationship between alcohol consumption and dementia risk is unclear. This investigation estimates the association between alcohol consumption reported in a population-based study in the mid-1980s and the risk for dementia up to 27 years later. The entire adult population in one Norwegian county was invited to the Nord-Trøndelag Health Study during 1984-1986 (HUNT1): 88 % participated. The sample used in this study includes HUNT1 participants born between 1905 and 1946 who completed the questionnaire assessing alcohol consumption. A total of 40,435 individuals, of whom 1084 have developed dementia, are included in the analysis adjusted for age, sex, years of education, hypertension, obesity, smoking, and symptoms of depression. When adjusting for age and sex, and compared to reporting consumption of alcohol 1-4 times during the last 14 days (drinking infrequently), both abstaining from alcohol and reporting consumption of alcohol five or more times (drinking frequently) were statistically significantly associated with increased dementia risk with hazard ratios of 1.30 (95 % CI 1.05-1.61) and 1.45 (1.11-1.90), respectively. In the fully adjusted analysis, drinking alcohol frequently was still significantly associated with increased dementia risk with a hazard ratio of 1.40 (1.07-1.84). However, the association between dementia and abstaining from alcohol was no longer significant (1.15, 0.92-1.43). Equivalent results for Alzheimer's disease and vascular dementia indicated the same patterns of associations. When adjusting for other factors associated with dementia, frequent alcohol drinking, but not abstaining from alcohol, is associated with increased dementia risk compared to drinking alcohol infrequently.

Headache as a predictor for dementia: The HUNT Study.

BACKGROUND: The impact of headache on dementia is largely unknown. This study examined the association between headache and dementia using data from a large population-based study. METHODS: This population-based study used data from the Nord-Trøndelag Health Surveys performed in 1995-1997 (HUNT2) and 2006-2008 (HUNT3). The reference group (controls) was participants aged ≥55 years who answered the headache questions in HUNT2 and later participated in HUNT3 (n = 15,601). The association with headache status in HUNT2 was investigated in sample of confirmed non-demented elderly evaluated with psychometric tests after HUNT3 (n = 96), and HUNT2 participants later diagnosed with dementia during 1997-2011 (n = 746). The association with headache was evaluated by logistical regression with adjustment for age, gender, level of education, comorbidity, smoking, and anxiety and depression. RESULTS: Any headache was more likely to be reported in HUNT2 among those who later were included in the dementia registry (OR 1.24; 95 % CI 1.04-1.49) compared to the reference group, but less likely among the confirmed non-demented individuals (OR 0.62; 95 % CI 0.39-0.98). This relationship was even stronger for non-migrainous headache, whereas such association was not found for migraine. CONCLUSIONS: Compared to the reference group, individuals with dementia were more likely to report non-previous migrainous headache in HUNT2, whereas a sample of confirmed non-demented were less likely to report previous non-migrainous headache.

Headache as a risk factor for dementia: a prospective population-based study.

BACKGROUND: Headache has not been established as a risk factor for dementia. The aim of this study was to determine whether any headache was associated with subsequent development of vascular dementia (VaD), Alzheimer's disease (AD) or other types of dementia. METHODS: This prospective population-based cohort study used baseline data from the Nord-Trøndelag Health Study (HUNT 2) performed during 1995-1997 and, from the same Norwegian county, a register of cases diagnosed with dementia during 1997-2010. Participants aged ≥20 years who responded to headache questions in HUNT 2 were categorized (headache free; with any headache; with migraine; with non-migrainous headache). Hazard ratios (HRs) for later inclusion in the dementia register were estimated using Cox regression analysis. RESULTS: Of 51,383 participants providing headache data in HUNT 2, 378 appeared in the dementia register during the follow-up period. Compared to those who were headache free, participants with any headache had increased risk of VaD ( N = 63) (multivariate-adjusted HR = 2.3, 95% CI 1.4-3.8, P = 0.002) and of mixed dementia (VaD and AD ( N = 52)) (adjusted HR = 2.0, 95% CI 1.1-3.5, P = 0.018). There was no association between any headache and later development of AD ( N = 180). CONCLUSION: In this prospective population-based cohort study, any headache was a risk factor for development of VaD.

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.

Association of personality, neighbourhood, and civic participation with the level of perceived social support: the HUNT study, a cross-sectional survey.

AIM: The aim of the current study was to examine the association of personality, neighbourhood, and civic participation with the level of perceived social support if needed. METHODS: The sample consists of a total of 35,797 men (16,035) and women (19,762) drawn from the Nord-Trøndelag Health Study 3 (HUNT3), aged 20-89, with a fully completed short version of the Eysenck Personality Questionnaire (EPQ) including a complete response to questions regarding perceived social support. A multinomial logistic regression model was used to investigate the association between the three-category outcomes (high, medium, and low) of perceived social support. RESULTS: The Chi-square test detected a significant (p < 0.001) association between personality, sense of community, civic participation, self-rated health, living arrangement, age groups, gender, and perceived social support, except between perceived social support and loss of social network, in which no significance was found. The crude and adjusted multinomial logistic regression models show a relation between medium and low scores on perceived social support, personality, and sources of social support. Interactions were observed between gender and self-rated health. CONCLUSIONS: There is an association between the level of perceived social support and personality, sense of community in the neighbourhood, and civic participation. Even if the interaction between men and self-reported health decreases the odds for low and medium social support, health professionals should be aware of men with poor health and their lack of social support.

Increased prevalence of depression in cohorts of the elderly: an 11-year follow-up in the general population - the HUNT study.

BACKGROUND: Depression is a common disorder in late life. As the elderly population continues to grow worldwide, depression is also likely to become an increasing health problem. The aim of this study was to examine changes in prevalence of depression in various age cohorts over an 11-year period. METHODS: This study involved two cross-sectional studies (HUNT 2 and HUNT 3) of all adult inhabitants of the Norwegian county of Nord-Trøndelag with an 11 year-interval between the two studies. The participants aged 45 years or above at HUNT 2 and with a valid depression rating at both HUNT 2 (baseline) and HUNT 3 (follow-up) (N = 16517), were included and divided into five-year age cohorts. Depression was measured by the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). RESULTS: A significant increase in depression was found in all age cohorts from 76 years at follow-up, with the greatest increase (9.6%) in the oldest age cohort (86-90 years at follow-up). The incidence of depression is increasing with age, with over 10% new cases in all age cohorts aged 81 years and above at follow-up. About 5% of the participants in all age cohorts reported depression at both measure points, and there is a decrease in recovery from depression from baseline to follow-up with increasing age. CONCLUSIONS: We found increased prevalence of depression and a large number of new cases of depression in the oldest age cohorts.

Association between social support and depression in the general population: the HUNT study, a cross-sectional survey.

AIM: The aim was to investigate the associations between perceived social support and depression in a general population in relation to gender and age. BACKGROUND: Social support is seen as one of the social determinants for overall health in the general population. Studies have found higher probability of experiencing depression among people who have a lack of social support; evidence from the general population has been more limited. Subjective perception that support would be available if needed may reduce and prevent depression and unnecessary suffering. DESIGN: A cross-sectional survey with self-reported health was used. METHOD: A total of 40,659 men and women aged 20-89 years living in Nord-Trøndelag County of Norway with valid ratings of depression subscale of the Hospital Anxiety and Depression Scale in the The Nord-Trøndelag Health Study 3 were used. Logistic regression was used to quantify associations between two types of perceived support (emotional and tangible) and depression. Gender, age and interaction effects were controlled for in the final model. RESULTS: The main finding was that self-rated perceived support was significantly associated with Hospital Anxiety and Depression Scale-defined depression, even after controlling for age and gender; emotional support (OR = 3·14) and tangible support (OR = 2·93). The effects of emotional and tangible support differ between genders. Interaction effects were found for age groups and both emotional and tangible support. CONCLUSION: Self-rated perceived functional social support is associated with Hospital Anxiety and Depression Scale-defined depression. In the group of older people who have a lack of social support, women seem to need more emotional support and men tangible support. RELEVANCE TO CLINICAL PRACTICE: Health care providers should consider the close association between social support and depression in their continuing care, particularly in the older people.

A comparison of depressive symptoms in elderly medical inpatients and the elderly in a population-based health study (the Nord-Trøndelag Health Study 3).

AIM: To compare depression in a sample of the medically hospitalized elderly with elderly people participating in a population-based health study in Norway and further to study the odds for depression, controlling for demographic and health differences between the two samples. METHOD: This cross-sectional observational study evaluated 484 medical inpatients from rural areas and 10,765 drawn from the Nord-Trøndelag Health Study 3 (HUNT-3 Study) including participants from rural and urban areas. All participants were elderly (≥65 years) with a mean (± standard deviation) age of 80.7 ± 7.4 and 73.3 ± 6.3 years, respectively. Symptoms of depression were screened by the Hospital Anxiety and Depression Scale (HAD). RESULTS: The prevalence of symptoms indicating mild, moderate or more severe depression (depression score ≥8) was about the same in both groups. In regression analyses, adjusting demographic and health differences, the odds for depression was lower for the elderly in the hospital sample than in the HUNT-3 Study. Older age, male gender, perceiving general health as poor, having impaired ability to function in daily life, previous consultation or treatment for emotional problems and anxiety (anxiety score ≥8) were associated with increased odds for depression in the elderly independent of being hospitalized or not. CONCLUSION: Surprisingly, we found the odds for depression after controlling for demographic and health variables to be lower in the hospitalized elderly individuals than in the elderly participating in the population-based health study. The health variables that were most strongly associated with an increased risk of depression were poor physical health and anxiety.

The relationship among neuroticism, extraversion, and depression in the HUNT Study: in relation to age and gender.

The purpose of this study was to examine the relationship between personality and depression in a general population in relation to gender and age. The Nord-Trøndelag Health Study (2006-2008), a large cross-sectional survey, was used. The sample consists of 35,832 men (16,104) and women (19,728) aged 20-89 years, living in the Nord-Trøndelag County of Norway, with valid ratings on the depression subscale of the Hospital Anxiety and Depression Scale (HADS) and Eysenck Personality Questionnaire (EPQ). This study demonstrates a relationship between depression and both neuroticism and extraversion in a general population. Older people score low more often on Extraversion (E) than younger people. Interactions were observed between neuroticism and age, gender, and extraversion with depression. The interaction term indicates a high score on Neuroticism (N) enhanced by introversion, older age, and being a male with depression. The findings suggest that health professionals may need to put extra effort into the care of patients with low extraversion and high neuroticism, in order to help those patients avoid depression.

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.

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.

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.

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.