Longitudinal trajectories of cognitive aging.

PURPOSE OF REVIEW: This review summarizes recent evidence related to the cognitive trajectories of aging, the factors associated with the different trajectories, and the effect of sex on cognitive decline. RECENT FINDINGS: Trajectories of cognitive aging identified in different studies vary in number, in the proportion of individuals falling into each of the classes and in the predictors of class membership. Trajectories observed include types with 'rapid decline', those with 'gradual decline' and those with 'maintenance of high level' of cognitive performance. Predictors of decline and predictors of maintenance of cognitive performance may be different. While factors such as education were in general associated with high performance, and reversely with low performance, other factors, such as depression were predictors only for some groups, particularly the declining ones. Sex differences in cognitive trajectories and the associated predictive factors have also been identified. SUMMARY: The findings on education may be particularly important in populations with low educational level, especially among women and the findings on depression have special interest in preventing cognitive decline in women. Further work is required to explain intriguing inconsistencies observed in the literature.

Chronic obstructive pulmonary disease mortality in Spain between 1999 and 2019 / Mortalidad por enfermedad pulmonar obstructiva crónica en España entre 1999 y 2019

Introduction Mortality from COPD has decreased in Spain in recent years, but it is unknown whether this decline has been homogeneous among the different regions. Methods From the Statistical Portal of the Ministry of Health of Spain we obtained the age-adjusted mortality rates/100,000 inhabitants for men and women in Spain and the Autonomous Communities for the years 1999–2019, using the coding of the International Classification of Diseases (ICD 10, sections J40–J44). With the adjusted rates we performed a jointpoint regression analysis to estimate an annual percentage change (APC), as well as identify possible points of trend change. Statistical significance was considered for a value of p<0.05. Results During the study period, COPD mortality rates adjusted in Spain decreased from 28.77 deaths/100,000 inhabitants in 1999 to 12.14 deaths/100,000 inhabitants in 2019. We observed a linear decline in COPD mortality in men at national level of −3.67% per year (95% CI −4.1 to −3.4; p<0.001), with differences between the Autonomous Communities. Mortality in women also experienced a decrease in mortality in two phases, with a first period from 1999 to 2006 with a fall of −6.8% per year (95% CI −8.6 to −5.0; p<0.001) and a second period from 2006 to 2019 with a decrease in mortality of −2.1% (95% CI −2.8 to −1.3; p<0.001), with again differences between the Autonomous Communities. Conclusion Mortality rates from COPD have decreased heterogeneously among the different Autonomous Communities in both men and women (AU)

Introducción La mortalidad por EPOC ha disminuido en España en los últimos años, pero se desconoce si esta caída ha sido homogénea entre las diferentes comunidades autónomas. Metodología consultando el Portal Estadístico del Ministerio de Sanidad de España obtuvimos las tasas ajustadas por edad/100.000 habitantes para hombres y mujeres de España y las CCAA para los años 1999 a 2019, utilizando la codificación de la Clasificación Internacional de Enfermedades (CIE 10, secciones J40 a J44). Con las tasas ajustadas realizamos un análisis de regresión de jointpoint con el objetivo de estimar un porcentaje anual de cambio (APC), así como identificar posibles puntos de cambio de tendencia. Se consideró la significación estadística para un valor de p<0.05. Resultados Durante el periodo de estudio, las tasas de mortalidad global ajustada por EPOC en España pasaron de 28.77 muertes/100.000 habitantes en 1999 a 12.14 muertes/100.000 habitantes en 2019. Observamos una caída de la mortalidad por EPOC en varones a nivel de España lineal del -3.67% anual (IC 95% -4.1 a -3.4; p<0.001), con diferencias entre las CCAA. La mortalidad en mujeres también experimentó una disminución de mortalidad en dos fases, con un primer periodo de 1999 a 2006 con caída del -6.8% anual (IC 95% -8.6 a -5.0; p<0.001) y un segundo periodo de 2006 a 2019 con un descenso de la mortalidad del -2.1% (IC 95% -2.8 a -1.3; p<0.001), encontrando diferencias entre las CCAA. Conclusiones Las tasas de mortalidad por EPOC han disminuido de forma heterogénea entre las diferentes CCAA (AU)

Prodromal symptoms and the duration of untreated psychosis in first episode of psychosis patients: what differences are there between early vs. adult onset and between schizophrenia vs. bipolar disorder?

To assess the role of age (early onset psychosis-EOP < 18 years vs. adult onset psychosis-AOP) and diagnosis (schizophrenia spectrum disorders-SSD vs. bipolar disorders-BD) on the duration of untreated psychosis (DUP) and prodromal symptoms in a sample of patients with a first episode of psychosis. 331 patients with a first episode of psychosis (7-35 years old) were recruited and 174 (52.6%) diagnosed with SSD or BD at one-year follow-up through a multicenter longitudinal study. The Symptom Onset in Schizophrenia (SOS) inventory, the Positive and Negative Syndrome Scale and the structured clinical interviews for DSM-IV diagnoses were administered. Generalized linear models compared the main effects and group interaction. 273 AOP (25.2 ± 5.1 years; 66.5% male) and 58 EOP patients (15.5 ± 1.8 years; 70.7% male) were included. EOP patients had significantly more prodromal symptoms with a higher frequency of trouble with thinking, avolition and hallucinations than AOP patients, and significantly different median DUP (91 [33-177] vs. 58 [21-140] days; Z = - 2.006, p = 0.045). This was also significantly longer in SSD vs. BD patients (90 [31-155] vs. 30 [7-66] days; Z = - 2.916, p = 0.004) who, moreover had different profiles of prodromal symptoms. When assessing the interaction between age at onset (EOP/AOP) and type of diagnosis (SSD/BD), avolition was significantly higher (Wald statistic = 3.945; p = 0.047), in AOP patients with SSD compared to AOP BD patients (p = 0.004). Awareness of differences in length of DUP and prodromal symptoms in EOP vs. AOP and SSD vs. BD patients could help improve the early detection of psychosis among minors.

Chronic obstructive pulmonary disease mortality in Spain between 1999 and 2019.

INTRODUCTION: Mortality from COPD has decreased in Spain in recent years, but it is unknown whether this decline has been homogeneous among the different regions. METHODS: From the Statistical Portal of the Ministry of Health of Spain we obtained the age-adjusted mortality rates/100,000 inhabitants for men and women in Spain and the Autonomous Communities for the years 1999-2019, using the coding of the International Classification of Diseases (ICD 10, sections J40-J44). With the adjusted rates we performed a jointpoint regression analysis to estimate an annual percentage change (APC), as well as identify possible points of trend change. Statistical significance was considered for a value of p<0.05. RESULTS: During the study period, COPD mortality rates adjusted in Spain decreased from 28.77 deaths/100,000 inhabitants in 1999 to 12.14 deaths/100,000 inhabitants in 2019. We observed a linear decline in COPD mortality in men at national level of -3.67% per year (95% CI -4.1 to -3.4; p<0.001), with differences between the Autonomous Communities. Mortality in women also experienced a decrease in mortality in two phases, with a first period from 1999 to 2006 with a fall of -6.8% per year (95% CI -8.6 to -5.0; p<0.001) and a second period from 2006 to 2019 with a decrease in mortality of -2.1% (95% CI -2.8 to -1.3; p<0.001), with again differences between the Autonomous Communities. CONCLUSION: Mortality rates from COPD have decreased heterogeneously among the different Autonomous Communities in both men and women.

Qualitative data collection to identify truck drivers' attitudes toward a transition to platooning systems.

The platooning technology allows for two or more trucks running in convoy at a pre-defined distance between each other, being virtually connected using connectivity technology and automated driving support systems. It is recognized that truck platooning systems bring economical and environmental advantages. Thus, it is time for a transition from the existing truck freight activity towards truck platooning systems. This requires an important improvement in terms of in-vehicle technology, together with infrastructure improvement and truck drivers' acquisition of new technology-related skills. A holistic approach is previewed to identify both the requirements for the development of truck platooning services and the requests for their safe deployment in the real world. Then, qualitative data were collected from truck drivers working for two different Portuguese freight companies using Focus Groups (FG). Thus, three FG sessions were organized and carried out with a total of 22 truck drivers. Considering that age and experience on the job are important factors to take into consideration for technological changes on the job, their potential impact on truck drivers' activity was addressed on the focus group discussions. Anyway, the potential users' attitudes regarding any innovation on the job were addressed as a prevention of further negative attitudes or misuse. Having safety in mind as a permanent attitude toward on job innovation is actually the most important factor toward success.

The Interface between Depression and Alzheimer's Disease. A Comprehensive Approach.

Depression and Alzheimer's disease (AD) are frequent interacting diseases in the elderly with a negative impact on the quality of life of patients and caregivers. Late-life depression may be regarded either as an early symptom of AD or a risk factor for AD, depending on the context. This review was focused on the latest developments in the fields of the neurobiological basis and treatment of depression in AD. We found that some plausible hypotheses are emerging to correlate with depression in AD, such as neuroinflammation and dysimmune regulation. It seems that depression is not related to amyloid deposition, but this issue is not completely resolved. The response to antidepressants is controversial according to the evidence from 10 small double-blind randomized placebo-controlled clinical trials with antidepressants in AD patients with depression: four with sertraline, one with three arms (sertraline, mirtazapine, placebo), one with fluoxetine, one with imipramine, one with clomipramine, one with escitalopram, and one with vortioxetine. The total number of treated patients completing the trials was 638. The main criterion of a positive response was a reduction in the scores of clinical scales for depression of at least 50%. The weighted OR (odds ratio) was calculated with the method of Mantel-Haenszel: 1.29; 95% CI: 0.77-2.16. No significant differences were found compared with placebo. Antidepressants did not have a meaningful negative influence on cognition, which was measured with the mini-mental state examination (MMSE) in 18 clinical trials. Alternatives other than drugs are also discussed. Although there have been important advances in this field, pathophysiology and treatment deserve further research.

Difficulties during delivery, brain ventricle enlargement and cognitive impairment in first episode psychosis.

BACKGROUND: Patients with a first episode of psychosis (FEP) display clinical, cognitive, and structural brain abnormalities at illness onset. Ventricular enlargement has been identified in schizophrenia since the initial development of neuroimaging techniques. Obstetric abnormalities have been associated with an increased risk of developing psychosis but also with cognitive impairment and brain structure abnormalities. Difficulties during delivery are associated with a higher risk of birth asphyxia leading to brain structural abnormalities, such as ventriculomegaly, which has been related to cognitive disturbances. METHODS: We examined differences in ventricular size between 142 FEP patients and 123 healthy control participants using magnetic resonance imaging. Obstetric complications were evaluated using the Lewis-Murray scale. We examined the impact of obstetric difficulties during delivery on ventricle size as well as the possible relationship between ventricle size and cognitive impairment in both groups. RESULTS: FEP patients displayed significantly larger third ventricle size compared with healthy controls. Third ventricle enlargement was associated with diagnosis (higher volume in patients), with difficulties during delivery (higher volume in subjects with difficulties), and was highest in patients with difficulties during delivery. Verbal memory was significantly associated with third ventricle to brain ratio. CONCLUSIONS: Our results suggest that difficulties during delivery might be significant contributors to the ventricular enlargement historically described in schizophrenia. Thus, obstetric complications may contribute to the development of psychosis through changes in brain architecture.

Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life: An Individual Participant Data Meta-Analysis.

Importance: The utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested. Objectives: To assess the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (age >60 years) with dementia and the moderating factors of age, sex, and racial group. Data Source and Study Selection: Longitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries (US, Brazil, Australia, China, Korea, Singapore, Central African Republic, Republic of Congo, Nigeria, Germany, Spain, Italy, France, Sweden, and Greece). Data Extraction and Synthesis: Participants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data reporting guidelines. Main Outcomes and Measures: The key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group. Results: The analysis included 17 studies with 34 519 community dwelling older adults (20 160 [58.4%] female) with a mean (SD) age of 72.5 (7.5) years and a mean (SD) follow-up of 4.3 (4.3) years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio [HR], 1.42; 95% CI 1.15-1.76; P = .001) and 26% increased risk compared with individuals with treated hypertension (HR, 1.26; 95% CI, 1.03-1.53; P = .02). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls (HR, 1.13; 95% CI, 0.99-1.28; P = .07). The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses. Conclusions and Relevance: This individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls.

Association of Prolactin, Oxytocin, and Homocysteine With the Clinical and Cognitive Features of a First Episode of Psychosis Over a 1-Year Follow-Up.

BACKGROUND: The clinical debut of schizophrenia is frequently a first episode of psychosis (FEP). As such, there is considerable interest in identifying associations between biological markers and clinical or cognitive characteristics that help predict the progression and outcome of FEP patients. Previous studies showed that high prolactin, low oxytocin, and high homocysteine are factors associated with FEP 6 months after diagnosis, at which point plasma levels were correlated with some clinical and cognitive characteristics. METHODS: We reexamined 75 patients at 12 months after diagnosis to measure the evolution of these molecules and assess their association with clinical features. RESULTS: At follow-up, FEP patients had lower prolactin levels than at baseline, and patients treated with risperidone or paliperidone had higher prolactin levels than patients who received other antipsychotic agents. By contrast, no changes in oxytocin and homocysteine plasma levels were observed between the baseline and follow-up. In terms of clinical features, we found that plasma prolactin and homocysteine levels were correlated with the severity of the psychotic symptoms in male FEP patients, suggesting that they might be factors associated with psychotic symptomatology but only in men. Together with oxytocin, these molecules may also be related to sustained attention, verbal ability, and working memory cognitive domains in FEP patients. CONCLUSION: This study suggests that focusing on prolactin, oxytocin, and homocysteine at a FEP may help select adequate pharmacological treatments and develop new tools to improve the outcome of these patients, where sex should also be borne in mind.

Corrigendum: Influence of clinical and neurocognitive factors in psychosocial functioning after a first episode non-affective psychosis: differences between males and females.

[This corrects the article DOI: 10.3389/fpsyt.2022.982583.].

Sex Differences in Longitudinal Trajectories of Cognitive Aging in Zaragoza, Spain.

OBJECTIVES: The objective of this study was to document the longitudinal trajectories of cognitive aging in a sample of cognitively healthy subjects of 55 years or older. The following differences between men and women were hypothesized: 1) in the cognitive loss through aging, 2) in the distinct trajectories identified; and 3) in the predictors associated with the identified trajectories. DESIGN AND SETTING: A 4-wave, population-based study in Zaragoza, Spain (1994-2006). PARTICIPANTS: A total of 2,403 individuals aged 55+ years, cognitively healthy at baseline. MEASUREMENTS: All participants had at least three measurements with the Mini-Mental State Examination (MMSE). Validated Spanish versions of international instruments were used for assessment. Random effects linear panel regression model for analyzing differences by sex in MMSE scores through aging were performed, and growth mixture models (GMM) applied independently for each sex for modeling the longitudinal cognitive trajectories. RESULTS: Women showed lower mean MMSE scores in all phases and significantly higher loss in the MMSE from phases 2 to 3 and 3 to 4. The best fitting age-adjusted model of the cognitive trajectories was a 4-class GMM in men and a 3-class in women. Education was a predictor of cognitive trajectories in both men and women. Dependence on iADLs and alcohol status were predictors only for men, and depression and diabetes only for women. CONCLUSIONS: The identified differences by sex in cognitive trajectories and their associated factors suggest that men and women may require a different strategy when addressing cognitive aging.

Parental history of dementia and the risk of dementia: A cross-sectional analysis of a global collaborative study.

BACKGROUND: Parental history of dementia appears to increase the risk of dementia, but there have been inconsistent results. We aimed to investigate whether the association between parental history of dementia and the risk of dementia are different by dementia subtypes and sex of parent and offspring. METHODS: For this cross-sectional study, we harmonized and pooled data for 17,194 older adults from nine population-based cohorts of eight countries. These studies conducted face-to-face diagnostic interviews, physical and neurological examinations, and neuropsychological assessments to diagnose dementia. We investigated the associations of maternal and paternal history of dementia with the risk of dementia and its subtypes in offspring. RESULTS: The mean age of the participants was 72.8 ± 7.9 years and 59.2% were female. Parental history of dementia was associated with higher risk of dementia (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.15-1.86) and Alzheimer's disease (AD) (OR = 1.72, 95% CI = 1.31-2.26), but not with the risk of non-AD. This was largely driven by maternal history of dementia, which was associated with the risk of dementia (OR = 1.51, 95% CI = 1.15-1.97) and AD (OR = 1.80, 95% CI = 1.33-2.43) whereas paternal history of dementia was not. These results remained significant when males and females were analyzed separately (OR = 2.14, 95% CI = 1.28-3.55 in males; OR = 1.68, 95% CI = 1.16-2.44 for females). CONCLUSIONS: Maternal history of dementia was associated with the risk of dementia and AD in both males and females. Maternal history of dementia may be a useful marker for identifying individuals at higher risk of AD and stratifying the risk for AD in clinical trials.

Exploration of cannabis use and polygenic risk scores on the psychotic symptom progression of a FEP cohort.

Cannabis use is highly prevalent in first-episode psychosis (FEP) and plays a critical role in its onset and prognosis, but the genetic underpinnings promoting both conditions are poorly understood. Current treatment strategies for cannabis cessation in FEP are clearly inefficacious. Here, we aimed to characterize the association between cannabis-related polygenic risk scores (PRS) on cannabis use and clinical course after a FEP. A cohort of 249 FEP individuals were evaluated during 12 months. Symptom severity was measured with the Positive and Negative Severity Scale and cannabis use with the EuropASI scale. Individual PRS for lifetime cannabis initiation (PRSCI) and cannabis use disorder (PRSCUD) were constructed. Current cannabis use was associated with increased positive symptoms. Cannabis initiation at younger ages conditioned the 12-month symptom progression. FEP patients with higher cannabis PRSCUD reported increased baseline cannabis use. PRSCI was associated with the course of negative and general symptomatology over follow-up. Cannabis use and symptom progression after a FEP were modulated by cannabis PRS, suggesting that lifetime initiation and use disorders may have partially independent genetic factors. These exploratory results may be the first step to identify those FEP patients more vulnerable to cannabis use and worse outcomes to ultimately develop tailored treatments.

Obstetric complications and genetic risk for schizophrenia: Differential role of antenatal and perinatal events in first episode psychosis.

BACKGROUND: Obstetric complications (OCs) are key contributors to psychosis risk. However, it is unclear whether they increase psychosis vulnerability independently of genetic risk, in interaction with it, or are a manifestation of psychosis proneness. We examined the role of distinct types of OCs in terms of psychosis risk and tested whether they interact differently with genetic vulnerability, whilst accounting for other known environmental risk factors. STUDY DESIGN: 405 participants (219 first episode psychosis patients and 186 healthy volunteers) underwent a comprehensive assessment of OCs, measured using the Lewis-Murray scale and divided into complications of pregnancy, abnormalities of foetal growth and development, and complications of delivery. Participants were compared in terms of history of OCs, polygenic risk score for schizophrenia (PRS-SZ) and interactions between these. RESULTS: Both complications of pregnancy and abnormalities of foetal growth were significantly associated with case-control status (p = 0.02 and 0.03, respectively), whereas complications of delivery were not. PRS-SZ showed a significant association with psychosis (p = 0.04), but there were no significant interactions between genetic risk for schizophrenia and OCs, either when these were considered globally or separated based on their timeframe. CONCLUSIONS: We observed no significant interaction between genetic and obstetric vulnerability, yet distinct types of OCs may have a different impact on psychosis risk, based on their nature and timeframe. Examining their differential role might clarify their relative contributions to this risk.

Obstetric complications and clinical presentation in first episode of psychosis.

OBJECTIVE: Psychotic disorders exhibit a complex aetiology that combines genetic and environmental factors. Among the latter, obstetric complications (OCs) have been widely studied as risk factors, but it is not yet well understood how OCs relate to the heterogeneous presentations of psychotic disorders. We assessed the clinical phenotypes of individuals with a first episode of psychosis (FEP) in relation to the presence of OCs. METHODS: Two-hundred seventy-seven patients with an FEP were assessed for OCs using the Lewis-Murray scale, with data stratified into three subscales depending on the timing and the characteristics of the obstetric event, namely: complications of pregnancy, abnormal foetal growth and development and difficulties in delivery. We also considered other two groups: any complications during the pregnancy period and all OCs taken altogether. Patients were clinically evaluated with the Positive and Negative Syndrome Scale for schizophrenia. RESULTS: Total OCs and difficulties in delivery were related to more severe psychopathology, and this remained significant after co-varying for age, sex, traumatic experiences, antipsychotic dosage and cannabis use. CONCLUSIONS: Our results highlight the relevance of OCs for the clinical presentation of psychosis. Describing the timing of the OCs is essential in understanding the heterogeneity of the clinical presentation.

Fiber Loop Mirror Based on Optical Fiber Circulator for Sensing Applications.

In this paper, a different Fiber Loop Mirror (FLM) configuration with two circulators is presented. This configuration is demonstrated and characterized for sensing applications. This new design concept was used for strain and torsion discrimination. For strain measurement, the interference fringe displacement has a sensitivity of (0.576 ± 0.009) pm‧µÎµ-1. When the FFT (Fast Fourier Transformer) is calculated and the frequency shift and signal amplitude are monitored, the sensitivities are (-2.1 ± 0.3) × 10-4 nm-1 µÎµ-1 and (4.9 ± 0.3) × 10-7 µÎµ-1, respectively. For the characterization in torsion, an FFT peaks variation of (-2.177 ± 0.002) × 10-12 nm-1/° and an amplitude variation of (1.02 ± 0.06) × 10-3/° are achieved. This configuration allows the use of a wide range of fiber lengths and with different refractive indices for controlling the free spectral range (FSR) and achieving refractive index differences, i.e., birefringence, higher than 10-2, which is essential for the development of high sensitivity physical parameter sensors, such as operating on the Vernier effect. Furthermore, this FLM configuration allows the system to be balanced, which is not possible with traditional FLMs.

Clinically significant anxiety as a risk factor for Alzheimer's disease: Results from a 10-year follow-up community study.

OBJECTIVE: There is growing evidence for an association between anxiety and an increased risk of dementia, but it is not clear whether anxiety is a risk factor or a prodromic symptom. In this study, we investigated if clinically significant anxiety increases the risk of developing Alzheimer's disease (AD) up to 10 years later. METHODS: We used data from the longitudinal Zaragoza Dementia and Depression (ZARADEMP) Project. Excluding subjects with dementia at baseline left us with 3044 individuals aged >65 years. The Geriatric Mental State-Automated Geriatric Examination for Computer Assisted Taxonomy (GMS-AGECAT) package was used to identify cases and subcases of anxiety. AD was diagnosed by a panel of research psychiatrists according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria. Multivariate survival analysis with a competing risk regression model was performed. RESULTS: We observed a significant association between clinically significant anxiety at baseline and AD risk within a 10-year follow-up (SHR 2.82 [95% CI 1.21-6.58]), after controlling for confounders including depression. In contrast, isolated symptoms of anxiety were not significantly associated with an increased incidence of AD. CONCLUSION: Our results support the hypothesis that clinically significant anxiety is an independent risk factor for AD and not just a prodromic symptom. Future studies should clarify if treating anxiety reduces the incidence of AD.