Long-Term Dementia Risk in Parkinson Disease.

BACKGROUND AND OBJECTIVES: It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies. METHODS: Participants from the Parkinson's Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score <21 and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I cognition score ≥3 as secondary end points for PPMI. In addition, estimated dementia probability by PD disease duration was tabulated for each study and end point. RESULTS: For the PPMI cohort, 417 participants with PD (mean age 61.6 years, 65% male) were followed, with an estimated probability of dementia at year 10 disease duration of 9% (site investigator diagnosis), 15% (MoCA), or 12% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 participants with PD (mean age 69.3 years, 67% male) were followed, with 184 participants (47% of cohort) eventually diagnosed with dementia. The interval-censored curve for the Penn cohort had a median time to dementia of 15 years (95% CI 13-15); the estimated probability of dementia was 27% at 10 years of disease duration, 50% at 15 years, and 74% at 20 years. DISCUSSION: Results from two large, prospective studies suggest that dementia in PD occurs less frequently, or later in the disease course, than previous research studies have reported.

Acquired Risk Factors that Influence Risk for Dementia and Possibly Alzheimer Disease.

Various medicinal agents aimed at improving Alzheimer disease (AD) include cholinesterase inhibitors, memantine, aducanumab, and antioxidants. These medications are typically prescribed once AD is diagnosed in the clinical setting in order to slow progression. Though initiating treatment after being diagnosed with AD is important, significance should be placed on recognizing known acquired risk factors in order to potentially decrease the likelihood of developing dementia and perhaps specifically AD. This article summarizes the acquired factors that influence risk for dementia.

Nonarteritic Anterior Ischemic Optic Neuropathy and the Risk of Dementia: A Nationwide Cohort Study.

BACKGROUND AND OBJECTIVES: While emerging theories suggest that vascular dysfunction may occur concurrently with the amyloid cascade in Alzheimer disease (AD) pathogenesis, the role of vascular components as primary neurodegeneration triggers remains uncertain. The aim of this retrospective, population-based cohort study conducted in Korea was to explore the link between nonarteritic anterior ischemic optic neuropathy (NAION) and dementia risk. METHODS: In this nationwide, population-based, retrospective cohort study, we identified newly diagnosed NAION from 2010 to 2017 in the Korean National Health Insurance Service database. The primary outcome was new dementia diagnoses confirmed by new ICD-10 claims coupled with antidementia medication prescriptions. We assessed dementia risk using hazard ratios (HRs) with 95% CIs over an average 2.69-year follow-up after a 1-year lag period. RESULTS: The cohort consisted of 42,943 patients with NAION and 214,715 age-matched and sex-matched controls without NAION (mean age 61.37 years ± 10.75 SD, 55.48% female). The study found a higher risk of all-cause dementia (ACD; HR 1.28, 95% CI 1.20-1.36), AD (HR 1.27, 95% CI 1.18-1.36), vascular dementia (VaD; HR 1.31, 95% CI 1.09-1.58), and other dementia (HR 1.39, 95% CI 1.11-1.73) among patients with NAION, regardless of other potential confounding factors such as age, sex, lifestyle behaviors, economic status, and preexisting health conditions. In subgroup analysis, the associations between NAION and ACD were stronger in the younger age group (HR 1.83 for those younger than 65 years vs 1.23 for those 65 years or older; p for interaction <0.001). Moreover, the association of NAION with both ACD and VaD was particularly strong among current smokers. DISCUSSION: We found a significant association between NAION and increased risk for ACD, AD, VaD, and other dementia even after adjusting for potential confounders such as lifestyle, health conditions, and demographic factors within a nationwide cohort. This study highlights the potential role of vascular pathology in dementia progression and suggests that NAION may serve as a robust predictor for dementia, highlighting the need for comprehensive neurologic assessment in patients with NAION. Further research is needed to clarify the association between NAION and dementia risk.

Cervical cancer and risk of dementia: real-world insights from a nationwide cohort study in Taiwan.

OBJECTIVE: Cervical cancer, linked to human papillomavirus (HPV), ranks fourth among women's cancers globally. Several studies have found an association between viral infections or cancer and dementia, which is a major public health concern. This study aimed to provide real-world data on the association between cervical cancer and the risk of dementia. METHODS: This population-based cohort study, utilizing Taiwan's National Health Insurance Research Database, included 53 905 patients, with 10 781 having cervical cancer, matching with 43 124 controls in a 1:4 ratio based on age and indexed date. Incidence density rates were used to calculate the incidence rate of dementia. Adjusting for comorbidities, a multivariable Cox proportional hazards regression model was used to estimate the hazard ratios and 95% confidence intervals. Additionally, the risk of dementia was further verified using the cumulative incidence analyzed by the Kaplan-Meier method. RESULTS: This study indicated a significantly higher dementia risk in the cervical cancer cohort compared with the non-cervical cancer cohort (adjusted HR (aHR)=1.64, 95% CI 1.16 to 2.26; p<0.001), suggesting a 1.64-fold increased risk. Notably, cervical cancer posed a greater risk of dementia (aHR=1.69, 95% CI 1.21 to 2.29; p<0.001) compared with carcinoma in situ of the cervix (p=0.18) and cervical intraepithelial neoplasia (p=0.23). The cumulative incidence of dementia in the cervical cancer group was significantly higher (log-rank test, p<0.001) than the control group. CONCLUSIONS: Cervical cancer (invasive disease) was associated with a significant risk of dementia, unlike carcinoma in situ of the cervix and cervical intraepithelial neoplasia (pre-invasive diseases), suggesting HPV infections may play a role in dementia, particularly oncogenic types. This highlights the importance of further investigation into the underlying mechanisms of the association between cervical cancer and dementia.

Vascular Contributions to Healthy Aging and Dementia.

Vascular pathologies are among the most common contributors to neurodegenerative changes across the spectrum of normal aging to dementia. Cerebral small vessel disease (SVD) encompasses a wide range of conditions affecting capillaries, small arteries, and arterioles, as well as perivascular spaces and fluid dynamics in the brain, playing a significant role in vascular contributions to cognitive impairment and dementia (VCID). These factors can accelerate the progression of SVD and neuronal degeneration. Since aging is the primary risk factor for Alzheimer's disease (AD) and AD-related dementias (ADRD), this Research Topic aims to gather recent research to better understand vascular contributions to healthy aging and age-related cognitive impairment. Other risk factors include diabetes, lifestyle factors, high cholesterol, vascular inflammation, and immune remodeling, all of which can accelerate cognitive dysfunction progression. This special issue includes a total of 21 articles comprising Reviews, Perspectives, and Original Research articles. The articles cover various technical and biological aspects related to recent progress in aging and dementia research. We aim to promote research exchange across different fields, including imaging, VCID, molecular biology, neuroinflammation, and immunology. Most papers in this special issue focus on understanding the disease mechanisms of AD/ADRD and developing new therapeutic strategies.

Associations of sugar intake, high-sugar dietary pattern, and the risk of dementia: a prospective cohort study of 210,832 participants.

BACKGROUND: Limited evidence demonstrated the potential relationship between dietary sugar intake and dementia. This association demands further clarification in a large-scale population. METHODS: A total of 210,832 participants from the UK Biobank cohort were included in this prospective cohort study. Absolute and relative sugar intake and high-sugar dietary scores were utilized to reflect dietary sugar intake. Absolute sugar intake was identified by the Oxford WebQ in the UK Biobank. Relative sugar intake was calculated by dividing the absolute sugar intake by total diet energy. High-sugar dietary pattern was identified using the method of reduced rank regression. Cox proportional hazards regression analyses and restricted cubic splines were performed to examine the longitudinal associations between dietary sugar intake and all-cause dementia and its main subtype, Alzheimer's disease. Explorative mediation analyses were conducted to explore underlying mechanisms. RESULTS: Increased absolute sugar intake (g/day) was significantly associated with a higher risk of all-cause dementia (HR = 1.003, [95%CI: 1.002-1.004], p < 0.001) and Alzheimer's disease (1.002, [1.001-1.004], 0.005). Relative sugar intake (%g/kJ/day) also demonstrated significant associations with all-cause dementia (1.317, [1.173-1.480], p < 0.001) and Alzheimer's disease (1.249, [1.041-1.500], 0.017), while the high-sugar dietary score was only significantly associated with a higher risk of all-cause dementia (1.090, [1.045-1.136], p < 0.001). In addition, both sugar intake and high-sugar dietary score demonstrated significant non-linear relationships with all-cause dementia and Alzheimer's disease (all p values for non-linearity < 0.05). CONCLUSIONS: Our study provided evidence that excessive sugar intake was associated with dementia. Controlling the excess consumption of dietary sugar may be of great public health implications for preventing dementia.

Exposure to source-specific air pollution in residential areas and its association with dementia incidence: a cohort study in Northern Sweden.

The aim of this study was to investigate the relationship between source-specific ambient particulate air pollution concentrations and the incidence of dementia. The study encompassed 70,057 participants from the Västerbotten intervention program cohort in Northern Sweden with a median age of 40 years at baseline. High-resolution dispersion models were employed to estimate source-specific particulate matter (PM) concentrations, such as PM10 and PM2.5 from traffic, exhaust, and biomass (mainly wood) burning, at the residential addresses of each participant. Cox regression models, adjusted for potential confounding factors, were used for the assessment. Over 884,847 person-years of follow-up, 409 incident dementia cases, identified through national registers, were observed. The study population's average exposure to annual mean total PM10 and PM2.5 lag 1-5 years was 9.50 µg/m3 and 5.61 µg/m3, respectively. Increased risks were identified for PM10-Traffic (35% [95% CI 0-82%]) and PM2.5-Exhaust (33% [95% CI - 2 to 79%]) in the second exposure tertile for lag 1-5 years, although no such risks were observed in the third tertile. Interestingly, a negative association was observed between PM2.5-Wood burning and the risk of dementia. In summary, this register-based study did not conclusively establish a strong association between air pollution exposure and the incidence of dementia. While some evidence indicated elevated risks for PM10-Traffic and PM2.5-Exhaust, and conversely, a negative association for PM2.5-Wood burning, no clear exposure-response relationships were evident.

Molecular Mechanisms of Dementia 2.0.

Dementia and the other neurodegenerative disorders represent a complex pathophysiological process [...].

Dementia after Ischemic Stroke, from Molecular Biomarkers to Therapeutic Options.

Ischemic stroke is a leading cause of disability worldwide. While much of post-stroke recovery is focused on physical rehabilitation, post-stroke dementia (PSD) is also a significant contributor to poor functional outcomes. Predictive tools to identify stroke survivors at risk for the development of PSD are limited to brief screening cognitive tests. Emerging biochemical, genetic, and neuroimaging biomarkers are being investigated in an effort to unveil better indicators of PSD. Additionally, acetylcholinesterase inhibitors, NMDA receptor antagonists, dopamine receptor agonists, antidepressants, and cognitive rehabilitation are current therapeutic options for PSD. Focusing on the chronic sequelae of stroke that impair neuroplasticity highlights the need for continued investigative trials to better assess functional outcomes in treatments targeted for PSD.

Age of type 2 diabetes onset as a risk factor for dementia: A 13-year retrospective cohort study.

AIMS: To examine whether age at type 2 diabetes onset is an independent predictor of dementia risk. METHODS: Retrospective cohort drawn from healthcare administrative records of all inhabitants within Romagna's catchment area, Italy, with an estimated onset of type 2 diabetes in 2008-2017 and aged ≥ 55, with follow-up until 2020. Time to dementia or censoring was estimated with the Kaplan-Meier method, using diabetes onset as the time origin. Age groups were compared with the log-rank test. Multivariable competing-risks analysis was used to assess predictors of dementia. RESULTS: In patients aged ≥ 75 years, dementia-free survival (DFS) declined to below 90 % within five years and linearly decreased to 68.8 % until the end of follow-up. In contrast, DFS for those aged 55-64 years showed a marginal decrease, reaching 97.4 % after 13 years. Competing-risks regression showed that individuals aged ≥ 75 and 65-74 had a significantly higher risk of dementia compared to those aged 55-64 years. Having more comorbidities at diabetes onset and initial treatment with ≥ 2 antidiabetics were clinical predictors. CONCLUSIONS: Later age at onset of diabetes is strongly associated with dementia. A better understanding of the diabetes-dementia relationship is needed to inform strategies for promoting specific healthcare pathways.

[Impairment of Attention in Dementia].

Impairment of attention, especially complex attention, appears in the early stage of dementia. Complex attention is one of the six neurocognitive domains, which are disturbed in dementia. Impairment of complex attention promotes symptoms of dementia, difficulties in activities of daily living (ADLs), and disturbed communication in dementia due to Alzheimer disease, Lewy body disease, and cerebrovascular diseases. Despite its importance, research on "impairment of attention in dementia" is scarce. We look forward to future studies addressing this topic. In this article, we emphasized on providing care for ADL and communication for people with dementia, who have attention deficits.

Incident traumatic spinal cord injury and risk of Alzheimer's disease and related dementia: longitudinal case and control cohort study.

STUDY DESIGN: Retrospective case/control longitudinal cohort study OBJECTIVES: Prevalent traumatic spinal cord injury (TSCI) is associated with Alzheimer's disease and related dementia (ADRD). We examined the hazard ratio for ADRD after incident TSCI and hypothesized that ADRD hazard is greater among adults with incident TSCI compared with their matched control of adults without TSCI. SETTING: Using 2010-2020 U.S. national private administrative claims data, we identified adults aged 45 years and older with probable (likely and highly likely) incident TSCI (n = 657). Our controls included one-to-ten matched cohort of people without TSCI (n = 6553). METHODS: We applied Cox survival models and adjusted them for age, sex, years of living with certain chronic conditions, exposure to six classes of prescribed medications, and neighborhood characteristics of place of residence. Hazard ratios were used to compare the results within a 4-year follow-up. RESULTS: Our fully adjusted model without any interaction showed that incident TSCI increased the risk for ADRD (HR = 1.30; 95% CI, 1.01-1.67). People aged 45-64 with incident TSCI were at high risk for ADRD (HR = 5.14; 95% CI, 2.27-11.67) and no significant risk after age 65 (HR = 1.20; 95% CI, .92-1.55). Our sensitivity analyses confirmed a higher hazard ratio for ADRD after incident TSCI at 45-64 years of age compared with the matched controls. CONCLUSIONS: TSCI is associated with a higher hazard of ADRD. This study informs the need to update clinical guidelines for cognitive screening after TSCI to address the heightened risk of cognitive decline and to shed light on the causality between TSCI and ADRD.

Association between new-onset atrial fibrillation and dementia among individuals with type 2 diabetes.

AIM: To assess the association between new-onset atrial fibrillation and dementia among patients with type 2 diabetes, a group with a high prevalence of atrial fibrillation. MATERIALS AND METHODS: This cohort study included 22 989 patients with type 2 diabetes from the UK Biobank. New-onset atrial fibrillation was ascertained from hospital admission records. We used an algorithm officially released by the UK Biobank to identify all-cause dementia, Alzheimer's disease and vascular dementia. The algorithm was developed using multiple sources, including hospital admissions and the death registry. Time-varying Cox regression analyses were performed to investigate the association between new-onset atrial fibrillation and dementia. RESULTS: A total of 2843 participants developed atrial fibrillation, whereas the remaining 20 146 did not. During the median of 12.3 years of follow-up, 844 all-cause dementia, 342 Alzheimer's disease and 246 vascular dementia cases occurred. Compared with participants without atrial fibrillation, those with atrial fibrillation had higher risks of all-cause dementia (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.80-2.57), Alzheimer's disease (HR 1.44, 95% CI 1.06-1.96) and vascular dementia (HR 3.11, 95% CI 2.32-4.17). CONCLUSIONS: New-onset atrial fibrillation was associated with a substantially higher risk of all-cause dementia, Alzheimer's disease and vascular dementia in patients with type 2 diabetes. Our findings highlight the significance of atrial fibrillation management in mitigating the risk of dementia in this demographic.

Severe psychiatric disorders are associated with increased risk of dementia.

BACKGROUND: Individuals with psychiatric disorders have an increased risk of developing dementia. Most cross-sectional studies suffer from selection bias, underdiagnosis and poor population representation, while there is only limited evidence from longitudinal studies on the role of anxiety, bipolar and psychotic disorders. Electronic health records (EHRs) permit large cohorts to be followed across the lifespan and include a wide range of diagnostic information. OBJECTIVE: To assess the association between four groups of psychiatric disorders (schizophrenia, bipolar disorder/mania, depression and anxiety) with dementia in two large population-based samples with EHR. METHODS: Using EHR on nearly 1 million adult individuals in Wales, and from 228 937 UK Biobank participants, we studied the relationships between schizophrenia, mania/bipolar disorder, depression, anxiety and subsequent risk of dementia. FINDINGS: In Secure Anonymised Information Linkage, there was a steep increase in the incidence of a first diagnosis of psychiatric disorder in the years prior to the diagnosis of dementia, reaching a peak in the year prior to dementia diagnosis for all psychiatric diagnoses. Psychiatric disorders, except anxiety, were highly significantly associated with a subsequent diagnosis of dementia: HRs=2.87, 2.80, 1.63 for schizophrenia, mania/bipolar disorder and depression, respectively. A similar pattern was found in the UK Biobank (HRs=4.46, 3.65, 2.39, respectively) and anxiety was also associated with dementia (HR=1.34). Increased risk of dementia was observed for all ages at onset of psychiatric diagnoses when these were divided into 10-year bins. CONCLUSIONS: Psychiatric disorders are associated with an increased risk of subsequent dementia, with a greater risk of more severe disorders. CLINICAL IMPLICATIONS: A late onset of psychiatric disorders should alert clinicians of possible incipient dementia.

Longitudinal Patterns of Systolic Blood Pressure, Diastolic Blood Pressure, Cardiorespiratory Fitness, and Their Association With Dementia Risk: The HUNT Study.

BACKGROUND: High blood pressure and poor cardiorespiratory fitness are independent risk factors for dementia. However, few studies have examined if combined longitudinal patterns of these modifiable risk factors are associated with dementia risk. METHODS: In this prospective cohort study, we used data from the population-based Trøndelag Health (HUNT) Study, Norway. We applied group-based multidimensional trajectory modeling to identify age-specific multidimensional trajectories of SBP, DBP, and estimated cardiorespiratory fitness across 3 surveys (HUNT1, 1984-1986 to HUNT3, 2006-2008). Dementia was diagnosed in the HUNT4 70+ substudy in 2017-2019. We used multivariate logistic regression to estimate odds ratios (ORs) and risk differences (RDs) of dementia. RESULTS: In total, 7 594 participants (54.9% women) were included, with a mean age of 44.7 (SD 6.3) years at HUNT1. Dementia was diagnosed in 1 062 (14.0%) participants. We identified 2 multidimensional trajectories throughout adulthood within 3 age groups: one with higher systolic blood pressure (SBP) and diastolic blood pressure (DBP), and lower estimated cardiorespiratory fitness (the poorer group), and one with lower SBP and DBP, and higher cardiorespiratory fitness (the better group). After adjustment for sex, apolipoprotein E ε4 status, education, marital status, and diabetes, the better group had consistently lower risk of dementia in all age groups with the lowest OR in the middle-aged group of 0.63 (95% confidence intervals [95% CI]: 0.51, 0.78) with corresponding RD of -0.07 (95% CI: -0.10, -0.04). CONCLUSIONS: Having a beneficial multidimensional trajectory of SBP, DBP, and cardiorespiratory fitness in adulthood was associated with reduced dementia risk. Aiming for optimal SBP, DBP, and estimated cardiorespiratory fitness throughout adulthood may reduce dementia risk.

Population attributable fractions of modifiable risk factors for dementia: a systematic review and meta-analysis.

BACKGROUND: More than 57 million people have dementia worldwide. Evidence indicates a change in dementia prevalence and incidence in high-income countries, which is likely to be due to improved life-course population health. Identifying key modifiable risk factors for dementia is essential for informing risk reduction and prevention strategies. We therefore aimed to estimate the population attributable fraction (PAF) for dementia associated with modifiable risk factors. METHODS: In this systematic review and meta-analysis, we searched Embase, MEDLINE, and PsycINFO, via Ovid, from database inception up to June 29, 2023, for population-derived or community-based studies and reviews reporting a PAF value for one or more modifiable risk factor for later-life dementia (prevalent or incident dementia in people aged ≥60 years), with no restrictions on dementia subtype, the sex or baseline age of participants, or the period of study. Articles were independently screened for inclusion by four authors, with disagreements resolved through consensus. Data including unweighted and weighted PAF values (weighted to account for communality or overlap in risk) were independently extracted into a predefined template by two authors and checked by two other authors. When five or more unique studies investigated a given risk factor or combination of the same factors, random-effects meta-analyses were used to calculate a pooled PAF percentage estimate for the factor or combination of factors. The review protocol was registered on PROSPERO, CRD42022323429. FINDINGS: 4024 articles were identified, and 74 were included in our narrative synthesis. Overall, PAFs were reported for 61 modifiable risk factors, with sufficient data available for meta-analysis of 12 factors (n=48 studies). In meta-analyses, the highest pooled unweighted PAF values were estimated for low education (17·2% [95% CI 14·4-20·0], p<0·0001), hypertension (15·8% [14·7-17·1], p<0·0001), hearing loss (15·6% [10·3-20·9], p<0·0001), physical inactivity (15·2% [12·8-17·7], p<0·0001), and obesity (9·4% [7·3-11·7], p<0·0001). According to weighted PAF values, low education (9·3% [6·9-11·7], p<0·0001), physical inactivity (7·3% [3·9-11·2], p=0·0021), hearing loss (7·2% [5·2-9·7], p<0·0001), hypertension (7·1% [5·4-8·8], p<0·0001), and obesity (5·3% [3·2-7·4], p=0·0001) had the highest pooled estimates. When low education, midlife hypertension, midlife obesity, smoking, physical inactivity, depression, and diabetes were combined (Barnes and Yaffe seven-factor model; n=9 studies), the pooled unweighted and weighted PAF values were 55·0% (46·5-63·5; p<0·0001) and 32·0% (26·6-37·5; p<0·0001), respectively. The pooled PAF values for most individual risk factors were higher in low-income and middle-income countries (LMICs) versus high-income countries. INTERPRETATION: Governments need to invest in a life-course approach to dementia prevention, including policies that enable quality education, health-promoting environments, and improved health. This investment is particularly important in LMICs, where the potential for prevention is high, but resources, infrastructure, budgets, and research focused on ageing and dementia are limited. FUNDING: UK Research and Innovation (Medical Research Council).