Lower Prevalence of Asymptomatic Alzheimer's Disease Among Healthy African Americans.

OBJECTIVE: Alzheimer's disease (AD) is believed to be more common in African Americans (AA), but biomarker studies in AA populations are limited. This report represents the largest study to date examining cerebrospinal fluid AD biomarkers in AA individuals. METHODS: We analyzed 3,006 cerebrospinal fluid samples from controls, AD cases, and non-AD cases, including 495 (16.5%) self-identified black/AA and 2,456 (81.7%) white/European individuals using cutoffs derived from the Alzheimer's Disease Neuroimaging Initiative, and using a data-driven multivariate Gaussian mixture of regressions. RESULTS: Distinct effects of race were found in different groups. Total Tauand phospho181-Tau were lower among AA individuals in all groups (p < 0.0001), and Aß42 was markedly lower in AA controls compared with white controls (p < 0.0001). Gaussian mixture of regressions modeling of cerebrospinal fluid distributions incorporating adjustments for covariates revealed coefficient estimates for AA race comparable with 2-decade change in age. Using Alzheimer's Disease Neuroimaging Initiative cutoffs, fewer AA controls were classified as biomarker-positive asymptomatic AD (8.0% vs 13.4%). After adjusting for covariates, our Gaussian mixture of regressions model reduced this difference, but continued to predict lower prevalence of asymptomatic AD among AA controls (9.3% vs 13.5%). INTERPRETATION: Although the risk of dementia is higher, data-driven modeling indicates lower frequency of asymptomatic AD in AA controls, suggesting that dementia among AA populations may not be driven by higher rates of AD. ANN NEUROL 2024;96:463-475.

Alzheimer incidence and prevalence with and without asthma: A Medicare cohort study.

BACKGROUND: International data suggest that asthma, like other inflammatory diseases, might increase Alzheimer disease (AD) risk. OBJECTIVE: We sought to explore risk pathways and future mitigation strategies by comparing diagnostic claims-based AD incidence and prevalence among US patients with asthma with those without asthma. METHODS: This cohort study included a national Medicare 20% random sample (2013-2015). Adult patients with asthma with more than 12 months continuous Medicare were compared with subjects without asthma overall and as matched. Asthma was defined by 1 inpatient or 2 outpatient codes for asthma. The main outcomes were 2-year incident or prevalent AD defined by International Classification of Diseases, Ninth Revision code 331.0 or Tenth Revision code G30.0, G30.1, G30.8, or G30.9. RESULTS: Among 5,460,732 total beneficiaries, 678,730 patients were identified with baseline asthma and more often identified as Black or Hispanic, were Medicaid eligible, or resided in a highly disadvantaged neighborhood than those without asthma. Two-year incidence of AD was 1.4% with asthma versus 1.1% without asthma; prevalence was 7.8% versus 5.4% (both P ≤ .001). Per 100,000 patients over 2 years, 303 more incident AD diagnoses occurred in those with asthma, with 2,425 more prevalent cases (P < .001). Multivariable models showed that asthma had greater odds of 2-year AD incidence (adjusted odds ratio, 1.33 [95% CI, 1.29-1.36]; matched 1.2 [95% CI, 1.17-1.24]) and prevalence (adjusted odds ratio, 1.48 [95% CI, 1.47-1.50]; matched 1.25 [95% CI, 1.22-1.27]). CONCLUSIONS: Asthma was associated with 20% to 33% increased 2-year incidence and 25% to 48% increased prevalence of claims-based AD in this nationally representative US sample. Future research should investigate risk pathways of underlying comorbidities and social determinants as well as whether there are potential asthma treatments that may preserve brain health.

The current state of apolipoprotein E in dyslipidemia.

PURPOSE OF REVIEW: Apolipoprotein E (apoE) plays a pivotal role in lipid metabolism in the peripheral circulation and in the brain. This has been recognized for decades; however, the importance of the full spectrum of variation in the APOE gene has been less investigated. This review focusses on current progresses in this field with main focus on apoE in dyslipidemia and vascular disease. RECENT FINDINGS: Whereas ε4 is the risk increasing allele for Alzheimer disease, ε2 is associated with increased risk for age-related macular degeneration. Rare functional ε2-like variants in APOE have previously been reported to have protective associations for Alzheimer disease but recent findings suggest a simultaneous high risk of age-related macular degeneration, in line with observations for the ε2 allele. SUMMARY: ApoE plays an important and well established role in dyslipidemia, vascular disease, and dementia. Recent evidence from large general population studies now also suggests that apoE is involved in age-related macular degeneration. ApoE-targeted therapeutics are being developed for multiple purposes; this heralds a promising change in the approach to disease processes involving apoE. The different risk profile for dementia and age-related macular degeneration should, however, be kept in mind when developing drugs targeting mechanisms resembling these variants.

Considerations for Use of Blood-Based Biomarkers in Epidemiologic Dementia Research.

Dementia represents a growing public health burden with large social, racial, and ethnic disparities. The etiology of dementia is poorly understood, and the lack of robust biomarkers in diverse, population-representative samples is a barrier to moving dementia research forward. Existing biomarkers and other measures of pathology-derived from neuropathology, neuroimaging, and cerebrospinal fluid samples-are commonly collected from predominantly White and highly educated samples drawn from academic medical centers in urban settings. Blood-based biomarkers are noninvasive and less expensive, offering promise to expand our understanding of the pathophysiology of dementia, including in participants from historically excluded groups. Although largely not yet approved by the Food and Drug Administration or used in clinical settings, blood-based biomarkers are increasingly included in epidemiologic studies on dementia. Blood-based biomarkers in epidemiologic research may allow the field to more accurately understand the multifactorial etiology and sequence of events that characterize dementia-related pathophysiological changes. As blood-based dementia biomarkers continue to be developed and incorporated into research and practice, we outline considerations for using them in dementia epidemiology, and illustrate key concepts with Alzheimer's Disease Neuroimaging Initiative (2003-present) data. We focus on measurement, including both validity and reliability, and on the use of dementia blood-based biomarkers to promote equity in dementia research and cognitive aging. This article is part of a Special Collection on Mental Health.

Update on modifiable risk factors for Alzheimer's disease and related dementias.

PURPOSE OF REVIEW: All human beings undergo a lifelong cumulative exposure to potentially preventable adverse factors such as toxins, infections, traumatisms, and cardiovascular risk factors, collectively termed exposome. The interplay between the individual's genetics and exposome is thought to have a large impact in health outcomes such as cancer and cardiovascular disease. Likewise, a growing body of evidence is supporting the idea that preventable factors explain a sizable proportion of Alzheimer's disease and related dementia (ADRD) cases. RECENT FINDINGS: Here, we will review the most recent epidemiological, experimental preclinical, and interventional clinical studies examining some of these potentially modifiable risk factors for ADRD. We will focus on new evidence regarding cardiovascular risk factors, air pollution, viral and other infectious agents, traumatic brain injury, and hearing loss. SUMMARY: While greater and higher quality epidemiological and experimental evidence is needed to unequivocally confirm their causal link with ADRD and/or unravel the underlying mechanisms, these modifiable risk factors may represent a window of opportunity to reduce ADRD incidence and prevalence at the population level via health screenings, and education and health policies.

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.

Increased risk of dementia differs across cardiovascular diseases and types of dementia - Data from a nationwide study.

AIMS: Dementia is a major health problem. Cardiovascular diseases (CVD) and risk factors are associated with incident dementia. However, whether there is an association among CVD, Alzheimer's disease (AD) and vascular dementia (VD) at the population level remains unclear. METHODS: We analysed the association between CVD (heart failure [HF], atrial fibrillation [AF], myocardial infarction [MI], peripheral arterial disease, stroke and transient ischemic attack) and the incidence of dementia using nationwide FinnGen data of 218,192 individuals. The last follow-up information on dementia was available from October 2021. RESULTS: The age at the end of the follow-up was 61.7 ± 17.1 years, and 53% were women. Overall, we observed 9701 (4.4%) dementia, 6323 (2.9%) AD and 1918 (0.7%) VD cases. Individuals with CVD had a higher risk of developing dementia than unexposed individuals. In the multivariable-adjusted Cox models, stroke was most strongly associated with dementia (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.6-1.8). CVD was more strongly associated with VD than with AD. Individuals with HF and MI had an increased risk of AD (HF: HR 1.11, 95% CI 1.04-1.19; MI: HR 1.10, 95% CI 1.02-1.18). AF was associated with VD (HR 1.58, 95% CI 1.42-1.77), but not with AD (HR 1.03, 95% CI 0.97-1.09). Clinical characteristics, such as diabetes, smoking and alcohol abuse, were associated with both types of dementia. CONCLUSION: All major CVDs were associated with an increased risk of developing dementia, particularly VD. Therefore, CVD onset should prompt an assessment of cognitive decline and possible preventive measures.

Risk of Alzheimer's Disease and Related Dementias in Persons with Glaucoma: A National Cohort Study.

PURPOSE: Glaucoma is a heterogeneous group of optic neuropathies that potentially may be associated with other cerebral neurodegenerative processes leading to dementia. However, prior studies have been inconsistent. We examined dementia risks after glaucoma diagnosis in a large population-based cohort. DESIGN: National matched cohort study. PARTICIPANTS: A total of 324 730 persons diagnosed with glaucoma during 1995-2017 in Sweden and 3 247 300 age- and sex-matched population-based controls without prior dementia. METHODS: Cox regression was used to compute hazard ratios (HRs) for Alzheimer's disease (AD), vascular dementia (VaD), and all-cause dementia in persons with glaucoma compared with controls, adjusting for sociodemographic factors and comorbidities. MAIN OUTCOME MEASURES: Alzheimer's disease, VaD, and all-cause dementia identified from nationwide inpatient and outpatient diagnoses through 2018. RESULTS: In 16 million person-years of follow-up, 32 339 persons (10%) with glaucoma and 226 896 controls (7%) were diagnosed with dementia. Persons with glaucoma had increased risks for AD (adjusted HR, 1.39; 95% confidence interval [CI], 1.35-1.43), VaD (1.66; 1.61-1.72), and all-cause dementia (1.57; 1.54-1.59). Among glaucoma subtypes, both primary open-angle and normal-tension glaucoma were associated with increased risk for AD (adjusted HR, 1.31; 95% CI, 1.27-1.36; and 1.28; 1.20-1.36, respectively) and VaD (1.61; 1.54-1.68; and 1.39; 1.28-1.50, respectively), whereas primary angle-closure glaucoma was associated with VaD (1.26; 1.02-1.56) but not AD (0.98; 0.82-1.18). These findings were similar in men and women. All risks were highest in persons diagnosed with glaucoma at ages ≥ 70 years and were not elevated for ages < 60 years. CONCLUSIONS: In this large national cohort, persons with glaucoma had increased risks for AD, VaD, and all-cause dementia, particularly those diagnosed with glaucoma at older ages. Persons with glaucoma may need increased monitoring for dementia to facilitate earlier detection and treatment. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Allergic Diseases and Risk of Incident Dementia and Alzheimer's Disease.

OBJECTIVE: To examine the associations between the allergic triad (asthma, allergic rhinitis, atopic dermatitis) and risk of dementia. METHODS: Participants comprised 6,785,948 adults aged ≥40 years who participated in a national health examination in 2009 without any history of dementia before baseline. From 2009 to 2017, we prospectively investigated the associations between physician-diagnosed allergic diseases and risk of incident dementia (all-cause, Alzheimer's disease [AD], vascular dementia [VaD]) ascertained using national health insurance claims data. RESULTS: During 8.1 years of follow-up, 260,705 dementia cases (195,739 AD, 32,789 VaD) were identified. Allergic diseases were positively associated with dementia risk. Compared with individuals without allergic diseases, multivariable hazard ratios (HRs) of all-cause dementia were 1.20 (95% confidence interval [CI] 1.19-1.22) in those with asthma, 1.10 (95% CI 1.09-1.12) with allergic rhinitis, 1.16 (95% CI 1.11-1.21) with atopic dermatitis, and 1.13 (95% CI 1.12-1.14) with any of these allergies. Similarly, individuals with any of the allergic triad had a higher risk of AD (HR 1.16, 95% CI 1.14-1.17) and VaD (HR 1.04; 95% CI 1.01-1.06) than those without any allergic disease. As the number of comorbid allergic diseases increased, the risk of dementia increased linearly (Ptrend ≤ 0.002). Compared with individuals without allergies, those with all three allergic diseases had substantially increased risk of all-cause dementia (HR 1.54, 95% CI 1.35-1.75), AD (HR 1.46; 95% CI 1.25-1.70), and VaD (HR 1.99, 95% CI 1.44-2.75). INTERPRETATION: Asthma, allergic rhinitis, and atopic dermatitis were significantly associated with increased risk of all-cause dementia and subtypes, with dose-effect relationships with the severity of allergic diseases. ANN NEUROL 2023;93:384-397.

Health Conditions Associated with Alzheimer's Disease and Vascular Dementia.

OBJECTIVE: We examined medical records to determine health conditions associated with dementia at varied intervals prior to dementia diagnosis in participants from the Baltimore Longitudinal Study of Aging (BLSA). METHODS: Data were available for 347 Alzheimer's disease (AD), 76 vascular dementia (VaD), and 811 control participants without dementia. Logistic regressions were performed associating International Classification of Diseases, 9th Revision (ICD-9) health codes with dementia status across all time points, at 5 and 1 year(s) prior to dementia diagnosis, and at the year of diagnosis, controlling for age, sex, and follow-up length of the medical record. RESULTS: In AD, the earliest and most consistent associations across all time points included depression, erectile dysfunction, gait abnormalities, hearing loss, and nervous and musculoskeletal symptoms. Cardiomegaly, urinary incontinence, non-epithelial skin cancer, and pneumonia were not significant until 1 year before dementia diagnosis. In VaD, the earliest and most consistent associations across all time points included abnormal electrocardiogram (EKG), cardiac dysrhythmias, cerebrovascular disease, non-epithelial skin cancer, depression, and hearing loss. Atrial fibrillation, occlusion of cerebral arteries, essential tremor, and abnormal reflexes were not significant until 1 year before dementia diagnosis. INTERPRETATION: These findings suggest that some health conditions are associated with future dementia beginning at least 5 years before dementia diagnosis and are consistently seen over time, while others only reach significance closer to the date of diagnosis. These results also show that there are both shared and distinctive health conditions associated with AD and VaD. These results reinforce the need for medical intervention and treatment to lessen the impact of health comorbidities in the aging population. ANN NEUROL 2023;93:805-818.

Associations between multimorbidity and neuropathology in dementia: consideration of functional cognitive disorders, psychiatric illness and dementia mimics.

BACKGROUND: Multimorbidity, the presence of two or more health conditions, has been identified as a possible risk factor for clinical dementia. It is unclear whether this is due to worsening brain health and underlying neuropathology, or other factors. In some cases, conditions may reflect the same disease process as dementia (e.g. Parkinson's disease, vascular disease), in others, conditions may reflect a prodromal stage of dementia (e.g. depression, anxiety and psychosis). AIMS: To assess whether multimorbidity in later life was associated with more severe dementia-related neuropathology at autopsy. METHOD: We examined ante-mortem and autopsy data from 767 brain tissue donors from the UK, identifying physical multimorbidity in later life and specific brain-related conditions. We assessed associations between these purported risk factors and dementia-related neuropathological changes at autopsy (Alzheimer's-disease related neuropathology, Lewy body pathology, cerebrovascular disease and limbic-predominant age-related TDP-43 encephalopathy) with logistic models. RESULTS: Physical multimorbidity was not associated with greater dementia-related neuropathological changes. In the presence of physical multimorbidity, clinical dementia was less likely to be associated with Alzheimer's disease pathology. Conversely, conditions which may be clinical or prodromal manifestations of dementia-related neuropathology (Parkinson's disease, cerebrovascular disease, depression and other psychiatric conditions) were associated with dementia and neuropathological changes. CONCLUSIONS: Physical multimorbidity alone is not associated with greater dementia-related neuropathological change; inappropriate inclusion of brain-related conditions in multimorbidity measures and misdiagnosis of neurodegenerative dementia may better explain increased rates of clinical dementia in multimorbidity.

Weight change in people with depression and the risk of dementia: a nationwide cohort study.

BACKGROUND: Depression is a risk factor for dementia and weight change can appear as a symptom of depression. However, the association between weight change after the diagnosis of depression and the risk of dementia is poorly established. This study aimed to investigate the association between weight change before and after a diagnosis of depression with the subsequent risk of dementia. METHODS: The National Health Insurance Sharing Service database was used. 1 308 730 patients aged ⩾40 years diagnosed with depression were identified to be eligible. Weight changes after their depression diagnosis were categorized and subsequent incidence of dementia was followed up. RESULTS: During an average follow-up period of 5.2 years (s.d., 2.0 years), 69 373 subjects were newly diagnosed with all-cause dementia (56 351 were Alzheimer's disease and 6877 were vascular dementia). Regarding all outcomes, compared to those with a minimal weight change (-5 to 5%), all groups with weight gain or loss showed increased risks of dementia after adjusting potential risk factors for dementia, in all analysis models with a dose-response relationship, showing a U-shaped association. CONCLUSIONS: Weight change as a symptom of depression could be a predictor for the future development of dementia.

African ancestry GWAS of dementia in a large military cohort identifies significant risk loci.

While genome wide association studies (GWASs) of Alzheimer's Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer's disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (n = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer's Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE (p = 2.48 × 10-101), in ROBO1 (rs11919682, p = 1.63 × 10-8), and RNA RP11-340A13.2 (rs148433063, p = 8.56 × 10-9). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p = 2.95 × 10-9), CD2AP (rs7738720, p = 1.14 × 10-9), and ABCA7 (rs73505251, p = 3.26 × 10-10), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.

Hypertensive disorders of pregnancy and the risk of maternal dementia: a systematic review and meta-analysis.

OBJECTIVE: Hypertensive disorders of pregnancy, including preeclampsia, are associated with an increased risk for maternal cardiovascular disease, stroke, and chronic kidney disease. However, their association with subsequent maternal dementia or cognitive impairment is less well understood. This study aimed to review and synthesize the published literature on hypertensive disorders of pregnancy and the subsequent risk for maternal dementia or cognitive impairment. DATA SOURCES: PubMed, Web of Science, Pyschinfo, and CINAHL were searched from database inception until July 31, 2022, for observational studies of hypertensive disorders of pregnancy and maternal dementia or cognitive impairment. STUDY ELIGIBILITY CRITERIA: Selected studies included the following: a population of pregnant women, exposure to a hypertensive disorder of pregnancy of interest, and at least 1 primary outcome (dementia) or secondary outcome (cognitive impairment). Two reviewers were involved in study selection. METHODS: We followed the Meta-analyses of Observational Studies in Epidemiology guidelines throughout. Random-effects meta-analyses were used to calculate the overall pooled estimates. Bias was assessed using an adapted version of the validated Newcastle-Ottawa Quality Assessment tool. RESULTS: A total of 25 eligible studies were identified and included 2,501,673 women. Preeclampsia was associated with a significantly increased risk for vascular dementia (adjusted hazard ratio, 1.89; 95% confidence interval, 1.47-2.43), whereas no clear association was noted between preeclampsia and Alzheimer's disease (adjusted hazard ratio, 1.27; 95% confidence interval, 0.95-1.70), nor between preeclampsia and any (undifferentiated) dementia (adjusted hazard ratio, 1.18; 95% confidence interval, 0.95-1.47). However, in an analysis restricted to women aged 65 years and older, preeclampsia was associated with an increased risk for Alzheimer's disease (adjusted hazard ratio, 1.92; 95% confidence interval, 1.35-2.73) and any dementia (adjusted hazard ratio, 1.87; 95% confidence interval, 1.21-2.91). CONCLUSION: Women whose pregnancies were complicated by preeclampsia seem to be at a substantially increased future risk for vascular dementia. The longer-term risks among these women with regards to Alzheimer's disease and other forms of dementia are less clear.

Depressive Symptoms and Plasma Markers of Alzheimer's Disease and Neurodegeneration: A Coordinated Meta-Analysis of 8 Cohort Studies.

BACKGROUND: Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD). There has been a recent emergence in plasma biomarkers for AD pathophysiology, such as amyloid-beta (Aß) and phosphorylated tau (p-tau), as well as for axonal damage (neurofilament light, NfL) and astrocytic activation (glial fibrillary acidic protein, GFAP). Hypothesizing that depressive symptoms may occur along the AD process, we investigated associations between plasma biomarkers of AD with depressive symptoms in individuals without dementia. METHODS: A two-stage meta-analysis was performed on 2 clinic-based and 6 population-based cohorts (N = 7210) as part of the Netherlands Consortium of Dementia Cohorts. Plasma markers (Aß42/40, p-tau181, NfL, and GFAP) were measured using Single Molecular Array (Simoa; Quanterix) assays. Depressive symptoms were measured with validated questionnaires. We estimated the cross-sectional association of each standardized plasma marker (determinants) with standardized depressive symptoms (outcome) using linear regressions, correcting for age, sex, education, and APOE ε4 allele presence, as well as subgrouping by sex and APOE ε4 allele. Effect estimates were entered into a random-effects meta-analysis. RESULTS: Mean age of participants was 71 years. The prevalence of clinically relevant depressive symptoms ranged from 1% to 22%. None of the plasma markers were associated with depressive symptoms in the meta-analyses. However, NfL was associated with depressive symptoms only in APOE ε4 carriers (ß 0.11; 95% CI: 0.05-0.17). CONCLUSIONS: Late-life depressive symptoms did not show an association to plasma biomarkers of AD pathology. However, in APOE ε4 allele carriers, a more profound role of neurodegeneration was suggested with depressive symptoms.

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.

The Australian National University Alzheimer's Disease Risk Index (ANU-ADRI) score as a predictor for cognitive decline and potential surrogate outcome in the FINGER lifestyle randomized controlled trial.

BACKGROUND AND PURPOSE: The complex aetiology of Alzheimer's disease suggests prevention potential. Risk scores have potential as risk stratification tools and surrogate outcomes in multimodal interventions targeting specific at-risk populations. The Australian National University Alzheimer's Disease Risk Index (ANU-ADRI) was tested in relation to cognition and its suitability as a surrogate outcome in a multidomain lifestyle randomized controlled trial, in older adults at risk of dementia. METHODS: In this post hoc analysis of the Finnish Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), ANU-ADRI was calculated at baseline, 12, and 24 months (n = 1174). The association between ANU-ADRI and cognition (at baseline and over time), the intervention effect on changes in ANU-ADRI, and the potential impact of baseline ANU-ADRI on the intervention effect on changes in cognition were assessed using linear mixed models with maximum likelihood estimation. RESULTS: A higher ANU-ADRI was significantly related to worse cognition, at baseline (e.g., estimate for global cognition [95% confidence interval] was -0.028 [-0.032 to -0.025]) and over the 2-year study (e.g., estimate for 2-year changes in ANU-ADRI and per-year changes in global cognition [95% confidence interval] was -0.068 [-0.026 to -0.108]). No significant beneficial intervention effect was reported for ANU-ADRI, and baseline ANU-ADRI did not significantly affect the response to the intervention on changes in cognition. CONCLUSIONS: The ANU-ADRI was effective for the risk prediction of cognitive decline. Risk scores may be crucial for the success of novel dementia prevention strategies, but their algorithm, the target population, and the intervention design should be carefully considered when choosing the appropriate tool for each context.

Comparison of Enlarged Perivascular Spaces in Early-Onset and Late-Onset Alzheimer Disease-related Cognitive Impairment: A Single Clinic-based Study in South Korea.

We examined whether there were differences in the presence of centrum semiovale-enlarged perivascular spaces (CSO-ePVS) and basal ganglia-ePVS (BG-ePVS) among patients with Alzheimer disease-related cognitive impairment (ADCI) based on their age of onset. Out of a total of 239 patients with cognitive impairment, 155 with positive amyloid-PET results were included. Among these, 43 had early-onset ADCI (EOADCI) and 112 had late-onset ADCI (LOADCI). Patients with LOADCI exhibited a higher prevalence of hypertension, lacunes, white matter hyperintensities, and BG-ePVS than those with EOADCI. BG-ePVS showed a significant correlation with age at the onset and the number of lacunes, whereas CSO-ePVS did not exhibit any association. The higher prevalence of BG-ePVS in patients with LOADCI might be attributable to vascular risk factors (hypertension) and cerebral small vessel disease (CSVD). These findings support the hypothesis that BG-ePVS is associated with CSVD and vascular risk factors, whereas CSO-ePVS is associated with cerebral amyloid angiopathy.

The transition to modernity and chronic disease: mismatch and natural selection.

The Industrial Revolution and the accompanying nutritional, epidemiological and demographic transitions have profoundly changed human ecology and biology, leading to major shifts in life history traits, which include age and size at maturity, age-specific fertility and lifespan. Mismatch between past adaptations and the current environment means that gene variants linked to higher fitness in the past may now, through antagonistic pleiotropic effects, predispose post-transition populations to non-communicable diseases, such as Alzheimer disease, cancer and coronary artery disease. Increasing evidence suggests that the transition to modernity has also altered the direction and intensity of natural selection acting on many traits, with important implications for public and global health.

Development of a smartphone screening test for preclinical Alzheimer's disease and validation across the dementia continuum.

BACKGROUND: Dementia prevalence is predicted to triple to 152 million globally by 2050. Alzheimer's disease (AD) constitutes 70% of cases. There is an urgent need to identify individuals with preclinical AD, a 10-20-year period of progressive brain pathology without noticeable cognitive symptoms, for targeted risk reduction. Current tests of AD pathology are either too invasive, specialised or expensive for population-level assessments. Cognitive tests are normal in preclinical AD. Emerging evidence demonstrates that movement analysis is sensitive to AD across the disease continuum, including preclinical AD. Our new smartphone test, TapTalk, combines analysis of hand and speech-like movements to detect AD risk. This study aims to [1] determine which combinations of hand-speech movement data most accurately predict preclinical AD [2], determine usability, reliability, and validity of TapTalk in cognitively asymptomatic older adults and [3], prospectively validate TapTalk in older adults who have cognitive symptoms against cognitive tests and clinical diagnoses of Mild Cognitive Impairment and AD dementia. METHODS: Aim 1 will be addressed in a cross-sectional study of at least 500 cognitively asymptomatic older adults who will complete computerised tests comprising measures of hand motor control (finger tapping) and oro-motor control (syllabic diadochokinesis). So far, 1382 adults, mean (SD) age 66.20 (7.65) years, range 50-92 (72.07% female) have been recruited. Motor measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 to develop an algorithm that classifies preclinical AD risk. Aim 2 comprises three sub-studies in cognitively asymptomatic adults: (i) a cross-sectional study of 30-40 adults to determine the validity of data collection from different types of smartphones, (ii) a prospective cohort study of 50-100 adults ≥ 50 years old to determine usability and test-retest reliability, and (iii) a prospective cohort study of ~1,000 adults ≥ 50 years old to validate against cognitive measures. Aim 3 will be addressed in a cross-sectional study of ~200 participants with cognitive symptoms to validate TapTalk against Montreal Cognitive Assessment and interdisciplinary consensus diagnosis. DISCUSSION: This study will establish the precision of TapTalk to identify preclinical AD and estimate risk of cognitive decline. If accurate, this innovative smartphone app will enable low-cost, accessible screening of individuals for AD risk. This will have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06114914, 29 October 2023. Retrospectively registered.