This review aims to explore the potential role of folate and related B vitamins (B12, B6 and riboflavin) in maintaining cognitive health in ageing, focusing particularly on their interactions with the gut microbiota and inflammation. Low B-vitamin status, common in older adults, is associated with poorer cognitive function and dementia. Furthermore, people with dementia are observed to have increased abundance of pro-inflammatory microbes and concomitant higher concentrations of cytokines in their circulation. Therefore, gut dysbiosis and chronic inflammation have been proposed as contributors of cognitive dysfunction. Although many observational studies report that low B-vitamin status, especially vitamin B6, is associated with a worse inflammatory state, the role of the gut microbiota is much less investigated. Pre-clinical evidence suggests higher B-vitamin intakes may beneficially modulate the gut bacterial profile and its metabolic activity, positively influencing inflammation. The evidence, however, is inconsistent, and the few human intervention studies available are confined to clinical populations or are limited by small sample size or to a single B-vitamin at high supplementation doses. Of note, one study in rats with Alzheimer’s-type dementia reported an association of folate and vitamin B12 deficiency with disturbed gut bacterial composition, neuroinflammation and impaired memory. In conclusion, optimising B-vitamin status may help promote cognitive health during ageing through modulation of the gut microbiota and immune function. Well-designed human studies are, however, required to confirm these relationships and inform evidence-based nutritional strategies for healthy ageing.

Consumption of red and processed meat makes an important contribution to protein and micronutrient intakes in UK adults (1) but can also be associated with adverse health and environmental outcomes (2) . Fish provides high-quality protein and at-risk nutrients including omega-3 fatty acids, vitamin D, B vitamins and iodine (3) , and also has a lower carbon footprint compared to red meat (3) , and thus may be a potential alternative protein food in the shift towards more sustainable dietary patterns. The implications for key nutrient intakes, however, of replacing meat with fish at a population level remain unclear. This study aimed to model the nutritional impact of partial or complete replacement of meat with fish in UK adults Dietary data from the National Diet and Nutrition Survey (Years 9-11; 2016/17-2018/19) (n=1912; ≥18) were analysed. A dietary model scenario was developed to simulate partial (25%, 50%, 75%) to complete (100%) replacement of meat intake with fish (including that from composite dishes). Average daily intakes of protein (g), omega-3 (g), vitamins D (µg), B6 (mg), B12 (µg), selenium (µg), iron (mg) and iodine (µg) were identified as targeted nutrients. Diet modelling was conducted using Dadiet© (Dazult, V.24.09). Modelled diet scenarios were compared with current consumption (baseline) for targeted nutrients using ANOVA, with post hoc tests (SPSS, v.31) All targeted nutrient intakes showed incremental changes from baseline across the levels of meat-to-fish substitution. Protein and vitamin B6 intakes each declined marginally, but significantly, from 72±23 to 65±22 g/d (−9%; p<0.001) and from 1.7±0.9 to 1.6±0.8 mg/d (−6%; p=0.001), respectively, from baseline to 100% substitution of meat-to-fish. In contrast, simulated intakes of all other nutrients increased by 4-64% from baseline to 100% meat-to-fish substitution: omega-3 (2.0±1.1 to 2.6±1.2 g/d, +30%, p<0.001); vitamin D (3.0±2.3 to 4.4±2.6 µg/d, +47%, p<0.001); vitamin B12 (5.0±3.9 to 8.2±4.7 µg/d, +64%, p<0.001); selenium (47±22 to 65±29 µg/d, +38%, p<0.001); iron (9.9±3.7 to 10.3±3.7, +4%, p=0.014) and iodine (155±102 to 196±107 µg/d, +26%, p<0.001). Notably, the significant improvements in simulated intakes of omega-3, vitamin B12, vitamin D, selenium and iodine were observed with only a 25% meat-to-fish substitution, and increased incrementally across each modelling scenario to 100% replacement. Based on current consumption patterns among UK adults, replacing as little as 25% of total meat intake with fish has the potential to improve nutrient intakes, particularly those of current public health concern (such as vitamins D, B12 and iodine). Translating this into simple consumer messaging, e.g. ‘swap 1-2 meat-based meals for fish every week’ could be an effective strategy to help consumers move towards a healthier, more sustainable diet. Future research is warranted to explore similar modelling scenarios in at-risk sub-groups, including women of childbearing age and older adults.

There is no universally accepted definition of vitamin B12 deficiency despite the severity of its medical consequences if not properly diagnosed and treated. Vitamin B12 deficiency can arise either from inadequate dietary intake, particularly among vegans/vegetarians, or various causes of impaired absorption or availability. The latter include Helicobacter pylori and autoimmune gastritis, other causes of malabsorption, and drug side effects. Vitamin B12 deficiency can display diverse clinical signs and symptoms, including hematological, neurological, psychiatric, and thromboembolic manifestations. The minutes and conclusions of 3 workshops at the FASEB "B-vitamins and One-Carbon Metabolism" Scientific Research Conferences (2022 and 2024) and the 2025 International Conference on One-Carbon Metabolism, B-Vitamins and Homocysteine, the examination of the literature and the National Institute for Health and Care Excellence/DELPHI guidelines allowed us to identify gaps and issues on diagnostic criteria and definition, evaluation of causation, and treatment strategies of vitamin B12 deficiency across different health care settings in adults aged >18 y. Our aim is to address these gaps and issues in global guidelines to be evaluated by the International Union of Nutritional Sciences. We identified 4 main goals: 1) definition of vitamin B12 deficiency; 2) assessment of causality; 3) differential diagnosis and evaluation of nutritional and metabolic comorbidities; and 4) treatment and follow-up. The objective of such guidelines should be to reduce both underdiagnosis and overdiagnosis of vitamin B12 deficiency by integrating clinical scoring and biomarker algorithms and considering cause-specific treatment pathways. This should ultimately improve patient outcomes worldwide and, by arriving at uniform diagnostic criteria, facilitate the conduct, interpretation, and integration of research observations.

Background:Cardiovascular and metabolic diseases account for an increasing share of morbidity and mortality globally. Folic acid supplementation has been linked to a lowered risk of stroke and some metabolic indicators due to its involvement in homocysteine and one-carbon metabolism and its role in the production of nitric oxide; however, the evidence on these associations is inconclusive. Methods:We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects from inception to February 2024 for systematic reviews and meta-analyses investigating the associations of folate (dietary intake, supplementation, or blood concentrations) with any cardiometabolic outcome. We performed screening, data abstraction, and risk of bias assessment in duplicate, and assessed the credibility of the evidence using predefined criteria. Results:We identified 113 unique associations from 49 reviews. The included syntheses mostly had low risk of bias of and provided pooled risk estimates from intervention trials or prospective cohorts. A larger volume of evidence was available for composite cardiovascular outcomes, coronary heart disease, and stroke compared to other outcomes. No association reached a convincing or highly suggestive level of credibility. Six directional associations and five null associations met the criteria for a suggestive level of credibility. Three dose-response relationships, all at suggestive levels of credibility, supported an association between higher dietary folate intake and a reduced risk of coronary heart disease and stroke. Conclusion:The available evidence on the association between folate status and cardiometabolic outcomes primarily focuses on secondary prevention of cardiometabolic diseases and substantially underrepresents low- and middle-income countries. More large-scale studies are warranted to validate a relationship between folate status and cardiometabolic events or indicators. Overall, the evidence landscape around folate and cardiometabolic diseases appears to be limited both in volume and scope. Registration:PROSPERO: CRD42021265041.

There is a tacit assumption that the majority of nutritional anemia is caused by iron deficiency. However, several other key micronutrients are involved in iron and/or erythrocyte metabolism and thus play a role in the development of nutritional anemia. This consensus paper provides an updated review that synthesizes current evidence on the role of individual micronutrients, beyond iron, in the development of nutritional anemia and identifies emerging hypotheses and potential mechanistic links to erythropoiesis and iron metabolism involving nutrients of both established and growing interest. To achieve this, we convened leading experts in micronutrients and nutritional anemia to categorize 10 key micronutrients of interest into a hierarchy based on the scope and strength of evidence for their roles in the development of anemia, erythropoiesis, and iron metabolism. Folate, vitamin B12, and vitamin A were ranked as having strong evidence, meaning data are consistent in describing a causal association between nutrient status and anemia development, and the evidence for the proposed mechanism(s) is well-established. Riboflavin, zinc, vitamin B6, vitamin C, and vitamin E were ranked as having moderate evidence, and vitamin D and copper were ranked as having potential and/or emerging evidence. We also identify critical gaps in the current evidence and propose priority areas for future research for each micronutrient. This perspective paper aims to serve as a comprehensive reference to inform future research priorities and guide global nutrition policy, strategy, and programming related to anemia prevention and control.

Background:Folate has been examined extensively in relation to carcinogenesis due to its role in one-carbon metabolism impacting the synthesis of DNA and RNA, methylation processes, and genomic integrity. Current evidence on the relationship between folate status and the risk of cancer is equivocal: low or deficient folate status may contribute to an increased risk of cancers, while high-dose folic acid supplementation may have adverse effects on carcinogenesis. Methods:We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects up to February 2024 for systematic reviews and meta-analyses investigating the associations of folate (measured as dietary intake, supplementation, or blood concentrations) with any specific cancer outcome. Screening, data extraction, and risk of bias assessment were performed in duplicate. We assessed the credibility of the evidence using predefined criteria. Results:We found 67 syntheses, of which 57 provided meta-analyses. Over half of the syntheses had a high risk of bias. We identified 168 unique associations (unique exposure - unique outcome - unique setting) across 10 cancer types, 3 system cancers, and total cancer. Of these, we assessed 15 directional associations (colorectal, oesophageal, and total cancers) to be at a highly suggestive level of credibility, and 17 directional and 10 null associations to be at a suggestive level of credibility. Conclusions:The available evidence for each category of unique association was generally limited. Highly suggestive associations were found for oesophageal, colorectal, childhood brain and spinal tumours and total cancers. More robust primary studies are warranted to follow-up the signal of a positive relationship reported for prostate cancer warranting further research. Evidence was weak for all but colorectal and oesophageal cancers, or the central nervous system cancers in children. Registration:PROSPERO: CRD42021265041.

Background:Folate is essential for normal growth and in human health throughout the lifecycle. Clinical deficiency of folate impairs DNA synthesis and results in megaloblastic anaemia, while suboptimal folate status before and in early pregnancy results in an elevated risk of neural tube defects (NTD). The evidence on the association of folate status with other health outcomes is largely fragmented and understudied. We conducted a series of umbrella reviews examining the association between folate and multiple health outcomes in various populations and settings. Methods:We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and DARE from inception to February 2024 for systematic reviews with or without meta-analyses examining an association between folate intake/status and any health outcome. We performed screening and data extraction in duplicate and assessed the risk of bias using the ROBIS tool. Evidence was then characterised into unique associations (unique exposure measure - unique outcome measure - unique setting). For each category of unique associations, we identified the evidence based on the statistical power, recency of publication and the potential risk of bias. All unique associations were evaluated for credibility using predefined criteria. Results:We retrieved 3565 records and included 283 in the final synthesis. The evidence on anaemia consisted of four intervention trials demonstrating effectiveness of folic acid supplementation during pregnancy in reducing the risk of megaloblastic anaemia (relative risk (RR) = 0.21; 95% CI = 0.11, 0.38; I2 = 15%). Maternal folic acid use was also significantly inversely related to the prevention of NTD at birth (RR = 0.31; 95% CI = 0.16, 0.60; I2 = 0%) and NTD recurrence (RR = 0.30; 95% CI = 0.14, 0.65; I2 = 0%). This relationship was supported by the inverse association reported between low maternal blood folate concentrations and the increased risk of NTD. Further evidence showed that fortification of food with folic acid was associated with the lower prevalence of NTD on a population-level. Conclusion:In NTDs and anaemia, we identified strong evidence supporting the protective role of folate status based on intervention trials and observational studies. More recent reviews examining the role of folate in other less well understood health conditions will be presented in the subsequent reports. Registration:PROSPERO: CRD42021265041.

Background Autoimmune diseases and bone density loss (osteopenia and osteoporosis) are chronic conditions of complex aetiology that affect diverse populations. Folate may be associated with a higher risk of these disorders due to its essential role in one-carbon metabolism required for nucleotide synthesis, homocysteine metabolism, and methylation processes. However, the evidence on this association is inconclusive. Methods We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects from inception to February 2024 for systematic reviews and meta-analyses investigating the associations between folate exposure (dietary intake, supplementation, or blood concentrations) and any autoimmune diseases or skeletal outcomes. Pairs of researchers screened the retrieved syntheses, extracted the relevant data, assessed their risk of bias using the ROBIS tool, and evaluated the credibility of the evidence using predefined criteria. Results We found 19 reviews reporting 25 unique associations: 15 on autoimmune diseases (multiple sclerosis, inflammatory bowel disease, psoriasis, human immunodeficiency virus, vitiligo, and systemic lupus erythematosus) and 10 on skeletal outcomes (fractures and bone mineral density loss). Most of the syntheses consisted of small-scale case-control studies. The risk of bias in the included syntheses was high. Owing to the small sample sizes, all the unique associations were assessed to be at a weak level of credibility. Conclusions The evidence on the relationship between folate status and autoimmune diseases or skeletal outcomes was limited in breadth and depth. Most of the 25 unique associations were reported by a single synthesis comprising small-scale studies. Subgroup analyses or dose-response analyses were severely limited or unavailable. More well-powered, prospective studies investigating the relationships between folate and autoimmune and skeletal conditions are warranted. Registration PROSPERO: CRD42021265041.

Background:The global burden of neuropsychiatric disorders has been increasing rapidly. Folate has been studied in the context of these disorders due to its role in cellular methylation capacity, which is crucial for normal neuronal gene expression and neurotransmitter syntheses. Epidemiological evidence linking folate and neuropsychiatric disorders is growing, yet inconclusive. Methods:We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects from inception to February 2024 for systematic reviews and meta-analyses investigating the associations between folate exposure and any neuropsychiatric disorders. Two independent reviewers screened the syntheses in two stages and extracted relevant data. Evidence was categorised into unique associations (unique exposure measure - unique outcome - unique setting). We identified evidence for each category of unique associations. We evaluated the risk of bias of all included syntheses using ROBIS and assessed the credibility of evidence using predefined criteria. Results:From a total of 76 syntheses, we identified 44 unique associations from meta-analyses and 18 unique associations from qualitative syntheses across 14 outcome categories. Most of the reviews consisted of case-control studies or cross-sectional studies, and most were at high risk of bias. We identified two associations at a suggestive level of credibility: folic acid supplementation during or before pregnancy was associated with a reduced risk of perinatal depression, while prenatal maternal folic acid use was associated with a reduced risk of autism spectrum disorder in offspring. Seven associations were downgraded to weak due to unavailable data. Other associations were at a weak level of credibility due to insufficient statistical power. Conclusions:The available evidence on the relationship between folate status and neuropsychiatric disorders primarily comprised data from observational studies, limiting causal inference on folate exposure and the risk of onset or progression of neuropsychiatric disorders. Prospective studies and sex-stratified analyses could add to the evolving knowledge on this topic. Registration:PROSPERO: CRD42021265041.

Vitamin D may influence lipid metabolism, with some studies suggesting a modest increase in high-density lipoprotein cholesterol (HDL-C) following vitamin D supplementation. However, observational studies examining the relationship between vitamin D status and lipid parameters have yielded inconsistent findings, partly due to confounding by statin use and other factors affecting lipid regulation. We aimed to examine the association between serum 25-hydroxyvitamin D [25(OH)D] concentrations and lipid profiles in older adults after excluding individuals using statins. Adults aged >60 yrs from the TUDA study were analysed after removal of current or prior statin users. Multivariable linear regression was used to examine the relationship of serum 25(OH)D to HDL-C, LDL-C, and TG, adjusting for age, sex, BMI, waist-hip ratio, socioeconomic status, smoking, alcohol, diabetes, timed-up-and-go, C-reactive protein, dairy/fish/meat intake, renal function, thiazide use, β-blocker use, and glucocorticoid use. A total of 2,197 participants were included in the study (mean age 74.2±8.6 years; 71.2% female; mean 25(OH)D 62.8±31.2 nmol/L). Higher levels of 25(OH)D were independently associated with higher HDL-C (P < 0.001). No significant associations were observed between 25(OH)D levels and LDL-C or TG. In statin-free older adults, higher vitamin D status was associated with higher HDL-C, but not with LDL-C or triglycerides. Vitamin D may enhance HDL metabolism by promoting apolipoprotein A-I and lecithin-cholesterol acyltransferase (LCAT), key proteins in HDL maturation and reverse cholesterol transport. No association was seen with vitamin D and atherogenic lipoproteins. Prospective studies are needed to confirm causality and clinical significance.

Thiazide diuretics are associated with higher bone mineral density (BMD) and reduced risk of hip fracture. The mechanisms underlying this association remain incompletely understood but are thought to include reduced urinary calcium excretion and potential direct skeletal effects. We aimed to explore the association between thiazide use and bone turnover markers (BTM), BMD, and hip fracture in older Irish adults. Methods: Participants aged >60 years from the TUDA cohort of Irish adults. The relationship between thiazide use and hip fracture was examined using multinomial regression, adjusting for age, sex, BMI, vitamin D, PTH, timed up and go, diabetes, lifestyle factors, eGFR, and steroid use. In a subsample excluding individuals on osteoporosis medications, thiazide use and BTM as well as densitometrically measured BMD at the hip and lumbar spine were explored, adjusting for similar covariates. BTMsmeasured were serum TRAP5b (tartrate-resistant acid phosphatase 5b) and bone-specific alkaline phosphatase (BAP). In the overall sample (n=4451; mean age 73.4±8.1 years; 66.9% female), 23.5% were thiazide users and 234 participants reported a previous hip fracture. Thiazide use was associated with lower risk of hip fracture before and after multivariate adjustment (OR 0.62, 95% CI:0.41–0.95, p=0.0286). In a subsample (n=1839), thiazide users had significantly lower serum TRAP5b (2.64 vs 2.81 U/L, p<0.001), lower BAP (15.4 vs 17.3 μg/L, p<0.001), and higher BMD at both the hip (1.007 vs 0.994 g/cm2, p=0.04) and lumbar spine (1.222 vs 1.203 g/cm2, p=0.04). Conclusion: These findings support a beneficial effect of thiazides on BMD and hip fracture risk, potentially mediated through bone turnover suppression. Experimental data suggest thiazides may directly affect osteoclast function, although few studies have specifically examined effects on BTMs While thiazides may have protective skeletal effects, their potential to increase fall risk in older adults must be carefully considered in clinical practice.

Several essential vitamins and minerals whose deficiencies are associated with metabolic and functional disorders, including increased morbidity and mortality from both communicable and noncommunicable diseases, are not being adequately addressed by large-scale, public health nutrition programs worldwide. These neglected micronutrients include thiamine, riboflavin, niacin, pyridoxine, vitamin B-12, vitamin D, vitamin K, calcium, selenium, and possibly others. In this narrative review, our objectives are to describe briefly the health implications of each of these deficiencies, summarize the limited available information on their epidemiology, and suggest possible approaches to address them. We conclude that more information, based on dietary assessments, nutritional biomarker surveys, and systematic surveillance of associated health conditions, is needed. Appropriate intervention programs, including changes in food systems to provide wider access to nutrient-rich foods, food fortification and targeted supplementation, should be implemented in settings where these deficiencies are confirmed.

Recent studies have shown an association between PPI use and increased risk of falls. A meta-analysis of eight studies (n=367,068) identified a 27% increased falls risk in PPI users. Potential mechanisms include reduced gut absorption of calcium, magnesium and other nutrients, altered gut microbiome and possible effects on muscle function. We aimed to explore the association between PPI use and falls risk in older adults. Participants were adults aged >60 yrs from the TUDA study. Exclusion criteria were MMSE <24, history of stroke and current or long-term steroid use. The relationship between PPI use and self- reported falls in the last year was explored in multinomial regression adjusting for age, sex, BMI, timed up and go (TUG), diabetes, vitamin D, serum B12, parathyroid hormone, depression, dizziness on standing, ischemic heart disease, MMSE, medications (antihypertensives, loop diuretics, NSAIDs, benzodiazepines, opioids, Z drugs). We also explored for an association in those with normal TUG (<10 seconds) and in high dose PPI users versus non-users. 3701 participants, mean age 73.1, 68.8% female, 32.6% fallen in last year, 35.3% PPI users. PPI use was associated with an increased risk of falls before and after multivariate adjustment (OR 1.29 CI 1.11-1.50, P<0.001). In a subsample (n=3059), high dose PPI users versus non-users had a greater risk of falls (OR 1.43, CI 1.17-1.75, p=0.0003). In those with normal TUG, the overall relationship remained significant (OR 1.34, CI 1.07-1.69, p=0.011) and also in high dose PPI users versus non-users (OR 1.89, CI 1.39-2.58, p<0.0001). Overall, PPI users had a 29% increased risk of falls independent of numerous factors and this remained significant in those without physical frailty. Furthermore, risk was greater risk in high dose PPI users. Future studies are needed to further explore this and the potential mechanisms.

The role of one-carbon metabolism and related B-vitamins in cognitive function in ageing is well-documented, particularly for folate and vitamin B12, with vitamin B6 and riboflavin receiving much less attention. ApoE is a well-established genetic risk factor for Alzheimer’s disease, but the role of B-vitamins in modifying this risk remains largely unexplored. We examined associations between folate, B12, B6, riboflavin, and cognitive function in older adults, including interactions with the ApoE ε4 genotype. Community-dwelling older adults (≥ 60 years) from the Trinity-Ulster-Department of Agriculture (TUDA) study were stratified as ApoE ε4 carriers (ε3/ε4 and ε4/ε4 genotypes; n = 1205) or non-ε4 carriers (n = 3348). Cognitive function was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), the Frontal Assessment Battery, and the Mini-Mental State Examination. Logistic regression models were used to evaluate the association between cognitive dysfunction (defined as RBANS score < 80) and a range of variables, including biomarkers of folate, vitamins B12, B6, and riboflavin status, plasma homocysteine levels, and ApoE ε4 genotype. Lower status of vitamin B12 (holotranscobalamin; adjusted odds ratio (ORadj 1.30; 95

BACKGROUND:Low folate status is one of the multiple factors thought to contribute to the development of schizophrenia. As of 2023, over 70 countries have implemented mandatory fortification of foods with folic acid, a public health measure aimed at reducing neural tube defects; however, the impact of such policy on schizophrenia has not been comprehensively investigated. METHOD:We assessed the impact of mandatory folic acid fortification on changes in the schizophrenia rates in 194 jurisdictions between 1990 and 2019 using publicly available data. We used weighted regression models adjusted for sociodemographic and sociopolitical factors, experience of natural disasters, and baseline schizophrenia rate. RESULTS:Age-adjusted prevalence and incidence of schizophrenia increased marginally between 1990 and 2019. In all geographic regions, schizophrenia prevalence and incidence per 100,000 positively correlated with countries' sociodemographic index and were lower with fortification. Schizophrenia burdens were higher among males compared to females. Lower prevalence and incidence of schizophrenia were associated with having mandatory fortification with modest magnitudes. Duration of fortification or the fortification dose did not appear to have a strong impact. However, in the 15-39 year age-group, both mandatory fortification (β = -13·14 (-22·60, -3·68)) and duration of fortification (β = -0·82 (-1·40, -0·23)) were significantly associated with lower schizophrenia with larger magnitude in both sexes. The highest dose tertile was reported to have the lowest incidence and the smallest increase in prevalence in this age-group. CONCLUSION:Folic acid fortification may be a beneficial intervention in lowering schizophrenia among adolescents and young adults.

Evidence increasingly supports the “infectious hypothesis” of Alzheimer Disease (AD) in older adults, proposing that common pathogens—particularly human herpesviruses—increase one's risk of AD. However, most studies have used medical records and clinically-diagnosed infections to test this association. To obtain a direct measure of viral exposure history, we developed a novel multiplex sero-assay enabling simultaneous measurement of antibodies to a broad variety of common infections and applied it to several unique clinical cohorts to interrogate the infectious hypothesis of AD. Using nearly 6,000 samples from three studies (TUDA, TIMC-BRAiN, NILVAD), plasma IgG to 50 pathogens was measured via a multiplex bead-based assay. Associations were examined in the community-based TUDA cohort and further explored in clinical cohorts (TIMC-BRAiN, NILVAD) using paired plasma/cerebrospinal fluid (CSF) samples and high-sensitivity biomarkers of inflammation and neurodegeneration. Linear regression results are presented as Beta Coefficients (B), 95% Confidence Intervals, and p-values with adjustment for important clinical covariates. In TUDA (n=4,796, age: 73.7±8.17 years, 67.2% female), Herpes Simplex Virus 1 (HSV1) seropositivity was significantly associated with poorer total RBANS scores (B: -3.78, 95%CI: -5.50 to -2.07, p<0.001) and poorer performance on all RBANS domains. Cytomegalovirus (CMV) seropositivity was significantly associated with poorer total RBANS performance (B: -1.38, 95%CI: -2.23 to -0.52, p=0.002). In NILVAD, CMV seropositivity was associated with greater baseline dementia severity (B: 1.47, 95%CI: 0.58 to 2.36, p=0.001 on CDR-Sb). In clinical cohorts (TIMC-BRAiN, NILVAD), pathogen seropositivity was not associated with AD biomarkers or AD clinical progression over 18-months. Across all three cohorts, herpesvirus seropositivity was consistently associated with elevated systemic inflammatory markers (IL-6, TNF-α). Herpesvirus exposure (HSV1, CMV) was robustly associated with poorer cognitive performance, potentially mediated by non-specific systemic inflammatory effects. However, direct involvement of HSV1 or CMV in AD pathogenesis or progression was not supported by the current analysis.

The Latent Block Model (LBM) is a prominent model-based co-clustering method, returning parametric representations of each block cluster and allowing the use of well-grounded model selection methods. The LBM, while adapted in literature to handle different feature types, cannot be applied to datasets consisting of multiple disjoint sets of features, termed views, for a common set of observations. In this work, we introduce the multi-view LBM, extending the LBM method to multi-view data, where each view marginally follows an LBM. In the case of two views, the dependence between them is captured by a cluster membership matrix, and we aim to learn the structure of this matrix. We develop a likelihood-based approach in which parameter estimation uses a stochastic EM algorithm integrating a Gibbs sampler, and an ICL criterion is derived to determine the number of row and column clusters in each view. To motivate the application of multi-view methods, we extend recent work developing hypothesis tests for the null hypothesis that clusters of observations in each view are independent of each other. The testing procedure is integrated into the model estimation strategy. Furthermore, we introduce a penalty scheme to generate sparse row clusterings. We verify the performance of the developed algorithm using synthetic datasets, and provide guidance for optimal parameter selection. Finally, the multi-view co-clustering method is applied to a complex genomics dataset, and is shown to provide new insights for high-dimension multi-view problems.

As global life expectancy increases, understanding mental health patterns and their associated risk factors in older adults becomes increasingly critical. Using data from the cross-sectional Trinity Ulster Department of Agriculture study (TUDA, 2008-2012; n = 5186 ; mean age 74.0 years) and a subset of participants followed-up longitudinally (TUDA 5+, 2014-2018; n = 953 ), we perform a multi-view co-clustering analysis to identify distinct mental health profiles and their relationships with potential risk factors. The TUDA multi-view dataset consists of five views: (1) mental health, measured with Center for Epidemiologic Studies Depression Scale [CES-D] and Hospital Anxiety and Depression Scale [HADS], (2) cognitive and neuropsychological function, (3) illness diagnoses and medical prescription history, (4) lifestyle and nutritional attainment, and (5) physical well-being. That is, each participant is described by five distinct sets of features. The mental health view serves as the target feature set, while the other four views are analyzed as potential contributors to mental health risks. Under the multi-view co-clustering framework, for each view data, the participants (rows) are partitioned into different row-clusters, and the features (columns) are partitioned into different column-clusters. Each row-cluster is most effectively explained by the features in one or two column-clusters. Notably, the row-clusterings across views are dependent. By analyzing the associations between row clusters in the mental health view and those in each of the other four views, we can identify which risk factors co-occur and contribute to an increased risk of poor mental health. We identify five distinct row-clusters in the mental-health view data, characterized by varying levels of depression and anxiety: Group 1, mild depressive symptoms and no symptoms of anxiety; Group 2, acute depression and anxiety; Group 3, less severe but persistent depression and anxiety symptoms; Group 4, symptoms of anxiety with no depressive symptoms; and Group 5, no symptoms of either depression or anxiety. Cross-view association analysis revealed the following key insights: Participants in Group 3 exhibit lower neuropsychological function, are older, more likely to live alone, come from more deprived regions, and have reduced physical independence. Contrasting Group 3, participants in Group 2 show better neuropsychological function, greater physical independence, and higher socioeconomic status. Participants in Group 5 report fewer medical diagnoses and prescriptions, more affluent backgrounds, less solitary living, and stronger physical independence. A significant portion of this group aligns with cognitive health row-clusters 1 and 3, suggesting a strong link between cognitive and mental health in older age. Participants with only depressive (Group 1) or anxiety symptoms (Group 4) exhibit notable differences. Those with anxiety symptoms are associated with healthier clusters across other views. The co-clustering methodology also categorizes the questions in the CES-D and HADS scales into meaningful clusters, providing valuable insights into the underlying dimensions of mental health assessment. In the CES-D scale, the questions are divided into four clusters: those related to loneliness and energy, those addressing feelings of insecurity, worthlessness, and fear, those concerning concentration and effort, and those focused on sleep disturbances. Similarly, the HADS questions are grouped into clusters that reflect themes such as a strong sense of impending doom, nervousness or unease, and feelings of tension or restlessness. By organizing the questions from both scales into these smaller groups, the methodology highlights distinct symptom patterns and their varying severity among participants. This approach could be leveraged to develop abridged versions of the assessment scales, enabling faster and more efficient triage in clinical practice.