Late-life Dementia Research Articles

Cell-Specific Gene Expressions Underlie Selective White Matter Loss Vulnerability in Mild Traumatic Brain Injury.

Traumatic brain injury (TBI), a risk factor for later-life dementia, leads to salient brain atrophy, particularly in the white matter. It is not clear how white matter atrophy progresses or why some brain regions are damaged while others are spared. We hypothesized that spatial variations of cell-specific gene expression contributed to the selective white matter loss vulnerability following mild TBI (mTBI). Gene expression data were sourced from the publicly available Allen Human Brain Atlas, which comprises microarray data spanning nearly the entire brain, derived from six neurologically normal adult donors. A total of 100 patients with acute stage (within 7 days post-injury) mTBI were enrolled. Of these, 60 patients were followed up at 3 months post-injury and 37 were followed up at 6-12 months post-injury. In addition, 59 healthy controls (HCs), matched for age, gender, and education, were included for comparative analysis. White matter volume changes were analyzed at both the acute stage, 3 months, and 6-12 months follow-up in mTBI patients compared with HCs. Patients with mTBI exhibited significant white matter atrophy in the frontal, parietal, and temporal cortices at 3 months post-injury, which even persisted at 6-12 months follow-up. In addition, mTBI patients with cognitive deficits showed more severe brain atrophy compared with those without cognitive deficits. Crucially, the gene expression marking endothelial cells and S1 pyramidal neurons were associated with increased brain atrophy, whereas the gene expression marking microglia and CA1 pyramidal neurons were associated with decreased brain atrophy in mTBI patients at 3 months post-injury. Microglia and endothelial cells can explain 23.6% of regional variations in the white matter atrophy. These findings suggested that modulating cellular activation, especially by promoting microglial activation at 3 months post-injury, might be a promising approach to prevent white matter atrophy, enhance cognitive outcomes, and reduce the risk of later-life dementia.

Dietary salt, vascular dysfunction, and cognitive impairment.

Excessive salt consumption is a major health problem worldwide leading to serious cardiovascular events including hypertension, heart disease and stroke. Additionally, high salt diet has been increasingly associated with cognitive impairment in animal models and late-life dementia in humans. High salt consumption is harmful for the cerebral vasculature, disrupts blood supply to the brain and could contribute to Alzheimer's disease pathology. Although animal models have advanced our understanding of the cellular and molecular mechanisms, additional studies are needed to further elucidate the effects of salt on brain function. Furthermore, the association between excessive salt intake and cognitive impairment will have to be more thoroughly investigated in humans. Since the harmful effects of salt on the brain are independent by its effect on blood pressure, in this review, I will specifically discuss the evidence, available in experimental models and humans, on the effects of salt on vascular and cognitive function in the absence of changes in blood pressure. Given the strong effects of salt on the function of immune cells, I will also discuss the evidence linking salt consumption to gut immunity dysregulation with particular attention to the ability of salt to disrupt T-helper 17 (Th17) cells homeostasis. Lastly, I will briefly discuss the data implicating IL-17A, the major cytokine produced by Th17 cells, in vascular dysfunction and cognitive impairment.

Is Common Denominator Lead to Misdiagnosis of Dementia and Late-Life Depression

Significant cognitive impairments are found in late life depression. This situation brings to mind the question of what are the common and distinct mechanisms of late life depression and dementia. In this review, neural and psychological mechanism are discussed within the scope of denominator and hallmark for both disorders. It is searched several databases e.g. MEDLINE, Web of Science Core Collection from 1974 to 2024 by using variant terms for the focal epilepsy subtypes and social cognition constructs. The pathology of dementia was correlated with late-life depression Studies indicate that depression may be an etiological factor for dementia as well as an increased risk. Also, many life-related stressors can lead to results such as increased reactive oxygen species, inflammatory responses, suppression of neurogenesis, and apical dendritic atrophy and altered functional connectivity in the medial prefrontal cortex. Based on this, it is possible to say that psychological stress factors increase the incidence of the disease in the development of dementia, just like in depression. Late depression should not be labeled as dementia because of they share similar symptoms and should be evaluated clinically correct so that it is not misdiagnosed. Besides, it is substantial to comprehend the relationship between the aging population and the risk of depression and dementia for current and future studies, especially in terms of prevention and treatment.

The association between BMI and cognition in India: data from the Longitudinal Aging Study in India (LASI)

BackgroundHigh body-mass index (BMI) is an established risk factor for late-life cognitive impairment and dementia, but most evidence comes from high-income contexts. Existing evidence from cross-sectional data in low- and middle-income settings is inconsistent, and many studies do not adequately address potential sources of bias.MethodsWe used data from Wave 1 of the Longitudinal Aging Study in India (LASI) (analytic N = 56,753) to estimate the association between BMI categories and cognitive functioning among older adults aged 45 + years using survey-weighted linear regression models stratified by gender and controlling for potential confounders including demographic factors, socio-economic status (SES) characteristics, and health-related behaviors. To probe potential sources of bias, including residual confounding and reverse causation, we used weighting and trimming methods, sample restriction, and explored effect modification.ResultsIn fully adjusted models, relative to normal BMI underweight BMI was associated with lower cognitive scores (Men: -0.16 SD difference, 95% CI -0.18, -0.13; Women: -0.12 SD, -0.15, -0.10). Overweight and obesity were associated with higher cognitive scores in both men (overweight: 0.09; 0.07, 0.12, obese: 0.10; 0.05, 0.15) and women (overweight: 0.09; 0.07–0.12, obese: 0.12; 0.08–0.15). Estimates were similar after weighting and trimming but were attenuated after excluding those with low cognition (≥1 SD below the mean relative to those with similar demographic characteristics). Positive associations between overweight and obese BMI and cognition were attenuated or null in those living in urban settings and those with higher levels of educational attainment.ConclusionsUnderweight BMI is a risk factor for poor cognitive outcomes in adults 45 years and older and may be indicative of poor nutritional status and life-course disadvantage in India. In tandem with existing literature, supplemental analyses and effect modification results indicate that unmeasured confounding and reverse causation may explain the observed positive associations between overweight and obese BMI and cognitive functioning from cross-sectional studies in low- and middle-income settings. Future data with longitudinal follow-up will be helpful to further disentangle biases.

Circulating IL-17A and Executive Function in Middle-Aged Adults with and without Type 2 Diabetes

Abstract Background Midlife cardiovascular risk factors, such as Type 2 Diabetes Mellitus (T2DM) and obesity, are associated with a greater risk of cognitive impairment and dementia in later life, with altered peripheral inflammation postulated as a crucial mechanistic link. Yet there is a significant gap in knowledge regarding when pathogenic alterations to these systemic inflammatory responses change during the early stages of cognitive dysfunction prior to overt disease development. To assess the earliest possible signs of this link, we recruited a cohort of middle-aged cognitively-unimpaired individuals with and without uncomplicated T2DM. Methods A comprehensive neuropsychological assessment was performed at baseline and at 4-year follow-up. A panel of ten serum chemokines and cytokines were measured at both time-points using high-sensitivity assays (Eotaxin, MCP-1, MIP-1β, CXCL-10, IL-6, IL-10, IL12p70, IL-17A, IFN-γ and TNF-α). Results Overall, 136 individuals were recruited including 90 with uncomplicated midlife T2DM (age 52.6 ± 8.3; 47% female) and 46 without (age 52.9 ± 8.03; 61% female). Cognitive trajectories were stable over time and did not differ by T2DM status. Yet on cross-sectional analyses, we observed consistent evidence across timepoints between greater circulating IL-17A and poorer performance on tests of executive function/attention (β: -0.21; -0.40, -0.02, p = 0.03 at baseline; β: -0.26; -0.46, -0.05, p = 0.02 at follow-up) as well as poorer reaction time (β: 0.34; 0.12, 0.56, p = 0.003 at follow-up). These persisted on covariate adjustment and did not differ by T2DM status. Conclusion We provide exploratory evidence that greater serum IL-17A levels are associated with poorer executive function in midlife. Long-term follow-up of this and other cohorts will further elucidate this relationship to provide further mechanistic insights and potentially identify individuals at greatest risk for later cognitive decline.

Dietary patterns and cardiorespiratory fitness in midlife and subsequent all-cause dementia: findings from the Cooper Center Longitudinal Study

BackgroundIdentifying lifestyle factors that independently or jointly lower dementia risk is a public health priority given the limited treatment options available to patients. In this cohort study, we examined the associations between Mediterranean or Dietary Approaches to Stop Hypertension (DASH) diet adherence and cardiorespiratory fitness (CRF) with later-life dementia, and assessed whether the associations between dietary pattern and dementia are modified by CRF.MethodsData are from 9,095 adults seeking preventive care at the Cooper Clinic (1987–1999) who completed a 3-day dietary record and a maximal exercise test. Alzheimer’s disease and related disorders or senile dementia (i.e., all-cause dementia) was identified from Medicare administrative claims (1999–2019). Illness-death models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between Mediterranean or DASH diet adherence (primary exposure), CRF (secondary exposure), and all-cause dementia, adjusted for demographic and clinical factors. An interaction term was included between diet score and CRF to assess effect modification by CRF.ResultsThe mean age at baseline was 50.6 (standard deviation [SD]: 8.4) years, and a majority of the study sample were men (77.5%) and White (96.4%). 1449 cases of all-cause dementia were identified over a mean follow-up of 9.2 (SD: 5.8) years. Neither Mediterranean nor DASH diet adherence was associated with dementia risk in fully adjusted models (HR per SD of Mediterranean diet score: 1.00, 95% CI: 0.94, 1.05; HR per SD of DASH diet score: 1.02, 95% CI: 0.96, 1.08). However, participants with higher CRF had a decreased hazard of dementia (HR, per metabolic equivalent of task [MET] increase, Mediterranean model: 0.95, 95% CI: 0.92, 0.98; HR, per MET increase, DASH model: 0.96, 95% CI: 0.92, 0.97). No effect modification by CRF was observed in the association between diet and dementia.ConclusionsIn this sample of apparently healthy middle-aged adults seeking preventive care, higher CRF at midlife was associated with a lower risk of all-cause dementia, though adherence to a Mediterranean or DASH diet was not, and CRF did not modify the diet-dementia association. CRF should be emphasized in multimodal interventions for dementia prevention and investigated among diverse samples.

Unraveling the role of the renin-angiotensin system in severe mental illnesses: An insight into psychopathology and cognitive deficits

Severe mental illnesses (SMI), especially schizophrenia and bipolar disorder (BD), are associated with significant distress to patients, reduced life expectancy and a higher cost of care. There is growing evidence that SMI may increase the risk of dementia in later life, posing an additional challenge in the management of these patients. SMI present a complex and highly heterogeneous pathophysiology, which has hampered the understanding of its underlying pathological mechanisms and limited the success of the available therapies. Despite the advances in therapeutic approaches in psychiatry over the past decades, treatment resistance is still a common problem in clinical practice, highlighting the urgent need for novel therapeutic targets for SMI. The discovery that renin-angiotensin system (RAS) components are expressed in the central nervous system opened new possibilities for investigating a potential role for this system in the neurobiology of SMI. The safety and efficacy of AT1 receptor blockers and angiotensin-converting enzyme inhibitors in cardiovascular and metabolic diseases, common medical comorbidities among SMI patients and well-known risk factors for dementia, suggest the potential scalability of these strategies for the management of SMI outcomes including the risk of subsequent dementia. This review aimed to discuss the available evidence from animal models and human studies of the potential involvement of RAS in the pathophysiology of SMI. We also provided a reflection on drawbacks and perspectives that can foster the development of new related therapeutic strategies.

Addressing Practice Affects in Population-based Studies of Trends in Late-Life Dementia and Cognitive Impairment.

Addressing Practice Affects in Population-based Studies of Trends in Late-Life Dementia and Cognitive Impairment.

Leptin bioavailability and markers of brain atrophy and vascular injury in the middle age.

We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle-aged adults. We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB-R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme-linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. Higher sOB-R was associated with lower fractional anisotropy (FA, β=-0.114±0.02, p<0.001), and higher free water (FW, β=0.091±0.022, p<0.001) and peak-width skeletonized mean diffusivity (PSMD, β=0.078±0.021, p<0.001). Correspondingly, higher FLI was associated with higher FA (β=0.115±0.027, p<0.001) and lower FW (β=-0.096±0.029, p=0.001) and PSMD (β=-0.085±0.028, p=0.002). Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle-aged adults, supporting the putative neuroprotective role of leptin in late-life dementia risk. Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

Proteomic analyses reveal plasma EFEMP1 and CXCL12 as biomarkers and determinants of neurodegeneration.

Plasma proteomic analyses of unique brain atrophy patterns may illuminate peripheral drivers of neurodegeneration and identify novel biomarkers for predicting clinically relevant outcomes. We identified proteomic signatures associated with machine learning-derived aging- and Alzheimer's disease (AD) -related brain atrophy patterns in the Baltimore Longitudinal Study of Aging (n=815). Using data from five cohorts, we examined whether candidate proteins were associated with AD endophenotypes and long-term dementia risk. Plasma proteins associated with distinct patterns of age- and AD-related atrophy were also associated with plasma/cerebrospinal fluid (CSF) AD biomarkers, cognition, AD risk, as well as mid-life (20-year) and late-life (8-year) dementia risk. EFEMP1 and CXCL12 showed the most consistent associations across cohorts and were mechanistically implicated as determinants of brain structure using genetic methods, including Mendelian randomization. Our findings reveal plasma proteomic signatures of unique aging- and AD-related brain atrophy patterns and implicate EFEMP1 and CXCL12 as important molecular drivers of neurodegeneration. Plasma proteomic signatures are associated with unique patterns of brain atrophy. Brain atrophy-related proteins predict clinically relevant outcomes across cohorts. Genetic variation underlying plasma EFEMP1 and CXCL12 influences brain structure. EFEMP1 and CXCL12 may be important molecular drivers of neurodegeneration.

Critical menarche age for late-life dementia and the role of education and socioeconomic status

ABSTRACT Estrogen exposure during menstrual years has been associated with late-life neuroprotection. We explored the presence of an age-sensitive menarche window for cognition in old age and the impact of socioeconomic status and education. We compared neuropsychological performance of 1082 older women [MeanAGE = 72.69 (5.48)] with menarche in childhood, early-, mid-, and late-adolescence and dementia prevalence, severity, and type, including the effects of education and socioeconomic status. Adjusting for covariates, menarche at 11–14 years of age was associated with better memory, executive and global cognitive functioning in old age, and stronger positive effects of education and socioeconomic status on cognition than those with menarche at 15–17 years. We found a critical age window for the neuroprotective effects of estrogens during early adolescence, putting women with later menarche at higher risk for cognitive decline. Effects of socioeconomic status and education in adulthood should be a focus of future research.

The Effect of Temporal Persistence of Loneliness on Dementia: A Longitudinal Analysis From the Hunter Community Study.

Loneliness is common and becoming a public health concern. Although there is the clear evidence of the variable effect of temporal differences in loneliness (transient/situational and persistent/chronic) on health, their effect on dementia risk is unclear. This study aims to assess the effect of transient/situational and persistent/chronic loneliness on dementia risk. Participants aged 55years and older from the Hunter Community Study were recruited. Loneliness was measured using a single item measure. Dementia was defined as per International Classification of Disease-10 (ICD 10) codes. The Fine-Gray subdistribution hazard model was performed to calculate dementia risk. Of 1968 total participants with mean age of 66years, (3%) 57 developed dementia and (7%) 135 died over the mean follow up of 10years. Both persistent/chronic and transient/situational loneliness significantly increased the risk of all cause dementia in adjusted models (HR 2.74, 95% CI 1.11-6.88, p 0.03 and HR 2.35, 95% CI 1.21-4.55, p 0.01 respectively) with mean time to event of 9.7years. Feeling lonely below the age of 70years elevated the risk of dementia in later life (HR 4.01, 95% CI 1.40-11.50, p 0.01). Loneliness (both persistent/chronic and transient/situational) was associated with increased risk of all cause dementia, especially if loneliness was experienced before the age of 70years. These results suggest that promoting coping strategies for loneliness especially in persons 70years and younger may play a role in preventing dementia.

Physical activity initiated from midlife on risk of dementia and cognitive impairment: The Health and Retirement Study.

Physical activity is associated with lower risk of dementia and cognitive impairment, but existing randomized controlled trials have shown conflicting results. As cognitive decline occurs decades before the onset of dementia, physical activity interventions initiated in late life may have missed the potential window for prevention. An ideal trial of physical activity initiated from midlife and lasts till incident dementia and cognitive impairment in late life is not feasible. We aimed to estimate the effectiveness of a hypothetical physical activity intervention initiated from midlife on reducing dementia and cognitive impairment by emulating target trials using observational data. The Health and Retirement Study was used to emulate target trials among noninstitutionalized participants aged 45 to 65 years with normal cognition who were physically inactive in the previous 2 years. Cognitive status was determined based on Langa-Weir classification of cognitive function (including immediate and delayed word recall tests, serial sevens subtraction, counting backward). Individuals were categorized as initiating physical activity or not, based on the self-reported physical activity. Intention-to-treat and per-protocol analysis were conducted with pooled logistic regression models with inverse-probability of treatment and censoring weights to estimate risk ratios (RRs), and 95% confidence intervals (95% CIs) were calculated with 200 sets of bootstrapping. Among 1505 participants (average age 57.6 ± 4.8 years, 67% women, 76.5% White), 72 cases of dementia and 409 cases of cognitive impairment occurred. After 12 years of follow-up, physical activity reduced dementia (RR = 0.70, 95% CI: 0.43, 0.99) for intention-to-treat analysis, and reduced dementia (RR = 0.51, 95% CI: 0.19, 0.99) and cognitive impairment (RR = 0.77, 95% CI: 0.61, 0.92) for per-protocol analysis. No significant reduction was found among older adults. Physical activity initiated during midlife may reduce dementia and cognitive impairment in late life, which highlights the importance of preventing cognitive outcomes at an earlier stage of life.

Changes in Alzheimer Disease Blood Biomarkers and Associations With Incident All-Cause Dementia

Plasma biomarkers show promise for identifying Alzheimer disease (AD) neuropathology and neurodegeneration, but additional examination among diverse populations and throughout the life course is needed. To assess temporal plasma biomarker changes and their association with all-cause dementia, overall and among subgroups of community-dwelling adults. In 1525 participants from the US-based Atherosclerosis Risk in Communities (ARIC) study, plasma biomarkers were measured using stored specimens collected in midlife (1993-1995, mean age 58.3 years) and late life (2011-2013, mean age 76.0 years; followed up to 2016-2019, mean age 80.7 years). Midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) were assessed for their associations with change in plasma biomarkers over time. The associations of biomarkers with incident all-cause dementia were evaluated in a subpopulation (n = 1339) who were dementia-free in 2011-2013 and had biomarker measurements in 1993-1995 and 2011-2013. Plasma biomarkers of amyloid-β 42 to amyloid-β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Quanterix Simoa platform. Incident all-cause dementia was ascertained from January 1, 2012, through December 31, 2019, from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance. Among 1525 participants (mean age, 58.3 [SD, 5.1] years), 914 participants (59.9%) were women, and 394 participants (25.8%) were Black. A total of 252 participants (16.5%) developed dementia. Decreasing Aβ42:Aβ40 ratio and increasing p-tau181, NfL, and GFAP were observed from midlife to late life, with more rapid biomarker changes among participants carrying the apolipoprotein E epsilon 4 (APOEε4) allele. Midlife hypertension was associated with a 0.15-SD faster NfL increase and a 0.08-SD faster GFAP increase per decade; estimates for midlife diabetes were a 0.11-SD faster for NfL and 0.15-SD faster for GFAP. Only AD-specific biomarkers in midlife demonstrated long-term associations with late-life dementia (hazard ratio per SD lower Aβ42:Aβ40 ratio, 1.11; 95% CI, 1.02-1.21; per SD higher p-tau181, 1.15; 95% CI, 1.06-1.25). All plasma biomarkers in late life had statistically significant associations with late-life dementia, with NfL demonstrating the largest association (1.92; 95% CI, 1.72-2.14). Plasma biomarkers of AD neuropathology, neuronal injury, and astrogliosis increase with age and are associated with known dementia risk factors. AD-specific biomarkers' association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia.

Vascular cognitive impairment: Advances in clinical research and management.

Vascular cognitive impairment (VCI) encompasses a wide spectrum of cognitive disorders, ranging from mild cognitive impairment to vascular dementia. Its diagnosis relies on thorough clinical evaluations and neuroimaging. VCI predominately arises from vascular risk factors (VRFs) and cerebrovascular disease, either independently or in conjunction with neurodegeneration. Growing evidence underscores the prevalence of VRFs, highlighting their potential for early prediction of cognitive impairment and dementia in later life. The precise mechanisms linking vascular pathologies to cognitive deficits remain elusive. Chronic cerebrovascular pathology is the most common neuropathological feature of VCI, often interacting synergistically with neurodegenerative processes. Current research efforts are focused on developing and validating reliable biomarkers to unravel the etiology of vascular brain changes in VCI. The collaborative integration of these biomarkers into clinical practice, alongside routine incorporation into neuropathological assessments, presents a promising strategy for predicting and stratifying VCI. The cornerstone of VCI prevention remains the control of VRFs, which includes multi-domain lifestyle modifications. Identifying appropriate pharmacological approaches is also of paramount importance. In this review, we synthesize recent advancements in the field of VCI, including its definition, determinants of vascular risk, pathophysiology, neuroimaging and fluid-correlated biomarkers, predictive methodologies, and current intervention strategies. Increasingly evident is the notion that more rigorous research for VCI, which arises from a complex interplay of physiological events, is still needed to pave the way for better clinical outcomes and enhanced quality of life for affected individuals.

Adverse Lipid Profiles Are Associated with Lower Dementia Risk in Older People

ObjectiveMidlife dyslipidemia is associated with higher risk of dementia in late-life dementia, but the impact of late-life dyslipidemia on dementia risk is uncertain. This may be due to the large heterogeneity in cholesterol measures and study designs employed. We used detailed data from a large prospective cohort of older persons to comprehensively assess the relation between a broad range of cholesterol measures and incident dementia, addressing potential biases, confounders, and modifiers. DesignPost hoc observational analysis based on data from a dementia prevention trial (PreDIVA).Setting and participants: 3392 community-dwelling individuals, without dementia, aged 70-78 years at baseline (recruited between June 2006 and March 2009). MethodsTotal cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and apolipoprotein A1 and B were assessed. Over a median of 6.7 years’ follow-up, dementia was established by clinical diagnosis confirmed by independent outcome adjudication. Hazard ratios (HRs) for dementia and mortality were calculated using Cox regression. ResultsDementia occurred in 231 (7%) participants. One-SD increase in LDL/HDL conveyed a 19% (P = .01) lower dementia risk and a 10% (P = .02) lower risk of dementia/mortality combined. This was independent of age, cardiovascular risk factors, cognitive function, apolipoprotein E genotype, and cholesterol-lowering drugs (CLD). This association was not influenced by the competing risk of mortality. Consistent and significant interactions suggested these associations were predominant in individuals with low body mass index (BMI) and higher education. Conclusions and implicationsDyslipidemia in older individuals was associated with a lower risk of dementia. Low BMI and higher education level mitigate poor outcomes associated with dyslipidemia. These findings suggest that a different approach may be appropriate for interpreting lipid profiles that are conventionally considered adverse in older adults. Such an approach may aid predicting dementia risk and designing intervention studies aimed at reducing dementia risk in older populations.

Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression

While immune function is known to play a mechanistic role in Alzheimer’s disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-β (Aβ) progression – a central feature of AD – remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aβ accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aβ progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aβ-positive status in the Atherosclerosis Risk in Communities (ARIC) study. Genetic variation that influenced plasma levels of CAT, CD36 and KRT19 predicted rates of Aβ accumulation, including causal relationships with Aβ PET levels identified with two-sample Mendelian randomization. In addition to associations with tau PET and plasma AD biomarker changes, as well as expression patterns in human microglia subtypes and neurovascular cells in AD brain tissue, we showed that 31 % of candidate proteins were related to mid-life (20-year) or late-life (8-year) dementia risk in ARIC. Our findings reveal plasma proteins associated with longitudinal Aβ accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology.

Subjective hearing and memory problems are associated with dementia and cognition in later life.

Subjective hearing and memory problems are detectable earlier than objective measures of sensory loss and cognitive decline, which are known to be related to an increased risk of dementia in later life. Using a population-representative cohort of 6006 individuals (aged 50-75) we examined whether participants who self-reported hearing and short-term memory issues showed greater rates of dementia within 17 years of follow-up. A sub-cohort was tested for audiometric threshold and cognition after 14 years. Hearing and memory problems were associated with a greater risk of dementia (hazard ratios [HRs]=1.42 [95% confidence interval: 1.11-1.81], 1.57 [1.30-1.90]), and poorer cognition 14 years later. The risk was greatest in those reporting both problems (HR=1.99 [1.42-2.80]). At follow-up, the level of hearing loss was associated with lower cognitive scores. Self-reports of hearing and short-term memory problems are associated with poorer cognitive performance and a greater risk of dementia. Subjective assessments may have predictive power over more than a decade. In a sample of older adults subjective hearing and memory problems were associated with dementia risk.Cross-sectionally, the audiometric screening threshold was associated with cognitive test scores.Subjective sensory and memory loss questions are easy to implement and show good predictive power.

What's New in Dementia Risk Prediction Modelling? An Updated Systematic Review.

Identifying individuals at high risk of dementia is critical to optimized clinical care, formulating effective preventative strategies, and determining eligibility for clinical trials. Since our previous systematic reviews in 2010 and 2015, there has been a surge in dementia risk prediction modelling. The aim of this study was to update our previous reviews to explore, and critically review, new developments in dementia risk modelling. MEDLINE, Embase, Scopus, and Web of Science were searched from March 2014 to June 2022. Studies were included if they were population- or community-based cohorts (including electronic health record data), had developed a model for predicting late-life incident dementia, and included model performance indices such as discrimination, calibration, or external validation. In total, 9,209 articles were identified from the electronic search, of which 74 met the inclusion criteria. We found a substantial increase in the number of new models published from 2014 (>50 new models), including an increase in the number of models developed using machine learning. Over 450 unique predictor (component) variables have been tested. Nineteen studies (26%) undertook external validation of newly developed or existing models, with mixed results. For the first time, models have also been developed in low- and middle-income countries (LMICs) and others validated in racial and ethnic minority groups. The literature on dementia risk prediction modelling is rapidly evolving with new analytical developments and testing in LMICs. However, it is still challenging to make recommendations about which one model is the most suitable for routine use in a clinical setting. There is an urgent need to develop a suitable, robust, validated risk prediction model in the general population that can be widely implemented in clinical practice to improve dementia prevention.

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

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. 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. 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. 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. UK Research and Innovation (Medical Research Council).