Given the projected trends in population ageing and population growth, the number of people with dementia is expected to increase. In addition, strong evidence has emerged supporting the importance of potentially modifiable risk factors for dementia. Characterising the distribution and magnitude of anticipated growth is crucial for public health planning and resource prioritisation. This study aimed to improve on previous forecasts of dementia prevalence by producing country-level estimates and incorporating information on selected risk factors.We forecasted the prevalence of dementia attributable to the three dementia risk factors included in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 (high body-mass index, high fasting plasma glucose, and smoking) from 2019 to 2050, using relative risks and forecasted risk factor prevalence to predict GBD risk-attributable prevalence in 2050 globally and by world region and country. Using linear regression models with education included as an additional predictor, we then forecasted the prevalence of dementia not attributable to GBD risks. To assess the relative contribution of future trends in GBD risk factors, education, population growth, and population ageing, we did a decomposition analysis.We estimated that the number of people with dementia would increase from 57·4 (95% uncertainty interval 50·4-65·1) million cases globally in 2019 to 152·8 (130·8-175·9) million cases in 2050. Despite large increases in the projected number of people living with dementia, age-standardised both-sex prevalence remained stable between 2019 and 2050 (global percentage change of 0·1% [-7·5 to 10·8]). We estimated that there were more women with dementia than men with dementia globally in 2019 (female-to-male ratio of 1·69 [1·64-1·73]), and we expect this pattern to continue to 2050 (female-to-male ratio of 1·67 [1·52-1·85]). There was geographical heterogeneity in the projected increases across countries and regions, with the smallest percentage changes in the number of projected dementia cases in high-income Asia Pacific (53% [41-67]) and western Europe (74% [58-90]), and the largest in north Africa and the Middle East (367% [329-403]) and eastern sub-Saharan Africa (357% [323-395]). Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia.Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group. Country-level estimates can be used to inform national planning efforts and decisions. Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia.Bill & Melinda Gates Foundation and Gates Ventures.Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Midlife vascular risk factors are associated with an elevated risk of dementia. However, the total contribution of vascular risk factors in midlife and late life with incident dementia is uncertain.To quantify the proportion of incident dementia attributable to modifiable vascular risk factors measured in midlife and late life and to examine differences by apolipoprotein ε4 genotype, self-reported race, and sex.This was a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study using 33 years of follow-up (1987-2020). The setting included ARIC field centers (Jackson, Mississippi; Forsyth County, North Carolina; Minneapolis suburbs, Minnesota; Washington County, Maryland). Study baseline in Black and White participants with complete exposure and covariate data was set by age at risk factor measurement (45-54 years, 55-64 years, and 65-74 years). Data were analyzed from August 2023 to December 2024.Hypertension (systolic blood pressure [BP] ≥130 mm Hg, diastolic BP ≥80 mm Hg, or use of medication for BP), diabetes (fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, self-reported physician's diagnosis, or use of any diabetes medication), and current smoking (self-reported).Incident dementia. Population attributable fractions were estimated by age 80 years, and separately after 80 years, from having at least 1 vascular risk factor by age at risk factor measurement.A total of 7731 participants were included in analysis of risk factors measured at age 45 to 54 years (4494 female [58%]; 2207 Black [29%]; 5524 White [71%]), 12 274 contributed to analysis of risk factors measured at age 55 to 64 years (6698 female [55%]; 2886 Black [24%]; 9388 White [76%]), and 6787 contributed to analysis of risk factors measured at age 65 to 74 years (3764 female [56%], 1375 Black [20%]; 5412 White [80%]). There were 801, 995, and 422 dementia cases by 80 years, respectively. The fraction of dementia by 80 years attributable to at least 1 vascular factor at age 45 to 54 years was 21.8% (95% CI, 14.3%-29.3%), at 55 to 64 years was 26.4% (95% CI, 19.1%-33.6%), and at 65 to 74 years was 44.0% (95% CI, 30.9%-57.2%). Attributable fractions for these factors were higher in apolipoprotein ε4 noncarriers at age 55 years and older (range, 33.3%-61.4%), Black individuals at age 45 years and older (range, 25.5%-52.9%), and female individuals at age 55 years and older (range, 29.2%-51.3%). Only 2% to 8% of dementia cases after 80 years were attributable to these factors.Results of this cohort study suggest that between 22% and 44% of incident dementia cases by 80 years in the ARIC study were attributed to midlife and late-life vascular risk factors. Assuming causal relationships, maintaining optimal vascular health across the life course could mitigate a sizeable proportion of dementia risk by 80 years.

Controversies persist regarding the association between blood pressure (BP) and the risks of cognitive impairment and dementia due to inconsistent definitions of BP exposure and varying population characteristics. Here, we searched PubMed and performed a meta-analysis of the influence of BP exposure on the risks of cognitive disorders in prospective studies. Dose-response analyses were performed to illustrate the existence of linear/nonlinear relationships. The credibility of each meta-analysis was evaluated according to the risk of bias, inconsistency, and imprecision. Of the 31 628 citations, 209 were included in our systematic review, among which 136 were eligible for the meta-analysis. Overall, stronger associations were found in midlife than late-life. Moderate-quality evidence indicated that midlife hypertension was related to a 1.19- to 1.55-fold excess risk of cognitive disorders. Dose-response analyses of 5 studies indicated that midlife systolic BP >130 mm Hg was associated with an increased risk of cognitive disorders. With regard to BP exposure in late-life, high systolic BP, low diastolic BP, excessive BP variability, and orthostatic hypotension were all associated with an increased dementia risk. Encouragingly, the use of antihypertensive medications exhibited a 21% reduction in dementia risk. The U-shaped dose-response curve indicated that the protective window of diastolic BP level was between 90 and 100 mm Hg for low risk of Alzheimer disease. The relationships between BP variables and cognitive disorders are age- and BP type-dependent. Antihypertensive medications were associated with a reduced risk of dementia. However, the optimal dose, duration, and type for preventing cognitive disorders warrant further investigation.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. The central underlying mechanisms of cardiovascular diseases are vascular aging and associated arterial stiffness. Arterial stiffness is characterized by structural (e.g., tunica media calcification, alterations in vascular smooth muscle cells, and fibrosis) and functional (e.g., loss of Windkessel function, elevated pulse pressure, and development of isolated systolic hypertension) vascular changes that cause microvascular dysfunction and end-organ damage (e.g., heart failure, vascular dementia, hypertensive retinopathy, and chronic kidney disease). Current research indicates that arterial stiffness is an independent risk factor for cardiovascular diseases and represents a potential target for personalized prevention and therapeutic approaches. In this review, we summarize the pathophysiological mechanisms of vascular aging and arterial stiffness, outline the resulting end-organ damage, present different methods for the measurement of arterial stiffness, highlight the potential role of prevention and therapy, and provide future perspectives for arterial stiffness research. The purpose of this review is to provide a state-of-the-art interdisciplinary and translational approach to arterial stiffness, highlighting unique pathophysiological mechanisms (e.g., perivascular adipose tissue, extracellular vesicles), clinical relevance, and future directions.

Pulse pressure and pulse wave velocity, markers of arterial stiffness, have been associated with stroke, dementia, and lowered levels of cognitive function. Here we examine longitudinal relations of pulse pressure and pulse wave velocity to multiple domains of cognitive function among nondemented, stroke-free persons. Up to 1749 participants from the Baltimore Longitudinal Study of Aging completed tests of verbal and nonverbal memory, attention, perceptuo-motor speed, confrontation naming, executive functions, and cognitive screening measures, as well as concurrent sphygmomanometric assessment of blood pressure (for derivation of pulse pressure) on 1 to 8 occasions over 14 years. A subset of <or=582 participants also underwent a single baseline assessment of pulse wave velocity and cognitive assessment on 1 to 6 occasions over 11 years. Results of mixed-effects regression models revealed a prospective decline on tests of verbal learning, nonverbal memory, working memory, and a cognitive screening measure among those with increasing levels of pulse pressure (P<0.05). Persons with higher baseline pulse wave velocity also exhibited prospective decline on tests of verbal learning and delayed recall, nonverbal memory, and a cognitive screening measure (P<0.05). Markers of arterial stiffness are associated prospectively with cognitive decline before dementia. Aggressive treatment of risk factors associated with greater arterial stiffness may help preserve cognitive function with individuals' increasing age.

Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear.To determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (≥80 years of age), and examine the relationship between pulse pressure and progression to dementia.In this retrospective cohort study, 877 participants without dementia (55-91 years of age) from the Alzheimer's Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and β-amyloid 1-42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months tracked progression to dementia.Regression and analysis of covariance analyses investigated relationships between pulse pressure and distinct cerebral spinal fluid biomarker profiles. Very old participants (80 years or older) were compared with younger participants (55-79 years of age) on clinical measures and pulse pressure × age group interactions were investigated. Survival analysis examined the effect of baseline pulse pressure on progression to dementia. Covariates were age, sex, apolipoprotein E genotype, body mass index, vascular risk factors, and antihypertensive medication use.Individuals with a P-tau-positive biomarker profile exhibited mean (SD) elevated pulse pressure regardless of age (62.0 [15.6] mm Hg for a P-tau-positive biomarker vs 57.4 [14.0] mm Hg for P-tau-negative biomarker; P = .04). In very old participants, a further increase in pulse pressure was observed in those exhibiting both P-tau elevation and β-amyloid 1-42 reduction vs either biomarkers alone (69.7 [16.0] mm Hg for both positive biomarkers vs 63.18 [13.0] mm Hg for P-tau alone vs 60.1 [16.4] mm Hg for β-amyloid 1-42 alone vs 56.6 [14.5] mm Hg for negative biomarkers; P =.003). Those with higher baseline pulse pressure progressed to dementia more rapidly (95% CI, 1.000-1.048; P =.05; hazard ratio = 1.024). Systolic pressure exhibited similar relationships with Alzheimer disease biomarkers and progression to dementia in the very old subgroup (P <.05) but showed no associations in the young old subgroup (P >.10). Diastolic pressure was reduced in young old participants with isolated phosphorylated tau elevation (P =.04).Pulse pressure, an index of vascular aging, was associated with neurodegenerative change prior to the onset of dementia across a broad age range. Among those with more advanced age, higher pulse pressure was also associated with cerebral amyloidosis in the presence of neurodegeneration and more rapid progression to dementia. Diastolic contributions to these biomarker associations were limited to young old participants whereas systolic contributions were found only in very old participants.

High blood pressure (BP) has been associated with increased risk of dementia. Concerns have been raised about lowering BP too far in the very elderly and thereby increasing risk. There is some evidence to suggest a potential 'J'-shaped relationship between DBP and risk of cognitive impairment. This was investigated using data from the HYpertension in the Very Elderly Trial (HYVET).HYVET was a double-blind, placebo-controlled trial of antihypertensives in patients aged at least 80 years with an untreated SBP of 160-199 mmHg. Active medication was indapamide sustained release 1.5 mg+/- perindopril 2-4 mg to reach goal pressure of less than 150/80 mmHg. Incident dementia was a secondary endpoint and was not significantly different between the two treatment groups. The relationship between pressure and incident dementia was assessed using Cox proportional hazards regression with BP entered as either a discrete (quartile analysis) or continuous predictor variable. Achieved BP was calculated as the mean of all pressures from the 9 month visit onwards.During a mean follow-up of 2.2 years 263 incident cases of dementia were diagnosed. After adjustment for various covariates, baseline DBP was inversely related to incident dementia (P=0.0064). Achieved DBP did not predict later dementia in the placebo group (P=0.43), but showed a U-shaped relationship in the active treatment group (P=0.0195). The relationship between incident dementia and DBP did however not differ significantly between the placebo and active treatment groups (P=0.38). SBP was not associated with incident dementia, at baseline (P=0.62) or during follow-up (placebo group P=0.13, active group P=0.36). Wider achieved pulse pressure (PP) was associated with increased risk of dementia in both treatment groups (placebo P=0.032, active P=0.0046). The same tendency was observed for baseline PP (P=0.095).Wider PP may possibly indicate an increased risk for dementia. Active treatment may act to change the shape of the relationship between DBP and dementia. Future studies need to focus on exploring the ideal goal pressure for this age group.

\n \n Background and Purpose—\n \n Previous studies have shown that midlife systolic blood pressure (SBP) predicts late-life cognitive decline and incident dementia. This study explores whether this association is attributable to the pulsatile, ie, pulse pressure (PP), or the nonpulsatile component of blood pressure (BP).\n

The relation of blood pressure with cognitive function and dementia has, in recent years, received much attention from epidemiological research. Some cross-sectional studies have shown an inverse association between blood pressure and the prevalence of dementia and Alzheimer's disease, whereas longitudinal studies yield mixed results that largely depend on the age at which blood pressure is measured and the time interval between blood pressure and outcome assessments. Some studies suggest that midlife high blood pressure is a risk factor for late-life cognitive impairment and dementia, and that low diastolic pressure and very high systolic pressure in older adults may be associated with subsequent development of dementia and Alzheimer's disease. Observational studies and randomised clinical trials provide limited evidence for a protective effect of antihypertensive therapy against dementia and stroke-related cognitive decline. Atherosclerosis resulting from long-standing hypertension, and cerebral hypoperfusion secondary to severe atherosclerosis and to low blood pressure may be major biological pathways linking both high blood pressure in midlife and low blood pressure in late-life to cognitive decline and dementia.

We examined the influence of arterial stiffening and ventricular ejection dynamics on the age-related increase in central pulse pressure. A total of 2033 women aged 18 to 91 years from the Twins UK cohort were studied. Aortic flow and central blood pressure were measured by Doppler sonography and carotid tonometry, respectively. Measured values of central pulse pressure were compared with values predicted from aortic pulse wave velocity and ventricular ejection characteristics. Central pulse pressure at the first shoulder (P1) increased with age from 29.2±8.0 in those <40 years to 44.2±13.8 mm Hg in those >70 years (means±SD; P<0.001), an increase explained almost entirely by the concomitant increase in aortic pulse wave velocity. Pulse pressure, at the second pressure peak (P2, usually equal to peak central pulse pressure) increased to a greater extent with age: from 29.1±7.8 mm Hg for those <40 years to 60.2±20.5 mm Hg for those >70 years (P<0.001). The ratio of P2/P1 closely mirrored the ratio of ejection volume to ejection velocity at corresponding time points, and the proportionately greater increase in P2 compared with P1 was explained by increased ventricular ejection up to the time of P2. This increased from 52.5±13.1 to 59.3±17.8 mL (P<0.001) in parallel with an age-related increase in stroke volume and body mass index. These results suggest that the age-related change in central pulse wave morphology is driven mainly by an increase in arterial stiffening and altered pattern of ventricular ejection.

Systolic blood pressure and pulse pressure are substantially higher in older adults. The relative contributions of increased forward versus reflected pressure wave amplitude or earlier arrival of the reflected wave to elevated pulse pressure remain controversial.We measured proximal aortic pressure and flow, forward pressure wave amplitude, global wave reflection, reflected wave timing, and pulse wave velocity noninvasively in 6417 (age range, 19 to 90 years; 53 women) Framingham Heart Study Third Generation and Offspring participants. Variation in forward wave amplitude paralleled pulse pressure throughout adulthood. In contrast, wave reflection and pulse pressure were divergent across adulthood: In younger participants, pulse pressure was lower and wave reflection was higher with advancing age, whereas in older participants, pulse pressure was higher and wave reflection was lower with age. Reflected wave timing differed modestly across age groups despite considerable differences in pulse wave velocity. Forward wave amplitude explained 80 (central) and 66 (peripheral) of the variance in pulse pressure in younger participants (<50 years) and 90 and 84 in the older participants (≥ 50 years; all P<0.0001). In a stepwise model that evaluated age-pulse pressure relations in the full sample, the late accelerated increases in central and peripheral pulse pressure were markedly attenuated when variation in forward wave amplitude was considered.Higher pulse pressure at any age and higher pulse pressure with advancing age is associated predominantly with a larger forward pressure wave. The influence of wave reflection on age-related differences in pulse pressure was minor.

Increased cerebral arterial pulsatility is associated with cerebral small vessel disease, recurrent stroke, and dementia despite the best medical treatment. However, no study has identified the rates and determinants of progression of arterial stiffness and pulsatility.

The arterial stiffening is attributed to the intrinsic structural stiffening and/or load-dependent stiffening by increased blood pressure (BP). The respective lifetime alterations and major determinants of the two components with normal aging are not clear.A total of 3053 healthy adults (1922 women) aged 18-79 years were enrolled. The carotid intima-media thickness, diameter, and local BPs were automatically determined by the radio frequency ultrasound system. The Peterson and Young elastic moduli were then calculated to represent total arterial stiffness. Structural stiffness was recalculated at a reference BP of 120/80 mmHg with established models. Load-dependent stiffness was the difference between total and structural stiffness.Both structural and load-dependent stiffness increased with aging, with much larger changes in the structural components. The age-related increasing rates were higher in women for the structural stiffness than men (P  < 0.05), but similar for the load-dependent stiffness. The clinical characteristics and arterial stiffness were widely correlated, but most correlations were quite weak (r  < 0.3) other than BPs. Multiple regression analyses adjusted for sex, age and other clinical correlates showed that structural stiffness increased with pulse pressure (PP) and load-dependent stiffness increased with mean arterial pressure (MAP), respectively.The age-related arterial stiffening is mainly caused by the intrinsic structural stiffening, which demonstrated significant age-sex interaction. BPs were the major clinical determinants of arterial stiffness, with PP and MAP associated with different arterial stiffness components. The differentiation of the structural and load-dependent arterial stiffness should be highlighted for the optimal vascular health management.Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.

\n Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (\n P\n  < 5 × 10\n −8\n ) from the largest single-stage blood pressure (BP) genome-wide association study to date (\n n\n  = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5–18.2 mmHg,\n P\n  = 2.22 × 10\n −126\n ) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54–9.70;\n P\n  = 4.13 × 10\n −44\n ) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781–0.801) to 0.826 (95% CI, 0.817–0.836, ∆AUROC, 0.035,\n P\n  = 1.98 × 10\n −34\n ). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.\n

To test the hypothesis that hypertension, high blood pressure, and high pulse pressure (PP) are independently associated with lower cognitive function.Cross-sectional study of persons examined in 1988 to 1994.U.S. noninstitutionalized population.Six thousand one hundred sixty-three men and women aged 60 and older who participated in the Third National Health and Nutrition Examination Survey (NHANES III).Measurements included blood pressure, short-portable Mini-Mental State Examination (sp-MMSE), self-reported history of hypertension, diagnosis, and treatment.In the initial bivariate analysis within age groups of 60 to 64, 65 to 69, and 70 to 74, optimal blood pressure (< 120/80 mmHg) was associated with best cognitive performance; the severe hypertension group had the poorest performance in all age groups except the very old (> or = 80), where the pattern was reversed, showing poorest performance in the optimal blood pressure group and best in the group with moderate hypertension. This pattern changed slightly in multiple regression analyses modeling sp-MMSE as the outcome variable. Higher stage of hypertension according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and higher PP were associated with worse cognitive performance than normal blood pressure at ages 70 to 79 and 80 and older. No significant negative association was seen in subjects aged 60 to 69. Subjects with treated but uncontrolled hypertension had significantly lower sp-MMSE scores than those without hypertension or with controlled hypertension after controlling for age, sex, ethnicity, income, and PP.At age 70 and older, high blood pressure, hypertension, and uncontrolled blood pressure are associated with poorer cognitive function than normal blood pressure. Optimal control of blood pressure may be useful in preserving neurocognitive loss as the population ages.

\n \n Background and Purpose—\n \n Elevated blood pressure has been found to increase the risk of dementia, including Alzheimer disease. We sought to investigate whether pulse pressure was predictive of Alzheimer disease and dementia.\n

\n \n Background and Purpose—\n \n Low blood pressure has been related to an increased risk of dementia. We sought to verify blood pressure variations before and after a dementia diagnosis and to relate blood pressure decline to subsequent Alzheimer disease and dementia.\n

Whether blood pressure (BP), and at what level of controlled BP, reduces risk of cognitive impairment remains uncertain. We investigated the association of BP and hypertension treatment status with mild cognitive impairment and dementia in older women.We prospectively analysed a sample of 7207 community-dwelling women aged 65-79 years participating in the Women's Health Initiative Memory Study (WHIMS). Participants were recruited between May 28, 1996, and Dec 13, 1999, at 39 US clinical centres, and they were followed up until Dec 31, 2019. Cognitive function was assessed annually. Mild cognitive impairment and probable dementia were defined through a centralised adjudication process. BP was measured by trained and certified staff at baseline. Pulse pressure (PP) was calculated as systolic BP (SBP) minus diastolic BP. Hypertension was defined using the American Heart Association 2017 Guideline for High BP in Adults. Outcomes were (1) mild cognitive impairment, (2) probable dementia, and (3) cognitive loss (the combined endpoint of either mild cognitive impairment or probable dementia, or both). We estimated hazard ratios (HRs) to assess the association between hypertension, SBP, and PP with the risk of study outcomes using Cox proportional hazards regression models, with adjustment for key covariates.During a median follow-up of 9 years (IQR 6-15), 1132 (15·7%) participants were classified as mild cognitive impairment, 739 (10·3%) as probable dementia, and 1533 (21·3%) as cognitive loss. The incidence rates per 1000 person-years were 15·3 cases (95% CI 14·4-16·2) for mild cognitive impairment, 9·7 cases (9·0-10·4) for probable dementia, and 20·3 (19·3-21·3) for cognitive loss. Elevated SBP and PP were significantly associated with increased risk of mild cognitive impairment and cognitive loss (test for trends across SBP and PP strata, p<0·01). Individuals with hypertension, but with controlled SBP of less than 120 mm Hg did not have a significantly increased risk of mild cognitive impairment (HR 1·33, 95% CI 0·98-1·82, p=0·071), and of cognitive loss (1·09, 0·82-1·44, p=0·57) compared with normotension. Individuals on anti-hypertensive treatment with PP of less than 50 mm Hg did not have a significantly higher risk of mild cognitive impairment (1·26, 0·98-1·62, p=0·07) and of cognitive loss (1·17, 0·94-1·46, p=0·16). There were no significant associations between hypertension, SBP, or PP and probable dementia.Results of our study show significant associations of hypertension and elevated SBP and PP levels with risk of mild cognitive impairment and the combined endpoint of either mild cognitive impairment or probable dementia, suggesting that intensive control of hypertension, SBP, and PP can preserve cognitive health in older women.National Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services.

Aiming to investigate the relationship between pulse pressure (PP) and cognitive decline, cognitively normal subjects from a community-based longitudinal cohort were followed-up for 4 years. The Mini-Mental State Examination (MMSE) was used to evaluate global cognitive function, and a ≥2-point decrease in the MMSE score from baseline was defined as cognitive decline. Restricted cubic spline, multivariable linear regression and logistic regression were used to investigate the relationship between PP and cognitive decline. A total of 1173 participants completed the follow-up, and 205 (17.5%) met the criteria for cognitive decline. Restricted cubic splines showed no nonlinear relationship between PP and ΔMMSE (Poverall = 0.037, Pnon-linear = 0.289) or cognitive decline (Poverall = 0.003, Pnon-linear = 0.845). Multivariable linear regression analysis showed that PP was positively related to ΔMMSE (b = 0.021, p = 0.020). Multivariable logistic regression analysis showed that PP was positively associated with cognitive decline (OR = 1.020, p = 0.023). A stratified analysis found an association between PP and cognitive decline in participants who were aged ≤65 years, male, and APOEε4 noncarriers and who had school education ≤6 years or hypertension. A sensitivity analysis after propensity-score matching did not alter our findings. These findings highlight that elevated PP is associated with rapid cognitive decline, particularly in males, middle-aged, low-educated, hypertensive individuals and APOEε4 noncarriers.

Less is known regarding the association of pulse pressure (PP) with memory function. This study aimed to characterize long-term patterns of PP in middle-aged and older adults and explore their impact on subsequent change in memory function.Data from the English Longitudinal Study of Ageing (ELSA, 2004-2018), were analyzed. Totally, 3587 dementia-free participants with three measurements of BP were included. All three visits of PP (2004-2012) were used to characterize longitudinal patterns of PP by group-based trajectory modeling (GBTM). Generalized estimating equation (GEE) models were fitted to explore the impact of PP trajectories on change in memory over a subsequent 6-year period (2012-2018).Using GBTM, three distinct trajectories of PP were identified: low-stable (38.1%), moderate-stable (48.6%), and elevated-increasing group (13.3%). GEE model suggested that memory declined over a 6-year period in all PP trajectories (all P<0.001). The overall interactions between patterns of PP changes and time with memory were statistically significant (χ  = 20.69, p = 0.002). Compared to participants in the low-stable group, those in the moderate-stable and elevated-increasing group exhibited a faster decline in memory.Longitudinal patterns of moderate-stable and elevated-increasing PP were associated with an accelerated decrease in memory. Controlling BP instability may be a promising interventional strategy for preventing cognitive decline among older adults.© 2022 The American Geriatrics Society.

Hypertension and enlarged perivascular spaces (EPVS) are thought to be associated with cognitive impairment. However, the correlations among hypertension, EPVS, and cognitive impairment have not been studied yet. We aimed to investigate the relationships between cumulative blood pressure (cBP) exposure with EPVS and cognitive impairment and whether EPVS may mediate the relationship between cBP and cognitive impairment.A total of 1507 subjects from the Kailuan prospective cohort study were enrolled. cBP was calculated from 2006 to 2022. The effects of cBP, EPVS scores, and cognitive impairment were evaluated using a logistic regression model. The relationships among cBP, EPVS score, and cognitive impairment were analyzed using a mediation model.An increase in cBP was positively correlated with an increase in EPVS score. For every SD increase in cBP, the odds ratios (95% CI) of increased EPVS score of the centrum semiovale were 1.67 (1.43-1.95), 1.63 (1.4-1.9), and 1.35 (1.17-1.56), respectively; the odds ratios (95% CI) of increased EPVS score of the basal ganglia were 1.83 (1.56-2.15), 2.01 (1.7-2.36), and 1.31 (1.13-1.52), respectively; and the odds ratios (95% CI) of developing cognitive impairment were 1.28 (1.06-1.53), 1.13 (0.95-1.34), and 1.28 (1.07-1.5), respectively. Basal ganglia-EPVS score accounted for 10.46% to 18.32% of the mediating effects on the relationships of cBP/SD with cognitive impairment.High cBP exposure was an independent risk factor for EPVS, and basal ganglia-EPVS score mediated the effects of cBP on cognitive impairment.URL: https://www.gov; Unique identifier: ChiCTR-TNRC-11001489.

Effects of chronic arterial stiffness on brain aging remain unclear. We, therefore, examined whether long-term trajectories of pulse pressure (PP) predicted brain microstructure, microstructure mediated PP-executive function associations, and APOE genotype modified PP-microstructure associations.We examined associations of PP trajectories with brain microstructure measured using restriction spectrum imaging in 146 community-dwelling older adults, whether microstructure mediated PP trajectory-executive function associations, and whether PP-restriction spectrum imaging correlations were modified by APOE-ε4 status.Participants with trajectories of high PP had lower restricted isotropic diffusion (RI) compared to those with low PP trajectories and PP-executive function associations were mediated by subcortical and white matter RI. High PP more strongly correlated with lower RI and higher hindered diffusion among APOE-ε4 carriers than non-carriers.Prolonged elevated PP predicts microstructural abnormalities which may contribute to impaired executive function. APOE-ε4 carriers may be most vulnerable to the adverse effects of PP on brain microstructure.© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

This study delineated the interrelationships among blood pressure (BP), cerebrospinal fluid (CSF) core biomarkers of Alzheimer's disease (AD), and cognition.The linear regression analyses were conducted in 1546 non-demented participants (mean age of 61.58 years, range 40 to 89 years; 40% female; average days of BP measurement, 9.10 days). Mediation analyses with 10,000 bootstrapped iterations were used to explore the mediation effects.A clear age-related pattern of BP was delineated. Mid-life hypertension (especially systolic BP), late-life lower diastolic BP, as well as mid- and late-life higher pulse pressure were associated with cognitive impairment and tau-related biomarkers. BP variability was associated only with cognition but not with CSF biomarkers. Overall, the associations between BP and cognition were partially mediated (proportion: 11% to 30%) by tau pathologies, independently of amyloid pathology.Tau pathologies might play important roles in the relationship between BP and cognition, with significant age- and BP-type dependences.© 2021 the Alzheimer's Association.

Dementia risk is significantly shaped by cardiovascular health, with elevated blood pressure emerging as a key risk factor for adverse brain aging. Blood biomarkers such as pTau181, Aβ42/40, NfL, and GFAP have improved our understanding of dementia pathophysiology, however, few studies have explored how specific blood pressure metrics relate to biomarker levels, which could inform personalized dementia prevention strategies as these biomarkers move into clinic. We examined how different blood pressure metrics associated with molecular markers of astrocytic activation (GFAP), neuronal axon breakdown (NfL), and Alzheimer's disease pathobiology (pTau181, Aβ42/40) in plasma.109 functionally intact (Clinical Dementia Rating Scale = 0) older adults completed blood draws with plasma assayed for Aβ42/40, GFAP, NfL, and pTau181 (Quanterix Simoa) and in-lab blood pressure quantification. Blood pressure metrics included diastolic blood pressure, systolic blood pressure, and pulse pressure (systolic minus diastolic). Separate regression models evaluated plasma biomarkers as a function of each blood pressure metric, adjusting for age and biological sex. Interaction models tested whether relationships between blood pressure metrics and plasma biomarkers differed by sex, age, or APOE-ε4 status.With the exception of Aβ42/40, higher pulse pressure related to higher levels of all plasma biomarkers examined (pTau181, NfL, GFAP). Additionally, higher systolic blood pressure related to higher pTau181, while diastolic blood pressure did not meaningfully associate with any biomarker. Interaction models revealed a significantly stronger relationship between elevated pulse pressure and higher GFAP concentrations in females compared to males, as well as a significantly stronger association between elevated pulse pressure and lower Aβ42/40 plasma concentrations in APOE-ε4 carriers compared to non-carriers.Our findings suggest that elevated pulse pressure, and to a lesser extent systolic blood pressure, are associated with increased Alzheimer's disease and neurodegenerative (axonal and astrocytic health) biology among typically aging adults. These associations underscore the importance of blood pressure management, particularly pulse pressure, for reducing dementia risk. Cardiovascular health may be incorporated with biomarkers to further personalize dementia prevention and management strategies.© 2025. The Author(s).

Cardiovascular ageing contributes to cognitive impairment. However, the unique and synergistic contributions of multiple cardiovascular factors to cognitive function remain unclear because they are often condensed into a single composite score or examined in isolation. We hypothesized that vascular risk factors, electrocardiographic features and blood pressure indices reveal multiple latent vascular factors, with independent contributions to cognition. In a population-based deep-phenotyping study (n = 708, age 18-88), path analysis revealed three latent vascular factors dissociating the autonomic nervous system response from two components of blood pressure. These three factors made unique and additive contributions to the variability in crystallized and fluid intelligence. The discrepancy in fluid relative to crystallized intelligence, indicative of cognitive decline, was associated with a latent vascular factor predominantly expressing pulse pressure. This suggests that higher pulse pressure is associated with cognitive decline from expected performance. The effect was stronger in older adults. Controlling pulse pressure may help to preserve cognition, particularly in older adults. Our findings highlight the need to better understand the multifactorial nature of vascular aging.© 2023. The Author(s).

Growing evidence suggests that vascular risk factors, especially hypertension, relate not only to cardiovascular disease but also to cognitive impairment. However, the impact of pulse pressure on cognitive function remains controversial. In this study, we evaluated the associations between pulse pressure and cognitive function in a Japanese health examination cohort using propensity matching analysis.We examined 2,546 individuals with a mean age of 60.8 ± 10.3 years who voluntarily participated in health examination. Clinical variables included pulse pressure, and brain magnetic resonance imaging (MRI). We divided the participants into the high and low pulse pressure groups with a pre-defined cut-off value of 65 mmHg and evaluated their physical examination data, cognitive functions including Okabe's test, Kohs' test, and silent brain lesions using propensity matching. To clarify whether pulse pressure and blood pressure have different implications for cognitive function, a mediating analysis was also conducted.From the 2,546 subjects, 439 (17.2%) were in the high PP group. The propensity matching algorithm produced 433 pairs of patients with similar propensities. Higher pulse pressure corresponded to lower Okabe and Kohs' scores (44.3 ± 7.1 vs 42.7 ± 7.5; p = 0.002, 97.9 ± 18.0 vs 95.0 ± 18.1 p = 0.019, respectively). The relationship between pulse pressure and cognitive impairment was not significantly mediated by systolic blood pressure. We observed no significant associations between silent brain lesions and pulse pressure.High pulse pressure was associated with lower cognitive performance without systolic blood pressure mediation in Japanese subjects without dementia.© 2022. The Author(s).

<i>Background/Aims:</i> Midlife hypertension is associated with an increased risk for dementia, but the association between blood pressure and dementia in very old age is unclear. <i>Methods:</i> In a population-based cohort study, a total of 102 individuals aged 85, 90 or ≧95 years participated in 2 examinations with a 5-year interval. The investigations consisted of a structured interview, blood pressure measurement, rating scales such as the Mini-Mental State Examination (MMSE) and an investigation of medical charts. <i>Results:</i> The majority of participants exhibited a decline in blood pressure. Baseline systolic blood pressure (SBP), diastolic blood pressure or pulse pressure (PP) were not associated with incident dementia or with decline in MMSE scores in multiple regression analyses adjusted for age and sex. However, incident dementia cases exhibited a greater decline in SBP (p = 0.02) and PP (p = 0.04), and decline in SBP was associated with a decline in MMSE score (p = 0.008). <i>Conclusion:</i> In this small longitudinal study on the very old, no association between baseline blood pressure and incident dementia was found, but individuals who developed dementia exhibited a greater blood pressure decline. Low blood pressure could be an effect of dementia in the very old.

To evaluate the association between various blood pressure (BP) measures at age 85 and future decline in physical and cognitive function the oldest old.Longitudinal study.The population-based Leiden 85-plus Study.Five hundred seventy-two 85-year-old community-dwelling individuals.BP was measured at age 85 during home visits. Activities of daily living (ADLs) and Mini-Mental State Examination (MMSE) were assessed at age 85 and annually thereafter up to age 90. On average, participants were followed for 3.2 years. Cross-sectional and longitudinal analyses were performed using linear regression models using systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) as the determinants. All analyses were adjusted for sociodemographic and cardiovascular factors.At age 85, higher SBP and PP were associated with lower ADL disability scores (both P =.01). Similarly, higher SBP, DBP, and MAP were associated with higher MMSE scores (all P <.05). From age 85 onward, higher SBP (P <.001), MAP (P =.01), and PP (P =.003) at age 85 were associated with lower annual increases in ADL disability scores. Likewise, higher SBP (P =.03) and PP (P =.008) at age 85 were associated with lower annual declines in MMSE scores. Additional analyses showed that the association between high BP and lower annual decline in MMSE score was most pronounced in participants with high ADL disability.In the oldest old, higher SBP and PP are associated with resilience to physical and cognitive decline, especially in individuals with pre-existing physical disability.© 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.

Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population.We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies.The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42]).Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted.Gates Ventures.Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Chronic conditions often co-occur in specific disease patterns. Certain chronic diseases contribute to incident frailty or cognitive impairment (CI), but the associations of multimorbidity patterns and the order of frailty and CI occurrence remain unclear.

Pulse pressure (PP) may play a role in the development of cardiovascular disease, and the optimal PP for different ages and sexes is unknown. In a prospective cohort, we studied subjects with favorable cardiovascular health (CVH), proposed the mean PP as the optimal PP values, and demonstrated its relationship with healthy lifestyles.

Elevated blood pressure is a well-established risk factor for age-related cognitive decline. Long linked to cognitive impairment on vascular bases, increasing evidence suggests a potential association of hypertension with the neurodegenerative pathology underlying Alzheimer disease. Hypertension is well known to disrupt the structural and functional integrity of the cerebral vasculature. However, the mechanisms by which these alterations lead to brain damage, enhance Alzheimer pathology, and promote cognitive impairment remain to be established. Furthermore, critical questions concerning whether lowering blood pressure by antihypertensive medications prevents cognitive impairment have not been answered. Recent developments in neurovascular biology, brain imaging, and epidemiology, as well as new clinical trials, have provided insights into these critical issues. In particular, clinical and basic findings on the link between neurovascular dysfunction and the pathobiology of neurodegeneration have shed new light on the overlap between vascular and Alzheimer pathology. In this review, we will examine the progress made in the relationship between hypertension and cognitive impairment and, after a critical evaluation of the evidence, attempt to identify remaining knowledge gaps and future research directions that may advance our understanding of one of the leading health challenges of our time.

\n Neuronal activity within the brain evokes local increases in blood flow, a response termed functional hyperemia. This response ensures that active neurons receive sufficient oxygen and nutrients to maintain tissue function and health. In this review, we discuss the functions of functional hyperemia, the types of vessels that generate the response, and the signaling mechanisms that mediate neurovascular coupling, the communication between neurons and blood vessels. Neurovascular coupling signaling is mediated primarily by the vasoactive metabolites of arachidonic acid (AA), by nitric oxide, and by K\n +\n. While much is known about these pathways, many contentious issues remain. We highlight two controversies, the role of glial cell Ca\n 2+\n signaling in mediating neurovascular coupling and the importance of capillaries in generating functional hyperemia. We propose signaling pathways that resolve these controversies. In this scheme, capillary dilations are generated by Ca\n 2+\n increases in astrocyte endfeet, leading to production of AA metabolites. In contrast, arteriole dilations are generated by Ca\n 2+\n increases in neurons, resulting in production of nitric oxide and AA metabolites. Arachidonic acid from neurons also diffuses into astrocyte endfeet where it is converted into additional vasoactive metabolites. While this scheme resolves several discrepancies in the field, many unresolved challenges remain and are discussed in the final section of the review.\n

As global life expectancy increases, age-related brain diseases such as stroke and dementia have become leading causes of death and disability. The aging of the neurovasculature is a critical determinant of brain aging and disease risk. Neurovascular cells are particularly vulnerable to aging, which induces significant structural and functional changes in arterial, venous, and lymphatic vessels. Consequently, neurovascular aging impairs oxygen and glucose delivery to active brain regions, disrupts endothelial transport mechanisms essential for blood-brain exchange, compromises proteostasis by reducing the clearance of potentially toxic proteins, weakens immune surveillance and privilege, and deprives the brain of key growth factors required for repair and renewal. In this review, we examine the effects of neurovascular aging on brain function and its role in stroke, vascular cognitive impairment, and Alzheimer's disease. Finally, we discuss key unanswered questions that must be addressed to develop neurovascular strategies aimed at promoting healthy brain aging.Copyright © 2024 Elsevier Inc. All rights reserved.

Optimal vascular structure and function are essential for maintaining the physiological functions of the cardiovascular system. Vascular remodelling involves changes in vessel structure, including its size, shape, cellular and molecular composition. These changes result from multiple risk factors and may be compensatory adaptations to sustain blood vessel function. They occur in diverse cardiovascular pathologies, from hypertension to heart failure and atherosclerosis. Dynamic changes in the endothelium, fibroblasts, smooth muscle cells, pericytes or other vascular wall cells underlie remodelling. In addition, immune cells, including macrophages and lymphocytes, may infiltrate vessels and initiate inflammatory signalling. They contribute to a dynamic interplay between cell proliferation, apoptosis, migration, inflammation, and extracellular matrix reorganisation, all critical mechanisms of vascular remodelling. Molecular pathways underlying these processes include growth factors (e.g., vascular endothelial growth factor and platelet-derived growth factor), inflammatory cytokines (e.g., interleukin-1β and tumour necrosis factor-α), reactive oxygen species, and signalling pathways, such as Rho/ROCK, MAPK, and TGF-β/Smad, related to nitric oxide and superoxide biology. MicroRNAs and long noncoding RNAs are crucial epigenetic regulators of gene expression in vascular remodelling. We evaluate these pathways for potential therapeutic targeting from a clinical translational perspective. In summary, vascular remodelling, a coordinated modification of vascular structure and function, is crucial in cardiovascular disease pathology.

Cognitive decline covers a broad spectrum of disorders, not only resulting from brain diseases but also from systemic diseases, which seriously influence the quality of life and life expectancy of patients. As a highly selective anatomical and functional interface between the brain and systemic circulation, the blood-brain barrier (BBB) plays a pivotal role in maintaining brain homeostasis and normal function. The pathogenesis underlying cognitive decline may vary, nevertheless, accumulating evidences support the role of BBB disruption as the most prevalent contributing factor. This may mainly be attributed to inflammation, metabolic dysfunction, cell senescence, oxidative/nitrosative stress and excitotoxicity. However, direct evidence showing that BBB disruption causes cognitive decline is scarce, and interestingly, manipulation of the BBB opening alone may exert beneficial or detrimental neurological effects. A broad overview of the present literature shows a close relationship between BBB disruption and cognitive decline, the risk factors of BBB disruption, as well as the cellular and molecular mechanisms underlying BBB disruption. Additionally, we discussed the possible causes leading to cognitive decline by BBB disruption and potential therapeutic strategies to prevent BBB disruption or enhance BBB repair. This review aims to foster more investigations on early diagnosis, effective therapeutics, and rapid restoration against BBB disruption, which would yield better cognitive outcomes in patients with dysregulated BBB function, although their causative relationship has not yet been completely established.© 2024. The Author(s).

Amyloid protein-β (Aβ) concentrations are increased in the brain in both early onset and late onset Alzheimer's disease (AD). In early onset AD, cerebral Aβ production is increased and its clearance is decreased, while increased Aβ burden in late onset AD is due to impaired clearance. Aβ has been the focus of AD therapeutics since development of the amyloid hypothesis, but efforts to slow AD progression by lowering brain Aβ failed until phase 3 trials with the monoclonal antibodies lecanemab and donanemab. In addition to promoting phagocytic clearance of Aβ, antibodies lower cerebral Aβ by efflux of Aβ-antibody complexes across the capillary endothelia, dissolving Aβ aggregates, and a "peripheral sink" mechanism. Although the blood-brain barrier is the main route by which soluble Aβ leaves the brain (facilitated by low-density lipoprotein receptor-related protein-1 and ATP-binding cassette sub-family B member 1), Aβ can also be removed via the blood-cerebrospinal fluid barrier, glymphatic drainage, and intramural periarterial drainage. This review discusses experimental approaches to increase cerebral Aβ efflux via these mechanisms, clinical applications of these approaches, and findings in clinical trials with these approaches in patients with AD or mild cognitive impairment. Based on negative findings in clinical trials with previous approaches targeting monomeric Aβ, increasing the cerebral efflux of soluble Aβ is unlikely to slow AD progression if used as monotherapy. But if used as an adjunct to treatment with lecanemab or donanemab, this approach might allow greater slowing of AD progression than treatment with either antibody alone.

Flow of cerebrospinal fluid (CSF) through perivascular spaces (PVSs) in the brain is important for clearance of metabolic waste. Arterial pulsations are thought to drive flow, but this has never been quantitatively shown. We used particle tracking to quantify CSF flow velocities in PVSs of live mice. CSF flow is pulsatile and driven primarily by the cardiac cycle. The speed of the arterial wall matches that of the CSF, suggesting arterial wall motion is the principal driving mechanism, via a process known as perivascular pumping. Increasing blood pressure leaves the artery diameter unchanged but changes the pulsations of the arterial wall, increasing backflow and thereby reducing net flow in the PVS. Perfusion-fixation alters the normal flow direction and causes a 10-fold reduction in PVS size. We conclude that particle tracking velocimetry enables the study of CSF flow in unprecedented detail and that studying the PVS in vivo avoids fixation artifacts.

It is unclear how pathological aging of the inflammatory system relates to Alzheimer’s disease (AD). We tested whether age-related inflammatory changes in cerebrospinal fluid (CSF) and plasma exist across different stages of AD, and whether such changes related to AD pathology. Linear regression was first used model chronological age in amyloid-β negative, cognitively unimpaired individuals (Aβ− CU; n = 312) based on a collection of 73 inflammatory proteins measured in both CSF and plasma. Fitted models were then applied on protein levels from Aβ+ individuals with mild cognitive impairment (Aβ+ MCI; n = 150) or Alzheimer’s disease dementia (Aβ+ AD; n = 139) to test whether the age predicted from proteins alone (“inflammatory age”) differed significantly from true chronological age. Aβ− individuals with subjective cognitive decline (Aβ− SCD; n = 125) or MCI (Aβ− MCI; n = 104) were used as an independent contrast group. The difference between inflammatory age and chronological age (InflammAGEscore) was then assessed in relation to core AD biomarkers of amyloid, tau, and cognition. Both CSF and plasma inflammatory proteins were significantly associated with age in Aβ− CU individuals, with CSF-based proteins predicting chronological age better than plasma-based counterparts. Meanwhile, the Aβ− SCD and validation Aβ− CU groups were not characterized by significant inflammatory aging, while there was increased inflammatory aging in Aβ− MCI patients for CSF but not plasma inflammatory markers. Both CSF and plasma inflammatory changes were seen in the Aβ+ MCI and Aβ+ AD groups, with varying degrees of change compared to Aβ− CU and Aβ− SCD groups. Finally, CSF inflammatory changes were highly correlated with amyloid, tau, general neurodegeneration, and cognition, while plasma changes were mostly associated with amyloid and cognition. Inflammatory pathways change during aging and are specifically altered in AD, tracking closely with pathological hallmarks. These results have implications for tracking AD progression and for suggesting possible pathways for drug targeting.

\n Cerebral small vessel disease (cSVD) encompasses a heterogeneous group of age-related small vessel pathologies that affect multiple regions. Disease manifestations range from lesions incidentally detected on neuroimaging (white matter hyperintensities, small deep infarcts, microbleeds, or enlarged perivascular spaces) to severe disability and cognitive impairment. cSVD accounts for approximately 25% of ischemic strokes and the vast majority of spontaneous intracerebral hemorrhage and is also the most important vascular contributor to dementia. Despite its high prevalence and potentially long therapeutic window, there are still no mechanism-based treatments. Here, we provide an overview of the recent advances in this field. We summarize recent data highlighting the remarkable continuum between monogenic and multifactorial cSVDs involving\n NOTCH3\n,\n HTRA1\n, and\n COL4A1/A2\n genes. Taking a vessel-centric view, we discuss possible cause-and-effect relationships between risk factors, structural and functional vessel changes, and disease manifestations, underscoring some major knowledge gaps. Although endothelial dysfunction is rightly considered a central feature of cSVD, the contributions of smooth muscle cells, pericytes, and other perivascular cells warrant continued investigation.\n

In older adults, elevated pulse pressure predicts cognitive decline, independent of overall blood pressure. It is proposed to compromise cerebrovascular integrity, potentially leading to brain damage, though the underlying mechanisms remain unclear. We hypothesized that pulse pressure affects cognition by disrupting white matter microstructure, and that it does so independently of other cardiovascular risk factors.Latent indices of pulse pressure, overall blood pressure, and heart rate variability were estimated in a cross-sectional, population-based cohort (n=708, aged 18-88 years). An indicator of white matter microstructure was derived from diffusion-weighted imaging, termed the peak width of skeletonized mean diffusivity (PSMD). Cognitive function was assessed using measures of processing speed.In robust regression, pulse pressure was significantly associated with PSMD, with PSMD also being associated with processing speed. Thus, higher pulse pressure was associated with greater white matter disruption, which in turn was associated with slower processing. This motivated testing whether PSMD mediates the effects of pulse pressure on processing speed using structural equation models. PSMD mediated this effect, accounting for 72% of the effect after adjusting for age, and remained significant after adjusting for other cardiovascular factors. We then expanded the model to show that vascular-related changes in processing speed also drive changes in higher cognitive functions.High pulse pressure disrupts the microstructural integrity of white matter in the brain, leading to slower processing speed. We propose that better management of pulse pressure could help to preserve white matter integrity and reduce cognitive decline in later life.

The hippocampus is essential for spatial and episodic memory but is damaged early in Alzheimer's disease and is very sensitive to hypoxia. Understanding how it regulates its oxygen supply is therefore key for designing interventions to preserve its function. However, studies of neurovascular function in the hippocampus in vivo have been limited by its relative inaccessibility. Here we compared hippocampal and visual cortical neurovascular function in awake mice, using two photon imaging of individual neurons and vessels and measures of regional blood flow and haemoglobin oxygenation. We show that blood flow, blood oxygenation and neurovascular coupling were decreased in the hippocampus compared to neocortex, because of differences in both the vascular network and pericyte and endothelial cell function. Modelling oxygen diffusion indicates that these features of the hippocampal vasculature may restrict oxygen availability and could explain its sensitivity to damage during neurological conditions, including Alzheimer's disease, where the brain's energy supply is decreased.