Time trends in herpesvirus seroepidemiology among Swedish adults.

BACKGROUND: Human herpesviruses are widespread among the human population. The infections often occur unnoticed, but severe disease as well as long-term sequelae are part of the symptom spectrum. The prevalence varies among subpopulations and with time. The aim of this study was to describe the seroprevalence of Immunoglobulin G against Herpes simplex 1, Herpes simplex 2, Epstein-Barr virus and Cytomegalovirus in the adult Swedish population over a time period of several decades. METHODS: Serum samples (n = 892) from biobanks, originating from 30-year-old women, 50-year-old men and 50-year-old women sampled between 1975 and 2018, were analyzed for presence of anti-herpesvirus antibodies. Linear regression analysis was used to test for a correlation between birth year and seroprevalence. Multiple linear regression analysis was used to differentiate between other factors such as age and gender. RESULTS: Birth year correlated negatively with the prevalence of immunoglobulin G against Herpes simplex 1 and Epstein-Barr virus (p = 0.004 and 0.033), and positively with Immunoglobulin G against Cytomegalovirus (p = 0.039). When participant categories were analyzed separately, birth year correlated negatively with the prevalence of Immunoglobulin G against Herpes simplex 1 and Herpes simplex 2 (p = 0.032 and 0.028) in 30-year-old women, and with the prevalence of Immunoglobulin G against Cytomegalovirus in 50-year-old men (p = 0.011). CONCLUSIONS: The prevalence of Immunoglobulin G against Herpes simplex 1, Herpes simplex 2 and Epstein-Barr virus decreases in later birth cohorts. This indicates a trend of declining risk of getting infected with these viruses as a child and adolescent.

Herpes Simplex Viral Infection Doubles the Risk of Dementia in a Contemporary Cohort of Older Adults: A Prospective Study.

Background: Evidence indicates that herpes simplex virus (HSV) participates in the pathogenesis of Alzheimer's disease (AD). Objective: We investigated AD and dementia risks according to the presence of herpesvirus antibodies in relation to anti-herpesvirus treatment and potential APOE ɛ4 carriership interaction. Methods: This study was conducted with 1002 dementia-free 70-year-olds living in Sweden in 2001-2005 who were followed for 15 years. Serum samples were analyzed to detect anti-HSV and anti-HSV-1 immunoglobulin (Ig) G, anti-cytomegalovirus (CMV) IgG, anti-HSV IgM, and anti-HSV and anti-CMV IgG levels. Diagnoses and drug prescriptions were collected from medical records. Cox proportional-hazards regression models were applied. Results: Cumulative AD and all-cause dementia incidences were 4% and 7%, respectively. Eighty-two percent of participants were anti-HSV IgG carriers, of whom 6% received anti-herpesvirus treatment. Anti-HSV IgG was associated with a more than doubled dementia risk (fully adjusted hazard ratio = 2.26, p = 0.031). No significant association was found with AD, but the hazard ratio was of the same magnitude as for dementia. Anti-HSV IgM and anti-CMV IgG prevalence, anti-herpesvirus treatment, and anti-HSV and -CMV IgG levels were not associated with AD or dementia, nor were interactions between anti-HSV IgG and APOE ɛ4 or anti-CMV IgG. Similar results were obtained for HSV-1. Conclusions: HSV (but not CMV) infection may be indicative of doubled dementia risk. The low AD incidence in this cohort may have impaired the statistical power to detect associations with AD.

Having Plans for the Future in Very Old People.

This study aimed to investigate the prevalence of having plans for the future among very old people and the factors associated with having such plans. A longitudinal population-based study with home visits for 85-, 90-, and ≥95-year-old participants in Sweden and Finland was used. Multivariate logistic regression and Cox proportional-hazards regression models with a maximum 5-year follow-up period were used. The prevalence of having plans for the future was 18.6% (174/936). More men than women and more people living in Sweden than in Finland had plans for the future. In multivariate models, having plans for the future was associated with speaking Swedish, being dentate, and living in the community in the total sample; speaking Swedish and being dentate among women; and speaking Swedish, having a lower Geriatric Depression Scale score, and urban residence among men. Having plans for the future was associated univariately, but not multivariately, with increased survival.

Longitudinal Effects of Herpesviruses on Multiple Cognitive Outcomes in Healthy Elderly Adults.

BACKGROUND: Herpesviruses have been proposed to be involved in Alzheimer's disease development as potentially modifiable pathology triggers. OBJECTIVE: To investigate associations of serum antibodies for herpes simplex virus (HSV)-1 and cytomegalovirus (CMV) and anti-herpesvirus treatment with cognitive outcomes in relation to interactions with APOE ɛ4. METHODS: The study included 849 participants in the population-based Prospective Investigation of the Vasculature in Uppsala Seniors study. Cognitive performance at the ages of 75 and 80 years was assessed using the Mini-Mental State Examination (MMSE), trail-making test (TMT) A and B, and 7-minute screening test (7MS). RESULTS: Anti- HSV-1 IgG positivity was associated cross-sectionally with worse performance on the MMSE, TMT-A, TMT-B, 7MS, enhanced free recall, and verbal fluency tests (p = 0.016, p = 0.016, p < 0.001, p = 0.001, p = 0.033, and p < 0.001, respectively), but not orientation or clock drawing. Cognitive scores did not decline over time and longitudinal changes did not differ according to HSV-1 positivity. Anti- CMV IgG positivity was not associated cross-sectionally with cognition, but TMT-B scores declined more in anti- CMV IgG carriers. Anti- HSV-1 IgG interacted with APOE ɛ4 in association with worse TMT-A and better enhanced cued recall. Anti- HSV IgM interacted with APOE ɛ4 and anti-herpesvirus treatment in association with worse TMT-A and clock drawing, respectively. CONCLUSION: These findings indicate that HSV-1 is linked to poorer cognition in cognitively healthy elderly adults, including impairments in executive function, memory, and expressive language. Cognitive performance did not decline over time, nor was longitudinal decline associated with HSV-1.

Temporal Dementia and Cognitive Impairment Trends in the Very Old in the 21st Century.

BACKGROUND: Long-increasing dementia incidence and prevalence trends may be shifting. Whether such shifts have reached the very old is unknown. OBJECTIVE: To investigate temporal trends in the incidence of dementia and cognitive impairment and prevalence of dementia, cognitive impairment, Alzheimer's disease, vascular dementia, and unclassified dementia among 85-, 90-, and ≥ 95-year-olds in Sweden during 2000-2017. METHODS: This study was conducted with Umeå 85 + /Gerontological Regional Database data from 2182 85-, 90-, and ≥ 95-year-olds in Sweden collected in 2000-2017. Using logistic regression, trends in the cumulative 5-year incidences of dementia and cognitive impairment; prevalences of dementia, cognitive impairment, Alzheimer's disease, and vascular dementia; and Mini-Mental State Examination thresholds for dementia diagnosis were estimated. RESULTS: Dementia and cognitive impairment incidences decreased in younger groups, which generally showed more-positive temporal trends. The prevalences of overall dementia, cognitive impairment, and Alzheimer's disease were stable or increasing; longer disease durations and increasing dementia subtype classification success may mask positive changes in incidences. Vascular dementia increased while unclassified dementia generally decreased. CONCLUSION: The cognitive health of the very old may be changing in the 21st century, possibly indicating a trend break.

PILRA polymorphism modifies the effect of APOE4 and GM17 on Alzheimer's disease risk.

PILRA (rs1859788 A > G) has been suggested to be a protective variant for Alzheimer's disease (AD) and is an entry co-receptor for herpes simplex virus-1. We conducted a nested case-control study of 360 1:1-matched AD subjects. Interactions between the PILRA-A allele, APOE risk variants (ε3/ε4 or ε4/ε4) and GM17 for AD risk were modelled. The associations were cross-validated using two independent whole-genome sequencing datasets. We found negative interactions between PILRA-A and GM17 (OR 0.72, 95% CI 0.52-1.00) and between PILRA-A and APOE risk variants (OR 0.56, 95% CI 0.32-0.98) in the discovery dataset. In the replication cohort, a joint effect of PILRA and PILRA × GM 17/17 was observed for the risk of developing AD (p .02). Here, we report a negative effect modification by PILRA on APOE and GM17 high-risk variants for future AD risk in two independent datasets. This highlights the complex genetics of AD.

Long-term time trends in reactivated herpes simplex infections and treatment in Sweden.

BACKGROUND: Our aim was to describe the annual prevalence of herpes simplex virus (HSV) reactivation in relation to solar ultraviolet (UV) radiation and antiviral drug use in the Swedish adult population. METHODS: The study comprised 2879 anti-HSV-1 immunoglobulin (Ig) G positive subjects from five different cohorts who had donated serum from 1988 to 2010. The sera were analyzed for anti-HSV IgM using enzyme-linked immunosorbent assay. Associations between the presence of anti-HSV IgM antibodies, the apolipoprotein E ε4 allele and the serum sampling year were assessed by logistic regression. Seasonality of anti-HSV IgM was evaluated in a UV radiation model. Data of antiviral drugs for the entire Swedish population were compiled from two different nationwide databases: the Swedish Prescribed Drug Register and the Swedish Association of the Pharmaceutical Industry. RESULTS: Cross-sectional and longitudinal analyses indicated that the prevalence of anti-HSV IgM antibodies declined between 1988 and 2010 (odds ratio [OR] = 0.912, p < .001), while the total annual use of antiviral drugs in Sweden gradually increased from 1984 to 2017. Higher UV radiation was associated with higher prevalence of anti-HSV IgM antibodies (OR = 1.071, p = .043). CONCLUSION: The declining time trend of HSV reactivation in a Swedish cohort coincides with a steady increase of antiviral drug use in the Swedish general population.

VALZ-Pilot: High-dose valacyclovir treatment in patients with early-stage Alzheimer's disease.

Introduction: Herpes simplex virus (HSV) may be involved in Alzheimer's disease (AD) pathophysiology. The antiviral valacyclovir inhibits HSV replication. Methods: This phase-II pilot trial involved valacyclovir administration (thrice daily, 500 mg week 1, 1000 mg weeks 2-4) to persons aged ≥ 65 years with early-stage AD, anti-HSV immunoglobulin G, and apolipoprotein E ε4. Intervention safety, tolerability, feasibility, and effects on Mini-Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarkers were evaluated. Results: Thirty-two of 33 subjects completed the trial on full dosage. Eighteen percent experienced likely intervention-related mild, temporary adverse events. CSF acyclovir concentrations were mean 5.29 ± 2.31 µmol/L. CSF total tau and neurofilament light concentrations were unchanged; MMSE score and CSF soluble triggering receptor expressed on myeloid cells 2 concentrations increased (P = .02 and .03). Discussion: Four weeks of high-dose valacyclovir treatment was safe, tolerable, and feasible in early-stage AD. Our findings may guide future trial design.

Antiviral treatment associated with reduced risk of clinical Alzheimer's disease-A nested case-control study.

INTRODUCTION: In this nested case-control study, we investigated if antiviral treatment given prior to onset of Alzheimer's disease (AD) could influence incident AD. METHODS: From a large population-based cohort study in northern Sweden, 262 individuals that later developed AD were compared to a non-AD matched control group with respect to prescriptions of herpes antiviral treatment. All included subjects were herpes simplex virus 1 (HSV1) carriers and the matching criteria were age, sex, apolipoprotein E genotype (ε4 allele carriership), and study sample start year. RESULTS: Among those who developed AD, 6 prescriptions of antivirals were found, compared to 20 among matched controls. Adjusted for length of follow-up, a conditional logistic regression indicated a difference in the risk for AD development between groups (odds ratio for AD with an antiviral prescription 0.287, P = .018). DISCUSSION: Antiviral treatment might possibly reduce the risk for later development of HSV1-associated AD.

Plasma Amyloid-ß in Relation to Antibodies Against Herpes Simplex Virus, Cytomegalovirus, and Chlamydophila pneumoniae.

BACKGROUND: Amyloid-ß (Aß), the key constituent of Alzheimer's disease (AD) plaques, has antimicrobial properties. OBJECTIVE: To investigate the association between plasma Aß and antibodies against the AD-related pathogens herpes simplex virus (HSV), cytomegalovirus (CMV), and C. pneumoniae. METHODS: Plasma from 339 AD cases, obtained on average 9.4 years (±4.00) before diagnosis, and their matched controls were analyzed for Aß40 and Aß42 concentrations with Luminex xMAP technology and INNOBIA plasma Aß-form assays. Enzyme-linked immunosorbent assays were utilized for analyses of anti-HSV immunoglobulin (Ig) G, anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG. Follow-up samples were available for 150 of the cases. RESULTS: Presence and levels of anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG did not correlate with concentrations of Aß42 or Aß40 in cases or controls. CONCLUSION: Levels of plasma Aß were not associated with antibodies against different AD-related pathogens.

Herpesvirus infections, antiviral treatment, and the risk of dementia-a registry-based cohort study in Sweden.

INTRODUCTION: Herpesviruses, including Herpes simplex virus type 1 (HSV1) and varicella zoster-virus (VZV), have been implicated in Alzheimer's disease (AD) development. Likewise, antiviral treatment has been suggested to protect against dementia development in herpes-infected individuals. METHODS: The study enrolled 265,172 subjects aged ≥ 50 years, with diagnoses of VZV or HSV, or prescribed antiviral drugs between 31 December 2005 and 31 December 2017. Controls were matched in a 1:1 ratio by sex and birth year. RESULTS: Antiviral treatment was associated with decreased risk of dementia (adjusted hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.86 to 0.92), while herpes infection without antiviral drugs increased the risk of dementia (adjusted HR 1.50, 95% CI 1.29 to 1.74). DISCUSSION: Antiviral treatment was associated with a reduced long-term risk of dementia among individuals with overt signs of herpes infection. This is consistent with earlier findings indicating that herpesviruses are involved in the pathogenesis of AD.

An Ig γ Marker Genotype Is a Strong Risk Factor for Alzheimer Disease, Independent of Apolipoprotein E ε4 Genotype.

Increasing evidence implicates HSV type 1 (HSV1) in the pathogenesis of late-onset Alzheimer disease (AD). HSV1 has evolved highly sophisticated strategies to evade host immunosurveillance. One strategy involves encoding a decoy Fcγ receptor (FcγR), which blocks Fc-mediated effector functions, such as Ab-dependent cellular cytotoxicity. Ig γ marker (GM) allotypes, encoded by highly polymorphic IGHG genes on chromosome 14q32, modulate this immunoevasion strategy, and thus may act as effect modifiers of the HSV1-AD association. In this nested case-control human study, 365 closely matched case-control pairs-whose blood was drawn on average 9.6 y before AD diagnosis-were typed for GM alleles by a TaqMan genotyping assay. APOE genotype and a genetic risk score based on nine additional previously known AD risk genes (ABCA7, BIN1, CD33, CLU, CR1, EPHA1, MS4A4E, NECTIN2, and PICALM) were extracted from a genome-wide association study analysis. Antiviral Abs were measured by ELISA. Conditional logistic regression models were applied. The distribution of GM 3/17 genotypes differed significantly between AD cases and controls, with higher frequency of GM 17/17 homozygotes in AD cases as compared with controls (19.8 versus 10.7%, p = 0.001). The GM 17/17 genotype was associated with a 4-fold increased risk of AD (odds ratio 4.142, p < 0.001). In conclusion, the results of this study demonstrate that Ig GM 17/17 genotype contributes to the risk of later AD development, independent of apolipoprotein ε4 genotype and other AD risk genes, and explain, at least in part, why every HSV1-infected person is not equally likely to develop HSV1-associated AD.

Urea dilution of serum for reproducible anti-HSV1 IgG avidity index.

BACKGROUND: Herpes simplex virus type 1 (HSV1), establishes life-long latency and can cause symptoms during both first-time infection and later reactivation. The aim of the present study was to describe a protocol to generate a reliable and discriminative avidity index (AI) for anti-HSV1 IgG content in human sera. METHODS: Human serum from two distinct cohorts; one a biobank collection (Betula) (n = 28), and one from a clinical diagnostics laboratory at Northern Sweden University Hospital (NUS) (n = 18), were assessed for presence of IgG antibodies against HSV1 by a commercially available ELISA-kit. Addition of urea at the incubation step reduces effective binding, and the ratio between urea treated sample and non-treated sample was used to express an avidity index (AI) for individual samples. RESULTS: AI score ranged between 43.2 and 73.4% among anti-HSV1 positive biobank sera. Clinical samples ranged between 36.3 and 74.9%. Reproducibility expressed as an intraclass correlation coefficient (ICC) was estimated at 0.948 (95% CI: 0.900-0.979) and 0.989 (95% CI 0.969-0.996) in the biobank and clinical samples, respectively. CONCLUSION: The method allows for AI scoring of anti-HSV1 IgG from individual human sera with a single measurement. The least significant change between two measurements at the p < 0.05 level was estimated at 5.4 and 3.2 points, respectively, for the two assessed cohorts.

Herpes Simplex Virus, APOEɛ4, and Cognitive Decline in Old Age: Results from the Betula Cohort Study.

BACKGROUND: Herpes simplex virus (HSV) has been suggested to play a role in Alzheimer's disease (AD) development. OBJECTIVE: The aim of the present study was to investigate the early AD-related symptom episodic memory decline in relation to HSV and carriage of allele 4 of the apolipoprotein E gene (APOEɛ4) in a large population-based cohort with a long follow-up time. METHODS: The study included 3,413 persons, with longitudinal data available for 1,293 persons with a mean follow-up time of 11.6 years. The associations between HSV carriage, APOEɛ4 carriage, and episodic memory was investigated at baseline, as well as in longitudinal analyses where individuals with and without HSV antibodies (HSV1/2 non-specific) were matched and episodic memory decline compared. RESULTS: Cross-sectional analyses revealed an age-dependent association of HSV carriage with lower episodic memory function, particularly among APOEɛ4 carriers (p = 0.008). Longitudinal analyses showed an increased risk of episodic memory decline in HSV carriers (≥65 years: p < 0.001, all ages: non-significant), and a significant interaction between HSV and APOEɛ4 for episodic memory decline (p < 0.001). CONCLUSION: In this large population-based cohort study, both cross-sectional and longitudinal results support an association between HSV carriage and declining episodic memory function, especially among APOEɛ4 carriers. The results strengthen the hypothesis that HSV is associated with AD development.

A genetic signature including apolipoprotein Eε4 potentiates the risk of herpes simplex-associated Alzheimer's disease.

INTRODUCTION: Herpes simplex virus type 1 (HSV1) in combination with genetic susceptibility has previously been implicated in Alzheimer's disease (AD) pathogenesis. METHODS: Plasma from 360 AD cases, obtained on average 9.6 years before diagnosis, and their age- and sex-matched controls, were analyzed for anti-HSV1 immunoglobulin (Ig) G with enzyme-linked immunosorbent assays (ELISAs). A POE genotype and nine other selected risk genes for AD were extracted from a genome-wide association study analysis by deCODE genetics, Reykjavik, Iceland. RESULTS: The interaction between APOEε4 heterozygosity (APOEε2/ε4 or ε3/ε4) and anti-HSV1 IgG carriage increased the risk of AD (OR 4.55, P = .02). A genetic risk score based on the nine AD risk genes also interacted with anti-HSV1 IgG for the risk of developing AD (OR 2.35, P = .01). DISCUSSION: The present findings suggest that the APOEε4 allele and other AD genetic risk factors might potentiate the risk of HSV1-associated AD.

Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer's Disease Development.

BACKGROUND: Several environmental factors, including infectious agents, have been suggested to cause Alzheimer's disease (AD). Cytomegalovirus (CMV) has been associated with AD in several recent studies. OBJECTIVE: To investigate whether carriage of CMV, alone or in combination with Herpes simplex virus (HSV), increased the risk of developing AD. METHODS: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years), taken an average of 9.6 years before AD diagnosis, and 360 age-, sex-, cohort-, and sampling date matched dementia-free controls were analyzed to detect anti-CMV (immunoglobulin [Ig] G and IgM), group-specific anti-HSV (IgG and IgM), and specific anti-HSV1 and HSV2 IgG antibodies by enzyme-linked immunosorbent assays. AD cases and dementia-free controls were compared using conditional logistic regression analyses. RESULTS: The presence of anti-CMV IgG antibodies did not increase the risk of AD (odds ratio [OR], 0.857; p = 0.497). Among AD cases, an association between CMV and HSV1 carriage was detected (OR 7.145, p < 0.001); in a conditional logistic regression model, the interaction between CMV and HSV1 was associated with AD development (OR 5.662; p = 0.007). CONCLUSION: The present findings do not support a direct relationship between CMV infection and the development of AD; however, an interaction between CMV and HSV1 was found to be associated significantly with AD development. These findings suggest that CMV infection facilitates the development of HSV1-associated AD, possibly via its effects on the immune system.

Systolic blood pressure decline in very old individuals is explained by deteriorating health: Longitudinal changes from Umeå85+/GERDA.

Declining systolic blood pressure (SBP) is common in very old age and is associated with adverse events, such as dementia. Knowledge of factors associated with SBP changes could explain the etiology of this decline in SBP. This study investigated longitudinal changes in socioeconomic factors, medical conditions, drug prescriptions, and assessments and their associations with SBP changes among very old followed individuals.The study was based on data from the Umeå85+/Gerontological Regional Database (GERDA) cohort study, which provided cross-sectional and longitudinal data on participants aged 85, 90, and ≥95 years from 2000 to 2015. Follow-up assessments were conducted after 5 years. The main outcome was a change in SBP. Factors associated with SBP changes were assessed using multivariate linear regression models.In the Umeå85+/GERDA study, 454 surviving individuals underwent follow-up assessment after 5 years. Of these, 297 had SBP measured at baseline and follow-up. The mean change ±â€Šstandard deviation in SBP was -12 ±â€Š25 mm Hg. SBP decline was associated independently with later investigation year (P = .009), higher baseline SBP (P < .001), baseline antidepressant prescription (P = .011), incident acute myocardial infarction during follow-up (P = .003), new diuretic prescription during follow-up (P = .044), and a decline in the Barthel Activities of Daily Living index at follow-up (P < .001).In conclusion, SBP declines among very old individuals. This decline seems to be associated with initial SBP level, investigation year, and health-related factors.

High blood pressure as a risk factor for incident stroke among very old people: a population-based cohort study.

INTRODUCTION: High blood pressure (BP) increases the risk of stroke, but there is limited evidence from studies including very old people. The aim was to investigate risk factors for incident stroke among very old people. METHODS: A prospective population-based cohort study was performed among participants aged at least 85 years in northern Sweden. The 955 participants were tested at their homes. BP was measured manually after 5-min supine rest. Incident stroke data were collected from medical charts guided by hospital registry, death records, and 5-year reassessments. Cox proportional hazards models were used. RESULTS: The stroke incidence was 33.8/1000 person-years (94 stroke events) during a mean follow-up period of 2.9 years. In a comprehensive multivariate model, atrial fibrillation [hazard ratio 1.85, 95% confidence interval (CI) 1.07-3.19] and higher SBP (hazard ratio 1.19, 95% CI 1.08-1.30 per 10-mmHg increase) were associated with incident stroke overall. However, higher SBP was not associated with incident stroke in participants with SBP less than 140 mmHg (hazard ratio 0.90, 95% CI 0.53-1.53 per 10-mmHg increase). In additional multivariate models, DBP at least 90 mmHg (hazard ratio 2.45, 95% CI 1.47-4.08) and SBP at least 160 mmHg (vs. <140 mmHg; hazard ratio 2.80, 95% CI 1.53-5.14) were associated with incident stroke. The association between BP and incident stroke was not affected by interactions related to sex, dependence in activities of daily living, or cognitive impairment. CONCLUSION: High SBP (≥160 mmHg) and DBP (≥90 mmHg) and atrial fibrillation appeared to be risk factors for incident stroke among very old people.

The association between SBP and mortality risk differs with level of cognitive function in very old individuals.

OBJECTIVE: Cognitive impairment and dementia are highly prevalent in very old populations. Cardiovascular disease is a common cause of death in people with dementia.This study investigated whether the association of blood pressure (BP) with mortality differed with respect to mini-mental state examination (MMSE) score in a representative sample of very old individuals. METHODS: The sample consisted of 1115 participants aged 85, 90, and at least 95 years from the Umeå85+/GErontological Regional DAtabase cohort study. The main outcome was all-cause mortality within 2 years according to BP and MMSE score, using Cox proportional-hazard regression models adjusted for sociodemographic and clinical characteristics associated with death. RESULTS: Mean age, MMSE score, and SBP and DBP were 89.4 ±â€Š4.6 years, 21.1 ±â€Š7.6, 146.1 ±â€Š23.4 mmHg, and 74.1 ±â€Š11.7 mmHg, respectively. Within 2 years, 293 (26%) participants died. BP was not associated independently with mortality risk, except among participants with MMSE scores of 0-10 among whom mortality risk was increased in association with SBP at least 165 mmHg and 125 mmHg or less, compared with 126-139 mmHg (adjusted hazard ratio 4.54, 95% confidence interval = 1.52-13.60 and hazard ratio 2.23, 95% confidence interval = 1.12-4.45, respectively). In age and sex-adjusted analyses, SBP 125 mmHg or less was associated with increased mortality risk in participants with MMSE scores at least 18. CONCLUSION: In people aged at least 85 years, the association of SBP with mortality appears to differ with respect to MMSE score. Very old individuals with very severe cognitive impairment and low or high BP may have increased mortality risk.