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Background

Plasma phosphorylated tau₂₁₇ (p-tau₂₁₇) is a robust biomarker of Alzheimer's disease (AD) pathology. However, its full potential as a dynamic marker has still not been verified in very old persons, i.e., those with the highest incidence of AD.ObjectiveTo examine the cross-sectional and longitudinal associations between plasma p-tau₂₁₇ concentration and cerebrospinal fluid (CSF) AD biomarkers. Further, to investigate the performance of p-tau₂₁₇ as a predictor of amyloid status in a cohort of very old men.

Methods

CSF AD biomarkers were analyzed in thirty-five 89-year-old men. Amyloid-β (Aβ) positivity was defined according to CSF Aβ₄₂ level. Plasma p-tau₂₁₇ concentration was measured at the mean age of 82, 87, and 91. Incident dementia diagnoses in survivors were identified through medical records up to the age of 102.

Results

Plasma p-tau₂₁₇ strongly correlated with CSF Aβ₄₂ concentration in Aβ-positive (n = 16, Spearman ρ: rho = −0.63, p = 0.009) but not in Aβ-negative (n = 19, rho = 0.111, p = 0.652) men and predicted Aβ status (area under the curve, AUC 0.91). Plasma p-tau₂₁₇ increased over ten years in the Aβ-positive group, while it remained unchanged in the negative group (p = 0.018).

Conclusions

Our findings indicate that plasma p-tau₂₁₇ is a predictor of brain Aβ deposition also in very old individuals.

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.

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 antiherpesvirus treatment and potential APOE epsilon 4 carriership interaction. Methods: This studywas 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: CumulativeADand 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 epsilon 4 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.

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.

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 epsilon 4.

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 epsilon 4 in association with worse TMT-A and better enhanced cued recall. Anti-HSV IgM interacted with APOE epsilon 4 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.

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 Ume degrees a 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.

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.

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 (epsilon 3/epsilon 4 or epsilon 4/epsilon 4) 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 x 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.

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 epsilon 4. Intervention safety, toler-ability, 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 per-cent experienced likely intervention-related mild, temporary adverse events. CSF acyclovir concentrations were mean 5.29 +/- 2.31 mu mol/L. CSF total tau and neuro-filament light concentrations were unchanged; MMSE score and CSF soluble trig-gering 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.

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.