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Key features: 

• The Northern Sweden Health and Disease Study (NSHDS) was initiated in the mid-1980s. The NSHDS is a population-based prospective longitudinal cohort comprising >140 000 participants in the two northernmost regions in Sweden, Norrbotten and Västerbotten, with >240 000 blood samples and 1.5 million person-years of follow-up.
• The NSHDS includes three sub-cohorts: the Västerbotten Intervention Programme (VIP), the expanded Northern Sweden Monitoring of Trends and Determinants of Cardiovascular Disease (MONICA) Study, and the Mammography Screening Project (MSP). The VIP is both a community-based cardiometabolic intervention programme encouraging healthy lifestyle (targeting individuals 40, 50, and 60 years of age), and a corresponding research cohort. The MONICA is an observational study focusing on cardiovascular disease and its associated risk factors, recruiting individuals aged 25–74 years. The MSP recruited women attending mammography during 1995–2006. The NSHDS median participation age is 50 years (53% women).
• Most participants contribute data on health, lifestyle, anthropometric measures, blood pressure, blood lipids, and glucose tolerance, along with research blood samples that are fractionated, frozen within an hour of collection, and stored at –80°C. Linkage to registries, clinical cohorts, and biological tissue archives facilitates studies of well-characterized participants (often combined with intervention studies).
• Collaborations are encouraged. Additional information can be found at: info.brs@umu.se; https://www.umu.se/en/biobank

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.

How acute hyperglycaemia affects memory functions and functional brain responses in individuals with and without type 2 diabetes is unclear. Our aim was to study the association between acute hyperglycaemia and working, semantic, and episodic memory in participants with type 2 diabetes compared to a sex- A nd age-matched control group. We also assessed the effect of hyperglycaemia on working memory-related brain activity. A total of 36 participants with type 2 diabetes and 34 controls (mean age, 66 years) underwent hyperglycaemic clamp or placebo clamp in a blinded and randomised order. Working, episodic, and semantic memory were tested. Overall, the control group had higher working memory (mean z-score 33.15 ± 0.45) than the group with type 2 diabetes (mean z-score 31.8 ± 0.44, p = 0.042) considering both the placebo and hyperglycaemic clamps. Acute hyperglycaemia did not influence episodic, semantic, or working memory performance in either group. Twenty-two of the participants (10 cases, 12 controls, mean age 69 years) were randomly invited to undergo the same clamp procedures to challenge working memory, using 1-, 2-, and 3-back, while monitoring brain activity by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). The participants with type 2 diabetes had reduced working memory during the 1- A nd 2-back tests. fMRI during placebo clamp revealed increased BOLD signal in the left lateral frontal cortex and the anterior cingulate cortex as a function of working memory load in both groups (3>2>1). During hyperglycaemia, controls showed a similar load-dependent fMRI response, whereas the type 2 diabetes group showed decreased BOLD response from 2-to 3-back. These results suggest that impaired glucose metabolism in the brain affects working memory, possibly by reducing activity in important frontal brain areas in persons with type 2 diabetes.

Background: There is a lack of trustworthy evidence-informed guidelines on the diagnosis and management of acute appendicitis in elderly patients.

Methods: We developed a rapid guideline in accordance with GRADE and AGREE II standards. The steering group consisted of general surgeons, members of the EAES Research Committee/Guidelines Subcommittee with expertise and experience in guideline development, advanced medical statistics and evidence synthesis, biostatisticians, and a guideline methodologist. The guideline panel consisted of three general surgeons, an intensive care physician, a geriatrician and a patient advocate. We conducted systematic reviews and the results of evidence synthesis were summarized in evidence tables. Recommendations were authored and published through an online authoring and publication platform (MAGICapp), with the guideline panel making use of an evidence-to-decision framework and a Delphi process to arrive at consensus.

Results: This rapid guideline provides a weak recommendation against the use of clinical scoring systems to replace cross-sectional imaging in the diagnostic approach of suspected appendicitis in elderly patients. It provides a weak recommendation against the use of antibiotics alone over surgical treatment in patients who are deemed fit for surgery, and a weak recommendation for laparoscopic over open surgery. Furthermore, it provides a summary of surgery-associated risks in elderly patients. The guidelines, with recommendations, evidence summaries and decision aids in user-friendly formats can also be accessed in MAGICapp: https://app.magicapp.org/#/guideline/4494.

Conclusions: This rapid guideline provides evidence-informed trustworthy recommendations on the diagnosis and management of acute appendicitis in elderly patients.

Background: Amyloid-β (Aβ), the key constituent of Alzheimer’s disease (AD) plaques, has antimicrobial properties.

Objective: To investigate the association between plasma Aβ 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 Aβ40 and Aβ42 concentrations with Luminex xMAP technology and INNOBIA plasma Aβ-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 Aβ42 or Aβ40 in cases or controls.

Conclusion: Levels of plasma Aβ were not associated with antibodies against different AD-related pathogens.

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.

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). APOE 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.

The number of older people living with cancer and cardiometabolic conditions is increasing, but little is known about how specific combinations of these conditions impact mortality.

A total of 22,692 participants aged 65 years and older from four international cohorts were followed-up for mortality for an average of 10 years (8,596 deaths). Data were harmonized across cohorts and mutually exclusive groups of disease combinations were created for cancer, myocardial infarction (MI), stroke, and diabetes at baseline. Cox proportional hazards models for all-cause mortality were used to estimate the age- and sex-adjusted hazard ratio and rate advancement period (RAP) (in years).

At baseline, 23.6% (n = 5,116) of participants reported having one condition and 4.2% (n = 955) had two or more conditions. Data from all studies combined showed that the RAP increased with each additional condition. Diabetes advanced the rate of dying by the most years (5.26 years; 95% confidence interval [CI], 4.536.00), but the effect of any single condition was smaller than the effect of disease combinations. Some combinations had a significantly greater impact on the period by which the rate of death was advanced than others with the same number of conditions, for example, 10.9 years (95% CI, 9.412.6) for MI and diabetes versus 6.4 years (95% CI, 4.38.5) for cancer and diabetes.

Combinations of cancer and cardiometabolic conditions accelerate mortality rates in older adults differently. Although most studies investigating mortality associated with multimorbidity used disease counts, these provide little guidance for managing complex patients as they age.

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.