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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: 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.

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.

Objective: This study aimed to explore changes to resident thriving in Swedish nursing homes over a 5-year period and describe changes in associated factors. Methods: Cross-sectional data were collected from a randomised sample of Swedish nursing homes in 2013/2014 (baseline) and 2018/2019 (follow-up). Descriptive statistics, independent samples t-tests, and chi squared tests were used to statistically evaluate differences between the samples. Simple and multiple linear regression analyses were used to explore associations between thriving and the study variables. Results: Resident characteristics were relatively consistent between the full baseline (N = 4831) and follow-up (N = 3894) samples. Within a sub-sample of nursing homes that participated in both data collections mean thriving scores were found to have increased from 152.9 to 155.2 (p <= 0.003; d =0.09) and overall neuropsychiatric index scores had decreased from 16.0 to 14.3 (p <= 0.004; d =0.09), as had the prevalence of several neuropsychiatric symptoms. Thriving was found to have a positive association with the neuropsychiatric symptom of elation/euphoria, and negative associations with the symptoms of aggression/agitation, depression/ dysphoria, apathy, and irritability. Conclusions: The results show an increase in overall thriving scores and a decrease in overall neuropsychiatric scores between baseline and follow-up. This study confirmed associations between thriving and certain neuropsychiatric symptoms and established comparative knowledge regarding changes in resident thriving, characteristics, and symptom prevalence. These findings could inform future care and organisational policies to support thriving in nursing homes, particularly among residents at risk of lower thriving due to cognitive impairment or neuropsychiatric symptoms.

Background: Amyloid-beta (A beta), the key constituent of Alzheimer's disease (AD) plaques, has antimicrobial properties. Objective: To investigate the association between plasma A beta 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 A beta(40) and A beta(42) oncentrations with Luminex xMAP technology and INNOBIA plasma A beta-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 A beta 42 or A beta 40 in cases or controls. Conclusion: Levels of plasma A beta 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 Fc gamma receptor (Fc gamma R), which blocks Fc-mediated effector functions, such as Ab-dependent cellular cytotoxicity. Ig gamma 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 TagMan 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 epsilon 4 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.

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.

IntroductionHerpes simplex virus type 1 (HSV1) in combination with genetic susceptibility has previously been implicated in Alzheimer's disease (AD) pathogenesis. MethodsPlasma from 360 AD cases, obtained on average 9.6years 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. ResultsThe interaction between APOE epsilon 4 heterozygosity (APOE epsilon 2/epsilon 4 or epsilon 3/epsilon 4) 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). DiscussionThe present findings suggest that the APOE epsilon 4 allele and other AD genetic risk factors might potentiate the risk of HSV1-associated AD.