Clinical studies indicate that systemic infections accelerate cognitive decline in Alzheimer’s disease. Animal models suggest that this may be due to enhanced pro-inflammatory changes in the brain. We have performed a post-mortem human study to determine whether systemic infection modifies the neuropathology and in particular, neuroinflammation, in the late-stage of the disease.Sections of cerebral cortex and underlying white matter from controls and Alzheimer's patients who died with or without a terminal systemic infection were immunolabelled and quantified for: (i) Αβ and phosphorylated-tau; (ii) the inflammation-related proteins Iba1, CD68, HLA-DR, FcγRs (CD64, CD32a, CD32b, CD16), CHIL3L1, IL4R and CCR2; and (iii) T-cell marker CD3. In Alzheimer's disease, the synaptic proteins synaptophysin and PSD-95 were quantified by ELISA, and the inflammatory proteins and mRNAs by MesoScale Discovery Multiplex Assays and qPCR, respectively.Systemic infection in Alzheimer's disease was associated with decreased CD16 (p = 0.027, grey matter) and CD68 (p = 0.015, white matter); increased CD64 (p = 0.017, white matter) as well as increased protein expression of IL6 (p = 0.047) and decreased IL5 (p = 0.007), IL7 (p = 0.002), IL12/IL23p40 (p = 0.001), IL15 (p = 0.008), IL16 (p < 0.001) and IL17A (p < 0.001). Increased expression of anti-inflammatory genes CHI3L1 (p = 0.012) and IL4R (p = 0.004) were detected in this group. T-cell recruitment to the brain was reduced when systemic infection was present. However, exposure to systemic infection did not modify the pathology. In Alzheimer's disease, CD68 (p = 0.026), CD64 (p = 0.002), CHI3L1 (p = 0.016), IL4R (p = 0.005) and CCR2 (p = 0.010) were increased independently of systemic infection.Our findings suggest that systemic infections modify neuroinflammatory processes in Alzheimer's disease. However, rather than promoting pro-inflammatory changes, as observed in experimental models, they seem to promote an anti-inflammatory, potentially immunosuppressive, environment in the human brain.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0592-3) contains supplementary material, which is available to authorized users.

The finding of more than one coexisting brain pathology in dementia sufferers is not unusual. However, it is unclear how these different diseases may interact or influence the evolution of one another. In this study we analyse the hippocampal expression patterns of hyperphosphorylated tau, paired helical filament (PHF)-related protein, beta-amyloid and synaptophysin in a group of Alzheimer's disease (AD) sufferers with and without additional pathology. Compared to cases with only AD-type pathology we found that the presence of additional vascular disease augmented the accumulation of hyperphosphorylated tau in the CA1 region of the hippocampus without affecting PHF formation in cases with mild AD changes and reduced the extent of PHF formation in the CA2/3 and CA4 regions of the hippocampus in cases with severe AD pathology. We also found that synaptophysin immunoreactivity in the CA4 and dentate gyrus in pure AD was inversely related to the extent of amyloid accumulation but not to neurofibrillary pathology in the same regions. These relationships were lost when additional pathology was present. Memory scores obtained during life correlated closely with hyperphosphorylated tau and PHF-related protein expression in CA1 in pure AD but not in AD with additional pathology. Total amyloid and synaptophysin expression in the hippocampus did not correlate with memory scores in any patient group. Our findings suggest that the interactions of two pathologies in the hippocampus are complex and may differ depending on the stage reached in the evolution of a progressive disease such as AD.

training (AT) can enhance cognition and brain volume of regions sensitive to both aging and neurodegeneration. However, a large degree of variation exists in exercise efficacy on cognition and notably, women seem to show greater cognitive benefit from AT than men. However, few studies have examined this sex difference directly or comprehensively. Apolipoprotein E type 4 allele (APOE4) influences disease progression in Alzheimer's disease (AD) and vascular cognitive impairment (VCI). Importantly, cumulating evidence suggests that APOE4 interacts with sex in AD and possibly VCI to infer greater risk in women. Thus, we examined whether sex interacts with APOE status to moderate the efficacy of AT in older adults at risk for dementia. Methods: A single-blind RCT was conducted in older adults (n¼29 per sex) with subcortical VCI who engaged in 6-months of AT (3x/week) or usual care (control group). Here, we conduct secondary analysis of executive functioning measured at baseline and 6-months using: 1) Trail Making Test (TMT; set-shifting); 2) Digit Symbol Substitution Test (DSST; sustained-attention); 3) Stroop Test (selective-attention, conflict resolution). APOE genotype was determined using TaqMan assay. Participants were categorized as either APOE4+ or APOE-. Analysis of covariance was conducted separately for each executive test, controlling for baseline performance, global cognitive functioning, and age. Results: In the TMT, compared with controls AT significantly enhanced performance in APOE+ females and tended to enhance performance in APOE-females. Interestingly, AT had the opposite effect in males. Compared with controls, AT reduced performance on the TMT in APOE+ males and had no effect in APOE-males. Closer inspection indicated that 3 of the 5 APOE+ males showed large decrements in performance after exposure to the AT intervention. Performance on the DSST and Stroop were not significantly influenced by sex or APOE status. Conclusions: Although preliminary, due to the small sample size, our results are compelling and suggest that biological sex can interact with genotype to moderate exercise efficacy on brain health in older adults at high risk for progression to dementia.Background: Ageing is known as the main risk factor for Alzheimer's Disease (AD) which is characterised by the accumulation of Amyloid-beta (A-beta) in the brain. It remains unclear how agerelated-changes affect the amyloid precursor protein (APP), or A-beta directly, during ageing and increase the extracellular accumulation of A-beta in AD. Using different A-beta and APP specific antibodies, we investigated age-related changes in APP and A-beta, in post-mortem human brain provided by Brains for Dementia Research and BRAIN UK. Methods: Parietal cortex from 27 AD cases and cognitive normal controls, including 32 AD age-matched (OC, >65 years old) and 11 young (YC, <65 years old) cases, were immunostained for: a) APP and A-beta (clone 4G8), b) specifically A-beta (clone 82E1), c) specifically APP (clone 22C11). Quantification was performed by...

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