APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE4 increases brain amyloid-β (Aβ) pathology relative to other ApoE isoforms1. However, whether APOE independently influences tau pathology, the other major proteinopathy of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knockin (KI) or ApoE knockout (KO) background, we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by 3 months of age compared to P301S/E2, P301S/E3 and P301S/EKO mice. By 9 months of age, P301S mice with different ApoE genotypes display distinct p-tau staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity following LPS treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of TNFα secretion and markedly reduced neuronal viability compared to neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNFα. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared to the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In Aβ-pathology positive individuals with symptomatic AD who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independent of Aβ pathology. ApoE4 exerts a “toxic” gain of function whereas the absence of ApoE is protective.

See Mander et al. (doi:10.1093/awx174) for a scientific commentary on this article.Sleep deprivation increases amyloid-β, suggesting that chronically disrupted sleep may promote amyloid plaques and other downstream Alzheimer's disease pathologies including tauopathy or inflammation. To date, studies have not examined which aspect of sleep modulates amyloid-β or other Alzheimer's disease biomarkers. Seventeen healthy adults (age 35-65 years) without sleep disorders underwent 5-14 days of actigraphy, followed by slow wave activity disruption during polysomnogram, and cerebrospinal fluid collection the following morning for measurement of amyloid-β, tau, total protein, YKL-40, and hypocretin. Data were compared to an identical protocol, with a sham condition during polysomnogram. Specific disruption of slow wave activity correlated with an increase in amyloid-β40 (r = 0.610, P = 0.009). This effect was specific for slow wave activity, and not for sleep duration or efficiency. This effect was also specific to amyloid-β, and not total protein, tau, YKL-40, or hypocretin. Additionally, worse home sleep quality, as measured by sleep efficiency by actigraphy in the six nights preceding lumbar punctures, was associated with higher tau (r = 0.543, P = 0.045). Slow wave activity disruption increases amyloid-β levels acutely, and poorer sleep quality over several days increases tau. These effects are specific to neuronally-derived proteins, which suggests they are likely driven by changes in neuronal activity during disrupted sleep.

IMPORTANCE Individuals in the presymptomatic stage of Alzheimer disease (AD) are increasingly being targeted for AD secondary prevention trials. How early during the normal life span underlying AD pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined. OBJECTIVE To characterize the within-person trajectories of cerebrospinal fluid (CSF) biomarkers of AD over time and their association with changes in brain amyloid deposition and cognitive decline in cognitively normal middle-aged individuals. DESIGN, SETTING, AND PARTICIPANTS As part of a cohort study, cognitively normal (Clinical Dementia Rating [CDR] of 0) middle-aged research volunteers (n = 169) enrolled in the Adult Children Study at Washington University, St Louis, Missouri, had undergone serial CSF collection and longitudinal clinical assessment (mean, 6 years; range, 0.91-11.3 years) at 3-year intervals at the time of analysis, between January 2003 and November 2013. A subset (n = 74) had also undergone longitudinal amyloid positron emission tomographic imaging with Pittsburgh compound B (PiB) in the same period. Serial CSF samples were analyzed for β-amyloid 40 ( Aβ40), Aβ42, total tau, tau phosphorylated at threonine 181 (P-tau 181 ), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Within-person measures were plotted according to age and AD risk defined by APOE genotype (ε4 carriers vs noncarriers). Linear mixed models were used to compare estimated biomarker slopes among middle-age bins at baseline (early, 45-54 years; mid, 55-64 years; late, 65-74 years) and between risk groups. Within-person changes in CSF biomarkers were also compared with changes in cortical PiB binding and progression to a CDR higher than 0 at follow-up. MAIN OUTCOMES AND MEASURESChanges in Aβ40, Aβ42, total tau, P-tau 181 , VILIP-1, and YKL-40 and, in a subset of participants, changes in cortical PiB binding.RESULTS While there were no consistent longitudinal patterns in Aβ40 (P = .001-.97), longitudinal reductions in Aβ42 were observed in some individuals as early as early middle age (P Յ .05) and low Aβ42 levels were associated with the development of cortical PiB-positive amyloid plaques (area under receiver operating characteristic curve = 0.9352; 95% CI, 0.8895-0.9808), especially in mid middle age (P < .001). Markers of neuronal injury (total tau, P-tau 181 , and VILIP-1) dramatically increased in some individuals in mid and late middle age (P Յ .02), whereas the neuroinflammation marker YKL-40 increased consistently throughout middle age (P Յ .003). These patterns were more apparent in at-risk ε4 carriers (Aβ42 in an allele dose-dependent manner) and appeared to be associated with future cognitive deficits as determined by CDR. CONCLUSIONS AND RELEVANCELongitudinal CSF biomarker patterns consistent with AD are first detectable during early middle age and are associated with later amyloid positivity and cognitive decline. Such measures may be useful for targeti...

Objectives: We compared the ability of molecular biomarkers for Alzheimer disease (AD), including amyloid imaging and CSF biomarkers (Ab 42 , tau, ptau 181 , tau/Ab 42 , ptau 181 /Ab 42 ), to predict time to incident cognitive impairment among cognitively normal adults aged 45 to 88 years and followed for up to 7.5 years.Methods: Longitudinal data from Knight Alzheimer's Disease Research Center participants (N 5 201) followed for a mean of 3.70 years (SD 5 1.46 years) were used. Participants with amyloid imaging and CSF collection within 1 year of a clinical assessment indicating normal cognition were eligible. Cox proportional hazards models tested whether the individual biomarkers were related to time to incident cognitive impairment. "Expanded" models were developed using the biomarkers and participant demographic variables. The predictive values of the models were compared.Results: Abnormal levels of all biomarkers were associated with faster time to cognitive impairment, and some participants with abnormal biomarker levels remained cognitively normal for up to 6.6 years. No differences in predictive value were found between the individual biomarkers (p . 0.074), nor did we find differences between the expanded biomarker models (p . 0.312). Each expanded model better predicted incident cognitive impairment than the model containing the biomarker alone (p , 0.005). Conclusions:Our results indicate that all AD biomarkers studied here predicted incident cognitive impairment, and support the hypothesis that biomarkers signal underlying AD pathology at least several years before the appearance of dementia symptoms. Biomarkers may signal underlying Alzheimer disease (AD) pathology a decade or more before the appearance of dementia symptoms.1,2 Therefore, understanding the temporal relationships between biomarker levels in cognitively normal adults, symptomatic AD (i.e., incident AD), and factors that modify those relationships is imperative.3 The National Institute on Aging/ Alzheimer's Association workgroup urges that the factors that best predict progression from normal cognition to cognitive impairment and dementia due to AD need to be determined. 3The most well-studied and promising molecular biomarkers of AD are those that reflect the presence of the signature lesions of AD: plaques, which comprise the amyloid-b (Ab) protein, and tangles, which comprise the tau protein. Both amyloid imaging, 4 used to identify fibrillar Ab plaques, and CSF biomarkers, 5 which reflect soluble Ab, tau, and phosphorylated tau (ptau), predict incident AD.6-8 However, until now, directly comparing the predictive ability of amyloid imaging with CSF biomarkers was difficult, given the recent development of amyloid imaging 4 and attendant short follow-up times, the lengthy hypothesized time between the appearance of AD

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