Increasing evidence suggests that apoE influences the innate immune response in neurodegeneration. Here, Ulrich et al. report that apoE influences amyloid plaque morphology and the microglial response to amyloid plaques, along with plaque-associated neuronal toxicity.
Objective Plasma phosphorylated‐tau‐181 (p‐tau181) reliably detects clinical Alzheimer's disease (AD) as well as asymptomatic amyloid‐β (Aβ) pathology, but is consistently quantified with assays using antibody AT270, which cross‐reacts with p‐tau175. This study investigates two novel phospho‐specific assays for plasma p‐tau181 and p‐tau231 in clinical and asymptomatic AD. Methods Plasma p‐tau species were quantified with Simoa in 44 AD patients, 40 spouse controls and an independent cohort of 151 cognitively unimpaired (CU) elderly who underwent Aβ‐PET. Simoa plasma Aβ42 measurements were available in a CU subset (N = 69). Receiver operating characteristics and Aβ‐PET associations were used to evaluate biomarker validity. Results The novel plasma p‐tau181 and p‐tau231 assays did not show cross‐reactivity. Plasma p‐tau181 accurately detected clinical AD (area under the curve (AUC) = 0.98, 95% CI 0.95–1.00) as well as asymptomatic Aβ pathology (AUC = 0.84, 95% CI 0.76–0.92), while plasma p‐tau231 did not (AUC = 0.74, 95% CI 0.63–0.85 and 0.61, 95% CI 0.52–0.71, respectively). Plasma p‐tau181, but not p‐tau231, detected asymptomatic Aβ pathology more accurately than age, sex and APOE combined (AUC = 0.64). In asymptomatic elderly, correlations between plasma p‐tau181 and Aβ pathology were observed throughout the cerebral cortex (ρ = 0.40, p < 0.0001), with focal associations within AD‐vulnerable regions, particularly the precuneus. The plasma Aβ42/p‐tau181 ratio did not reflect asymptomatic Aβ pathology better than p‐tau181 alone. Interpretation The novel plasma p‐tau181 assay is an accurate tool to detect clinical as well as asymptomatic AD and provides a phospho‐specific alternative to currently employed immunoassays.
IntroductionAlzheimer's disease is one of the great challenges in the coming decades, and despite great efforts, a widely effective disease-modifying therapy in humans remains elusive. One particular promising non-pharmacological therapy that has received increased attention in recent years is based on the Gamma ENtrainment Using Sensory stimulation (GENUS), a high-frequency neural response elicited by a visual and/or auditory stimulus at 40 Hz. While this has shown to be effective in animal models, studies on human participants have reported varying success. The current work hypothesizes that the varying success in humans is due to differences in cognitive workload during the GENUS sessions.MethodsWe recruited a cohort of 15 participants who underwent a scalp-EEG recording as well as one epilepsy patient who was implanted with 50 subdural surface electrodes over temporo-occipital and temporo-basal cortex and 14 depth contacts that targeted the hippocampus and insula. All participants completed several GENUS sessions, in each of which a different cognitive task was performed.ResultsWe found that the inclusion of a cognitive task during the GENUS session not only has a positive effect on the strength and extent of the gamma entrainment, but also promotes the propagation of gamma entrainment to additional neural areas including deep ones such as hippocampus which were not recruited when no cognitive task was required from the participants. The latter is of particular interest given that the hippocampal complex is considered to be one of the primary targets for AD therapies.DiscussionThis work introduces a possible improvement strategy for GENUS therapy that might contribute to increasing the efficacy of the therapy or shortening the time needed for the positive outcome.
Language dysfunction is common in Alzheimer’s disease. There is increasing interest in the preclinical or asymptomatic phase of Alzheimer’s disease. Here we examined in 35 cognitively intact older adults (age range 52–78 years at baseline, 17 male) in a longitudinal study design the association between accumulation of amyloid over a five to six year period, measured using PET, and functional changes in the language network measured over the same time period using task-related functional MRI. In the same participants, we also determined the association between the longitudinal functional MRI changes and a cross-sectional measure of tau load as measured with 18F-AV1451 PET. As predicted, the principal change occurred in posterior temporal cortex: In the cortex surrounding the right superior temporal sulcus, the response amplitude during the associative-semantic versus visuoperceptual task increased over time as amyloid load accumulated (Pcorrected = 0.008). In a whole-brain voxelwise analysis, amyloid accumulation was also associated with a decrease in response amplitude in the left inferior frontal sulcus (Pcorrected = 0.009) and the right dorsomedial prefrontal cortex (Pcorrected = 0.005). In cognitively intact older adults, cross-sectional tau load was not associated with longitudinal changes in fMRI response amplitude. Our findings confirm the central role of the neocortex surrounding the posterior superior temporal sulcus as the area of predilection within the language network in the earliest stages of Alzheimer’s disease. Amyloid accumulation has an impact on cognitive brain circuitry in the asymptomatic phase of Alzheimer’s disease.
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