In Alzheimer's disease (AD), the brain's primary immune cells, microglia, become activated and are found in close apposition to amyloid beta (Aβ) protein plaques and neurofibrillary tangles (NFT). The present study evaluated microglia density and morphology in a large group of aged chimpanzees (
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Background: Sex differences impact Alzheimer’s disease (AD) neuropathology, but cell-to-network level dysfunctions in the prodromal phase are unclear. Alterations in hippocampal excitation-inhibition balance (EIB) have recently been linked to early AD pathology. Objective: Examine how AD risk factors (age, APOE ɛ4, amyloid-β) relate to hippocampal EIB in cognitively normal males and females using connectome-level measures. Methods: Individuals from the OASIS-3 cohort (age 42–95) were studied (N = 437), with a subset aged 65+ undergoing neuropsychological testing (N = 231). Results: In absence of AD risk factors (APOE ɛ4/Aβ+), whole-brain EIB decreases with age more significantly in males than females (p = 0.021, β= –0.007). Regression modeling including APOE ɛ4 allele carriers (Aβ–) yielded a significant positive AGE-by-APOE interaction in the right hippocampus for females only (p = 0.013, β= 0.014), persisting with inclusion of Aβ+ individuals (p = 0.012, β= 0.014). Partial correlation analyses of neuropsychological testing showed significant associations with EIB in females: positive correlations between right hippocampal EIB with categorical fluency and whole-brain EIB with the Trail Making Test (p < 0.05). Conclusions: Sex differences in EIB emerge during normal aging and progresses differently with AD risk. Results suggest APOE ɛ4 disrupts hippocampal balance more than amyloid in females. Increased excitation correlates positively with neuropsychological performance in the female group, suggesting a duality in terms of potential beneficial effects prior to cognitive impairment. This underscores the translational relevance of APOE ɛ4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population.
more » « less- Award ID(s):
- 2045848
- NSF-PAR ID:
- 10518792
- Publisher / Repository:
- IOS Press
- Date Published:
- Journal Name:
- Journal of Alzheimer's Disease
- Volume:
- 95
- Issue:
- 4
- ISSN:
- 1387-2877
- Page Range / eLocation ID:
- 1449 to 1467
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract n = 20, ages 37–62 years) with varying degrees of AD‐like pathology. Using immunohistochemical and stereological techniques, we quantified the density of activated microglia and morphological variants (ramified, intermediate, and amoeboid) in postmortem chimpanzee brain samples from prefrontal cortex, middle temporal gyrus, and hippocampus, areas that show a high degree of AD pathology in humans. Microglia measurements were compared to pathological markers of AD in these cases. Activated microglia were consistently present across brain areas. In the hippocampus, CA3 displayed a higher density than CA1. Aβ42 plaque volume was positively correlated with higher microglial activation and with an intermediate morphology in the hippocampus. Aβ42‐positive vessel volume was associated with increased hippocampal microglial activation. Activated microglia density and morphology were not associated with age, sex, pretangle density, NFT density, or tau neuritic cluster density. Aged chimpanzees displayed comparable patterns of activated microglia phenotypes as well as an association of increased microglial activation and morphological changes with Aβ deposition similar to AD patients. In contrast to human AD brains, activated microglia density was not significantly correlated with tau lesions. This evidence suggests that the chimpanzee brain may be relatively preserved during normal aging processes but not entirely protected from neurodegeneration as previously assumed. -
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The amyloid precursor protein (APP) is linked to the genetics and pathogenesis of Alzheimer's disease (AD). It is the parent protein of the β-amyloid (Aβ) peptide, the main constituent of the amyloid plaques found in an AD brain. The pathways from APP to Aβ are intensively studied, yet the normal functions of APP itself have generated less interest. We report here that glutamate stimulation of neuronal activity leads to a rapid increase in
App gene expression. In mouse and human neurons, elevated APP protein changes the structure of the axon initial segment (AIS) where action potentials are initiated. The AIS is shortened in length and shifts away from the cell body. The GCaMP8f Ca2+reporter confirms the predicted decrease in neuronal activity. NMDA antagonists or knockdown ofApp block the glutamate effects. The actions of APP on the AIS are cell-autonomous; exogenous Aβ, either fibrillar or oligomeric, has no effect. In culture, APPSwe(a familial AD mutation) induces larger AIS changes than wild type APP. Ankyrin G and βIV-spectrin, scaffolding proteins of the AIS, both physically associate with APP, more so in AD brains. Finally, in humans with sporadic AD or in the R1.40 AD mouse model, both females and males, neurons have elevated levels of APP protein that invade the AIS.In vivo asin vitro , this increased APP is associated with a significant shortening of the AIS. The findings outline a new role for the APP and encourage a reconsideration of its relationship to AD.SIGNIFICANCE STATEMENT While the amyloid precursor protein (APP) has long been associated with Alzheimer's disease (AD), the normal functions of the full-length Type I membrane protein have been largely unexplored. We report here that the levels of APP protein increase with neuronal activity.In vivo andin vitro , modest amounts of excess APP alter the properties of the axon initial segment. The β-amyloid peptide derived from APP is without effect. Consistent with the observed changes in the axon initial segment which would be expected to decrease action potential firing, we show that APP expression depresses neuronal activity. In mouse AD models and human sporadic AD, APP physically associates with the scaffolding proteins of the axon initial segment, suggesting a relationship with AD dementia. -
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Abstract INTRODUCTION Alzheimer's disease (AD) initiates years prior to symptoms, underscoring the importance of early detection. While amyloid accumulation starts early, individuals with substantial amyloid burden may remain cognitively normal, implying that amyloid alone is not sufficient for early risk assessment.
METHODS Given the genetic susceptibility of AD, a multi‐factorial pseudotime approach was proposed to integrate amyloid imaging and genotype data for estimating a risk score. Validation involved association with cognitive decline and survival analysis across risk‐stratified groups, focusing on patients with mild cognitive impairment (MCI).
RESULTS Our risk score outperformed amyloid composite standardized uptake value ratio in correlation with cognitive scores. MCI subjects with lower pseudotime risk score showed substantial delayed onset of AD and slower cognitive decline. Moreover, pseudotime risk score demonstrated strong capability in risk stratification within traditionally defined subgroups such as early MCI, apolipoprotein E (
APOE ) ε4+ MCI,APOE ε4– MCI, and amyloid+ MCI.DISCUSSION Our risk score holds great potential to improve the precision of early risk assessment.
Highlights Accurate early risk assessment is critical for the success of clinical trials.
A new risk score was built from integrating amyloid imaging and genetic data.
Our risk score demonstrated improved capability in early risk stratification.
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null (Ed.)Abstract Sleep disruption has been associated with increased beta-amyloid deposition and greater risk for later development of Alzheimer’s disease. Studies indicate that sleep disturbance correlates with regional brain volumes, but data are limited. We sought to determine the effect of sleep disturbance on regional brain volumes by cognitive and apolipoprotein e (APOE) e4 status. We conducted a secondary analysis of the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set using complete structural imaging data from 1,371 participants (mean age: 70.5; SD: 11.7). Multiple linear regression was used to estimate the adjusted effect of sleep disturbance (via Neuropsychiatric Inventory Questionnaire) on regional brain volumes through measurement of 30 structural MRI biomarkers. Sleep disruption was associated with greater volumes in the right and left lateral ventricles and greater volume of total white matter hyperintensities (p<.05). Lower mean volumes in total brain, total gray matter, and total cerebrum grey matter volumes, and in 12 hippocampal, frontal, parietal, and temporal lobe volumes were observed among participants who reported sleep disturbance. Males, Hispanic participants, and those with less education were more likely to report sleep disruption. Cognitive status moderated the relationship between sleep disturbance and lateral ventricular volumes, while APOE e4 moderated the effect between sleep disturbance and parietal lobe volumes. These findings suggest that disrupted sleep is associated with atrophy across multiple brain regions and ventricular hydrocephalus ex vacuo, after controlling for intracranial volume and demographic covariates. The influence of cognition and APOE e4 status indicates that this relationship is affected by co-occurring physiological processes.more » « less
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Background: Apolipoprotein E (APOE) genotypes typically increase risk of amyloid-β deposition and onset of clinical Alzheimer’s disease (AD). However, cognitive assessments in APOE transgenic AD mice have resulted in discord. Objective: Analysis of 31 peer-reviewed AD APOE mouse publications (n = 3,045 mice) uncovered aggregate trends between age, APOE genotype, gender, modulatory treatments, and cognition. Methods: T-tests with Bonferroni correction (significance = p < 0.002) compared age-normalized Morris water maze (MWM) escape latencies in wild type (WT), APOE2 knock-in (KI2), APOE3 knock-in (KI3), APOE4 knock-in (KI4), and APOE knock-out (KO) mice. Positive treatments (t+) to favorably modulate APOE to improve cognition, negative treatments (t–) to perturb etiology and diminish cognition, and untreated (t0) mice were compared. Machine learning with random forest modeling predicted MWM escape latency performance based on 12 features: mouse genotype (WT, KI2, KI3, KI4, KO), modulatory treatment (t+, t–, t0), mouse age, and mouse gender (male = g_m; female = g_f, mixed gender = g_mi). Results: KI3 mice performed significantly better in MWM, but KI4 and KO performed significantly worse than WT. KI2 performed similarly to WT. KI4 performed significantly worse compared to every other genotype. Positive treatments significantly improved cognition in WT, KI4, and KO compared to untreated. Interestingly, negative treatments in KI4 also significantly improved mean MWM escape latency. Random forest modeling resulted in the following feature importance for predicting superior MWM performance: [KI3, age, g_m, KI4, t0, t+, KO, WT, g_mi, t–, g_f, KI2] = [0.270, 0.094, 0.092, 0.088, 0.077, 0.074, 0.069, 0.061, 0.058, 0.054, 0.038, 0.023]. Conclusion: APOE3, age, and male gender was most important for predicting superior mouse cognitive performance.more » « less
