Search

Similar manifestations of functional decline in ageing and Alzheimer's disease obscure differences in the underlying cognitive mechanisms of impairment. We sought to examine the contributions of top-down attentional and bottom-up perceptual factors to visual self-movement processing in ageing and Alzheimer's disease. We administered a novel heading discrimination task requiring subjects to determine direction of simulated self-movement from left or right offset optic flow fields of several sizes (25 degrees, 40 degrees or 60 degrees in diameter) to 18 Alzheimer's disease subjects (mean age = 75.3, 55% female), 21 older adult control subjects (mean age = 72.4, 67% female), and 26 younger control subjects (mean age = 26.5, 63% female). We also administered computerized measures of processing speed and divided and selective attention, and psychophysical measures of visual motion perception to all subjects. Both older groups showed significant difficulty in judging the direction of virtual self-movement [F(2,194) = 40.5, P less than 0.001] and optic flow stimulus size had little effect on heading discrimination for any group. Both older groups showed impairments on measures of divided [F(2,62) = 22.2, P less than 0.01] and selective [F(2,62) = 63.0, P less than 0.001] attention relative to the younger adult control group, while the Alzheimer's disease group showed a selective impairment in outward optic flow perception [F(2,64) = 6.3, P = 0.003] relative to both control groups. Multiple linear regression revealed distinct attentional and perceptual contributions to heading discrimination performance for the two older groups. In older adult control subjects, poorer heading discrimination was attributable to attentional deficits (R[superscript 2] adj = 0.41, P = 0.001) whereas, in Alzheimer's disease patients, it was largely attributable to deficits of visual motion perception (R[superscript 2] adj = 0.57, P less than 0.001). These findings suggest that successive attentional and perceptual deficits play independent roles in the progressive functional impairments of ageing and Alzheimer's disease. We speculate that the attentional deficits that dominate in older adults may promote the development of the perceptual deficits that further constrain performance in Alzheimer's disease.

Background: Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development. Method: We assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer's Biomarker Consortium‐Down Syndrome (ABC‐DS) and 265 mutation‐carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated‐years‐to‐symptom‐onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC‐DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40. Result: The relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ ‐23 but was not elevated in DS until EYO ≥ ‐15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5). Conclusion: These results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5‐10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy. [ABSTRACT FROM AUTHOR]

Background: Plasma tau phosphorylated at threonine 217 (P‐tau217) and glial fibrillary acidic protein (GFAP) are promising diagnostic and prognostic biomarkers of Alzheimer's disease (AD). We aimed to determine the usefulness of plasma P‐tau217 and GFAP to detect AD‐related pathology in individuals with Down syndrome (DS). Method: This cross‐sectional study included adults with DS (N=300) and non‐DS sibling controls (N=37) with baseline blood samples enrolled in the Alzheimer's Biomarker Consortium‐Down Syndrome study. Participants with DS all underwent plasma P‐tau217 and GFAP assessments as well as tau‐PET, β‐amyloid (Aβ)‐PET and cognitive testing. We examined association of plasma P‐tau217 and GFAP with tau‐PET, Aβ‐PET and cognitive measures using regression models and ROC curve analysis and investigated if combining P‐tau217 and GFAP together and with other plasma AD biomarkers (Aβ42/40, neurofilament light [NfL], total tau [T‐tau]) and age could improve their performance for identifying individuals with abnormal tau‐PET or Aβ‐PET. Result: Plasma levels of P‐tau217 were increased in Aβ‐PET‐positive tau‐PET‐positive (A+T+) DS and A+T– DS compared with A–T– DS while GFAP was only increased in A+T+ DS (Figure 1). Plasma P‐tau217 levels were also higher in A+T+ DS than A+T– DS. In participants with DS, plasma P‐tau217 and GFAP (but not plasma Aβ42/40, t‐tau and NfL) were consistently associated with abnormal tau‐PET and Aβ‐PET status in models covaried for age (ORrange, 1.59‐2.46, p<0.028). A combination of P‐tau217 and age performed best when detecting tau‐PET abnormality in the temporal and neocortical regions (AUCrange, 0.96‐98), whereas the most parsimonious model for Aβ‐PET status included P‐tau217, T‐tau and age (AUC=0.95) (Figure 2). Higher levels of plasma P‐tau217 were associated with worse performance on DS Mental Status Examination and Cued Recall tests in Aβ‐PET positive (βrange, ‐0.231–[‐0.559], p<0.036) but not in Aβ‐PET negative DS. Conclusion: Plasma p‐tau217 is an accurate biomarker of both tau and Aβ pathological brain changes in DS that could facilitate inclusion of individuals with DS in future AD clinical trials, especially when combined with age as a covariate. [ABSTRACT FROM AUTHOR]

ntroduction: Representation of Mexican Americans in Alzheimer’s disease (AD) clinical research has been extremely poor. Methods: Data were examined from the ongoing community-based, multi-ethnic Health & Aging Brain among Latino Elders (HABLE) study. Participants underwent functional exams, clinical labs, neuropsychological testing, and 3T magnetic resonance imaging of the brain. Fasting proteomic markers were examined for predicting mild cognitive impairment (MCI) and AD using support vector machine models. Results: Data were examined from n = 1649 participants (Mexican American n = 866; non-Hispanic White n = 783). Proteomic profiles were highly accurate in detecting MCI (area under the curve [AUC] = 0.91) and dementia (AUC = 0.95). The proteomic profiles varied significantly between ethnic groups and disease state. Negative predictive value was excellent for ruling out MCI and dementia across ethnic groups.Discussion: A blood-based screening tool can serve as a method for increasing access to state-of-the-art AD clinical research by bridging between community-based and clinic-based settings. [ABSTRACT FROM AUTHOR]

Background: Human GWAS have identified variants of the triggering receptor expressed on myeloid cells 2 (TREM2) gene as a major genetic risk factor for Alzheimer's disease (AD). TREM2 is necessary for maintaining microglial metabolic fitness and may be critical for providing cellular energy demands for microglial‐dependent β amyloid phagocytosis. Here, we examine the plasma metabolome of Trem2 R47H NSS mice in the presence of β amyloid plaques to examine alterations of cellular energy metabolites. Method: We examined the abundance of plasma metabolites obtained from homozygous Trem2 R47H NSS (Jax #034036), 5xFAD x Trem2 R47H NSS, 5xFAD hemizygous, and control (WT) mice (n = 10 each group) at 4 months of age. We measured 762 lipids and 204 polar metabolites from peripheral plasma using liquid chromatography mass spectrometry (LC‐MS). We conducted differential abundance (DA) analysis for the individual metabolites and compared the groups using FDR correction (q < 0.05). We used DA metabolites in pathway analysis to examine which metabolic pathways were impacted by TREM2 R47H and the presence of amyloid (5xFAD hemizygous background). Result: Homozygous Trem2 R47H NSS mice, both in the presence and absence of amyloid plaques (i.e. 5xFAD hemizygous or non‐transgenic background), had significantly lower abundance α‐D‐glucose and lactate compared to their relevant control groups (q's < 0.05). 5xFAD x Trem2 R47H NSS mice also showed significantly lower phosphatidylethanolamine (PE) abundance relative to 5xFAD hemizygous mice (q's < 0.05) and this was especially apparent for female mice (q's < 0.05). KEGG pathway analysis using DA features revealed enrichment on Glycerophospholipid Metabolism and Glycolysis/Gluconeogenesis pathways. Conclusion: We report lower levels of the entry substrate to glycolysis (Glucose) and an end product metabolite (Lactate) in homozygous Trem2 R47H NSS mice, especially in the presence of amyloid. The depletion of these energy metabolites in circulating blood may reflect failure of the immunometabolic switch from oxidative phosphorylation to glycolysis in support of increased energy demands of activated microglia. We also find significant depletion of glycerophospholipids in Trem2 R47H NSS mice, which was more pronounced for female mice. These results suggest cellular energy dyshomeostasis associated with microglial activation which can be measured in peripheral blood. [ABSTRACT FROM AUTHOR]

Background: People with Down syndrome (DS) have a higher risk of developing Alzheimer disease (AD), due to an extra copy of the amyloid precursor protein (APP) gene on chromosome 21. Overexpression of APP is associated with increased production of amyloid beta (Aβ) in DS, and contributes to early onset of AD. Some studies suggest women with DS are at a higher risk for AD, while others find the opposite. Sex differences may be mediated by estrogen, which is critically involved in neuronal survival and modulation. We hypothesized that lower levels of ERα protein would correlate with increasing AD pathology in DS. Method: We examined 34 brains (frontal and occipital cortices) of people with DS and DS with AD. Serial sections were immunostained for phosphorylated tau (pTau ‐AT8) and Aβ (6E10) along with ERα and quantified using QuPath. Spearman rank correlations using log transformed % load data were calculated, Kruskal‐Wallis was used to compare men (n = 19) and women(n = 15). Result: No significant differences in protein levels of ERα, Aβ, or tau were observed when comparing men and women with DS. However, we found higher levels of ERα protein were associated with higher levels of Aβ in the gray matter of the occipital cortex (r = 0.7078; p = 0.0005) in all cases. This positive correlation was driven primarily by women. Females with DS showed a significant positive association with Aβ and ERα (r = 0.93; p = 0.00012) whereas men showed a weaker trend (r = 0.62; p = 0.057). In contrast, no significant associations between ERα, Aβ or pTau were observed in the frontal cortex. PTau measures in the occipital cortex in women with DS were positively associated with ERα (r = 0.61; p = 0.055), whereas men with DS showed a slight negative, though not significant association (r = ‐0.29; p = 0.41). There was no such trend in the frontal cortex. Conclusion: These results suggest ERα, in contrast to our original hypothesis, may be increasing in response to AD pathology to preserve neuronal health in the occipital cortex. Lack of similar positive associations in the frontal cortex may be related to AD progression, with the occipital cortex being affected later in disease, giving us the opportunity to observe increased ERα. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysregulation has been implicated in the pathobiology of Alzheimer's disease (AD), including familial autosomal dominant AD (ADAD). Recent metabolic neuroimaging of preclinical ADAD mutation carriers has suggested that levels of the reactive glial marker myo‐inositol increase with proximity to expected age at dementia onset. It remains unclear, however, if similar metabolic change related to anticipated phenoconversion can be observed at network‐scale in the peripheral plasma metabolome of ADAD mutation carriers. Method: We collected peripheral blood plasma from ADAD mutation carriers with and without objective cognitive decline (ncarrier = 55) who participated in a longitudinal kindred study. We used untargeted liquid chromatography‐ mass spectrometry (LC‐MS) metabolomics to infer putative metabolic pathway and protein disruptions associated with impending dementia diagnosis at whole‐genome scale. Spearman 흆 correlation coefficients were determined for each identified mass feature in relation to clinical, family‐wise estimated years to diagnosis prior to the submission of these summary statistics to metabolomic modeling. Result: A total of 91 LC‐MS mass features were significantly correlated with estimated years to dementia onset, nominal p's <.05. Pathway‐based, genome‐scale metabolomic modeling analysis revealed a de novo plasma metabolomic activity network composed of interconnected lipid and small, polar metabolite hubs. These same correlations were also submitted to gene‐inferring, whole‐genome metabolomic modeling using PIUmet. Intriguingly, mRNA expression of prioritized genes was not limited to the brain and involved multiple peripheral tissues. In the CNS itself, however, genes prioritized by PIUMet metabolomic modeling frequently demonstrated expression in glia. Conclusion: Consistent with prior metabolic findings in ADAD mutation carriers, network alterations to the peripheral plasma metabolome correspond with increasing proximity to expected age of dementia onset. Because neuroinflammation has been previously described as an immunometabolic process in pathological aging, emerging metabolic network disintegrity in ADAD may index reactive glial pathobiology previously suggested by prior metabolic investigations of this population. These perturbed networks inferred from participant blood plasma suggest targetable CNS‐peripheral metabolic dyshomeostases which otherwise precipitate pathobiological "failures of compensation" and concomitant cognitive decline in carriers of Mendelian ADAD mutations. [ABSTRACT FROM AUTHOR]