Associated Alzheimer's Disease Research Articles

Basal forebrain atrophy along the Alzheimer's disease continuum in adults with Down syndrome.

Basal forebrain (BF) degeneration occurs in Down syndrome (DS)-associated Alzheimer's disease (AD). However, the dynamics of BF atrophy with age and disease progression, its impact on cognition, and its relationship with AD biomarkers have not been studied in DS. We included 234 adults with DS (150 asymptomatic, 38 prodromal AD, and 46 AD dementia) and 147 euploid controls. BF volumes were extracted from T-weightedmagnetic resonance images using a stereotactic atlas in SPM12. We assessed BF volume changes with age and along the clinical AD continuum and their relationship to cognitive performance, cerebrospinal fluid (CSF) and plasma amyloid/tau/neurodegeneration biomarkers, and hippocampal volume. In DS, BF volumes decreased with age and along the clinical AD continuum and significantly correlated with amyloid, tau, and neurofilament light chain changes in CSF and plasma, hippocampal volume, and cognitive performance. BF atrophy is a potentially valuable neuroimaging biomarker of AD-related cholinergic neurodegeneration in DS.

Tet1-mediated modulation of Alzheimer's disease.

Human sequencing studies have identified roughly 30 risk loci associated Alzheimer's disease (AD). However, these loci only explain a portion of disease pathogenicity. Recent studies support a link between gene-environment interactions and AD, and published work from our lab indicates Tet1 mediates gene-environment interactions and Tet1 KO reduces stress response in mice [1]. Furthermore, DNA deep sequencing studies identified an enrichment of rare Tet2 variants associated with AD [2]. This study examines how knockout of the Tet1, a DNA 5-hydroxymethylcytosine (5hmC) regulator, influences AD-associated transcription and pathological outcomes in the 5xFAD AD mouse model. We measured cognitive/behavioral, 5hmC, and expression profiles of a Tet1 heterozygous knockout in the 5xFAD mouse model to examine the influences of Tet1 KO on AD pathogenicity. We show significant differences in behavior, cognition, 5hmC methylation and expression profiles of FAD/Tet1+/- mice relative to WT and FAD. In relation to FAD, FAD/Tet1+/- improved stress response in the Tail-Suspension Assay (p = 0.0438), and relative to WT mice, FAD/Tet1+/- mice display a reduction in their latency to mount the platform in the Morris water maze (p = 0.01). Analysis of 5hmC capture data revealed 2536 differentially hydroxymethylated regions (DhMRs) upregulated in FADTet1 and 410 DhMRs downregulated relative FAD (FDR > 0.05). Analysis of the expression data highlighted 132 differentially expressed genes (DEGs) in FAD/Tet1+/- relative to FAD (FDR > 0.05). Among the genes exclusive to the FAD/Tet1 mice were Nr4A1, Arc, and APLP1. Notably, Nr4A1 appeared in both the 5hmC and RNA-Seq data with increased levels of 5hmC and gene expression relative to FAD mice. Gene ontology analysis of RNA expression data identified significant changes in pathways involved in regulation of ion transmembrane transport, behavioral fear response, regulation of trans-synaptic signaling, and learning or memory. Taken together, these results suggest Tet1 modulates AD-associated gene regulation, expression and pathology.

Synaptic stimulation induces tau clearance by enhancing autophagosomal/lysosomal degradation.

Alterations of synaptic excitability and reduced brain metabolism are some of the earliest changes associated Alzheimer's disease (AD) pathogenesis (Reiman et al., 2004; Sperling et al., 2009). Among different approaches for therapeutics, the stimulation of synaptic activity exerts protective effects in models of AD, and deep brain stimulation (DBS) has been shown to ameliorate AD symptoms in certain patients (Sankar et al., 2015; Swaab and Bao, 2010; Tampellini, 2015). Such positive effects might be the result of changes occurring at cellular level upon activity induction, which promote cellular mechanisms correcting neuronal and synaptic dysfunctions. We have demonstrated that synaptic stimulation, via DBS or other methods, is protective in mouse models of AD and frontotemporal dementia (FTD) by enhancing autophagy and lysosomal degradation of pathologic tau, and by protecting synapses (Akwa et al., 2018; Mann et al., 2018). Our more recent investigations are revealing the involvement of Transcription factor EB (TFEB), a pivotal player in lysosomal biogenesis and autophagy (Sardiello et al., 2009), and its downstream genes in the enhancement of lysosomal activity upon stimulation. 3xTg mice received deep brain stimulation by electrode implantation in the entorhinal cortex (Mann et al., 2018). Cultured neurons were prepared from E15 PS19 mouse embryos (Akwa et al., 2018) and stimulated at 14 days in vitro (Ehlers, 2003). Confocal immunofluorescence, Western blot and statistical analyses were performed as described (Akwa et al., 2018). RT-qPCR was performed as described (Napolitano et al., 2018). DBS was able to reduce levels of hyperphosphorylated and oligomeric (but not total) tau restoring levels of synaptic proteins back to wild-type in 3xTg mice. Pathological tau clearance occurred via autophagic pathway and lysosomal activity, the latest being enhanced by synaptic stimulation. TFEB was required for tau clearance as its inhibition prevented activity-induced reduction of pathological tau. In addition, RT-qPCR data analyses revealed increase expressions of TFEB downstream genes, including ATP6-V1H, ATP6-V0D1, and mucolipin-1 in neurons during synaptic stimulation. Protective effects of DBS/synaptic stimulation against pathological tau include the involvement TFEB and the enhancement of autophagy and lysosomal degradation.

Is diabetes associated with increased pathological burden in Alzheimer's disease?

IntroductionWe examined the association between Alzheimer's disease (AD) and type 2 diabetes mellitus (DM) and hypothesized that diabetes is associated with an increased pathological burden in clinically and pathologically diagnosed AD.MethodsAll data were obtained from the Uniform Data Set (UDS) v3, the Neuropathology Data Set, and the Researcher's Data Dictionary‐Genetic Data from the National Alzheimer's Coordinating Center. The dataset (37 cases with diabetes and 1158 cases without) relies on autopsy‐confirmed data in clinically diagnosed AD patients who were assessed for diabetes type in form A5 or D2 during at least one visit. Differences in scores were explored using a general linear model. Effect sizes were calculated using sample means and standard deviations (Cohen's d).ResultsThe presence of diabetes was associated with a lower Thal phase of amyloid plaques (A score; 4.6 ± 0.79 vs. 4.3 ± 0.85, P < .05) and lower Braak stage for neurofibrillary degeneration (B score; 5.58 ± 0.72 vs. 5.16 ± 0.96, P < 0.05) but not for density of neocortical neuritic plaques (CERAD score‐C score). The National Institute on Aging–Alzheimer's Association Alzheimer's disease neuropathologic change (ABC score) was not different between AD+DM and AD‐DM.DiscussionThis pilot study found a significantly lower Thal phase of amyloid plaques and Braak stage for neurofibrillary degeneration in AD‐confirmed individuals with diabetes compared to those without. Thus type 2 DM is not associated with increased AD pathology in clinically and pathologically confirmed cases of AD.

PET Tau Imaging and Motor Impairments Differ Between Corticobasal Syndrome and Progressive Supranuclear Palsy With and Without Alzheimer's Disease Biomarkers.

Introduction: Frontotemporal lobar degeneration (FTLD)-related syndrome includes progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). PSP is usually caused by a tauopathy but can have associated Alzheimer's disease (AD) while CBS can be caused by tauopathy, transactive response DNA binding protein 43 kDa, or AD pathology. Our aim was to compare the parkinsonian syndromes presenting without AD biomarkers (CBS/PSP-non-AD) to parkinsonian syndromes with AD biomarkers (CBS/PSP-AD).Materials and Methods: Twenty-four patients [11 males, 13 females; age (68.46 ± 7.23)] were recruited for this study. The whole cohort was divided into parkinsonian syndromes without AD biomarkers [N = 17; diagnoses (6 CBS, 11 PSP)] and parkinsonian syndromes with AD biomarkers [N = 7; diagnoses (6 CBS-AD, 1 PSP-AD)]. Anatomical MRI and PET imaging with tau ligand [18F]-AV1451 tracer was completed. Cerebrospinal fluid analysis or [18F]-AV1451 PET imaging was used to assess for the presence of AD biomarkers. Progressive supranuclear palsy rating scale (PSPRS) and unified Parkinson's disease rating scale (UPDRS) motor exam were implemented to assess for motor disturbances. Language and cognitive testing were completed.Results: The CBS/PSP-non-AD group [age (70.18 ± 6.65)] was significantly older (p = 0.028) than the CBS/PSP-AD group [age (64.29 ± 7.32)]. There were no differences between the groups in terms of gender, education, years of disease duration, and disease severity as measured with the Clinical Dementia Rating scale. The CBS/PSP-non-AD group had significantly lower PET Tau Standard Volume Uptake Ratio (SUVR) values compared to the CBS/PSP-AD group in multiple frontal and temporal areas, and inferior parietal (all p < 0.03). The CBS/PSP-non-AD group had significantly higher scores compared to the CBS/PSP-AD group on PSPRS (p = 0.004) and UPDRS motor exam (p = 0.045). The CBS/PSP-non-AD group had higher volumes of inferior parietal, precuneus, and hippocampus (all p < 0.02), but lower volume of midbrain (p = 0.02), compared to the CBS/PSP-AD group.Discussion: The CBS/PSP-non-AD group had higher motor disturbances compared to the CBS/PSP-AD group; however, both groups performed similarly on neuropsychological measures. The AD biomarker group had increased global uptake of PET Tau SUVR and lower volumes in AD-specific areas. These results show that the presenting phenotype of CBS and PSP syndromes and the distribution of injury are strongly affected by the presence of AD biomarkers.

Does Treating Vascular Risk Factors Prevent Dementia and Alzheimer's Disease? A Systematic Review and Meta-Analysis.

Epidemiological evidence has associated Alzheimer's disease (AD) with vascular risk factors (VRFs), but whether treatment of VRFs reduces the incidence of dementia and AD is uncertain. To conduct a systematic review and meta-analysis to summarize available data on the impact of treatment of VRFs on dementia and AD incidence. Pertinent studies published until 1 January 2018 were identified from PubMed. Both randomized controlled trials (RCT) and prospective studies that investigated the impact of treatment of VRFs on dementia or AD incidence were included. Eight RCTs and 52 prospective studies were identified. Antihypertensive treatment was associated with a non-significant reduced risk of dementia in RCTs (n = 5; relative risk [RR], 0.84; 95% confidence interval [CI], 0.69-1.02) and prospective studies (n = 3; RR, 0.77; 95% CI, 0.58-1.01) and with reduced AD risk in prospective studies (n = 5; RR = 0.78; 95% CI, 0.66-0.91). In prospective studies, treatment of hyperlipidemia with statins, but not nonstatin lipid-lowering agents, was associated with reduced risk of dementia (n = 17; RR, 0.77; 95% CI, 0.63-0.95) and AD (n = 13; RR, 0.86; 95% CI, 0.80-0.92). The single RCT on statins and dementia incidence showed no association. Data from one RCT and six prospective studies did not support a beneficial impact of antidiabetic drugs or insulin therapy on dementia risk. Current evidence indicates that antihypertensives and statins might reduce the incidence of dementia and AD. Further trials to determine the effect of VRF on AD are needed.

Detection of Cortical Microbleeds in Postmortem Brains of Patients with Lewy Body Dementia: A 7.0-Tesla Magnetic Resonance Imaging Study with Neuropathological Correlates

Background: It is unclear whether associated cerebrovascular pathology contributes to the clinical spectrum of Lewy body dementia (LBD). Summary: The present postmortem 7.0-tesla MRI study investigates the anatomical distribution of cortical microbleeds (CoMBs) in LBD brains with and without associated Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). CoMBs predominated in the frontal section of the LBD brains and were associated to severe white matter lesions. No differences were observed when LBD brains with and without AD and CAA were compared. Key Messages: In LBD, there is a specific distribution of CoMBs that is different from that in other neurodegenerative diseases. The increase of frontal CoMBs is not due to the frequently associated AD and CAA features but due to the LBD itself.

Intranasal Insulin as a Treatment for Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

Research in animals and humans has associated Alzheimer’s disease (AD) with decreased cerebrospinal fluid levels of insulin in combination with decreased insulin sensitivity (insulin resistance) in the brain. This phenomenon is accompanied by attenuated receptor expression of insulin and insulin-like growth factor, enhanced serine phosphorylation of insulin receptor substrate-1, and impaired transport of insulin across the blood-brain barrier. Moreover, clinical trials have demonstrated that intranasal insulin improves both memory performance and metabolic integrity of the brain in patients suffering from AD or its prodrome, mild cognitive impairment. These results, in conjunction with the finding that insulin mitigates hippocampal synapse vulnerability to beta amyloid, a peptide thought to be causative in the development of AD, provide a strong rationale for hypothesizing that pharmacological strategies bolstering brain insulin signaling, such as intranasal administration of insulin, could have significant potential in the treatment and prevention of AD. With this view in mind, the review at hand will present molecular mechanisms potentially underlying the memory-enhancing and neuroprotective effects of intranasal insulin. Then, we will discuss the results of intranasal insulin studies that have demonstrated that enhancing brain insulin signaling improves memory and learning processes in both cognitively healthy and impaired humans. Finally, we will provide an overview of neuroimaging studies indicating that disturbances in insulin metabolism—such as insulin resistance in obesity, type 2 diabetes and AD—and altered brain responses to insulin are linked to decreased cerebral volume and especially to hippocampal atrophy.

Cerebrospinal fluid F2‐isoprostane levels are increased in Alzheimer's disease

Postmortem studies have associated Alzheimer's disease (AD) with regionally increased oxidative damage to brain. Lacking, however, is a specific marker of oxidative damage to brain that may be measured during life. We tested the hypothesis that cerebrospinal fluid (CSF) concentrations of F2-isoprostanes (F2-IsoPs), stable products of arachidonate peroxidation, are increased in CSF of AD patients. CSF from lateral ventricles (VF) was analyzed from 11 AD patients and 11 control subjects who participated in a rapid autopsy program. VF F2-IsoP concentrations were significantly elevated in AD patients compared with control subjects (72 +/- 7 vs 46 +/- 4 pg/ml) and were significantly linearly correlated with brain weight (-0.3 pg/ml/g, r2 = 0.32). These results suggest that quantification of CSF F2-IsoP concentrations may provide a useful biomarker of central nervous system oxidative damage in AD.

The Spatial Patterns of Lewy Bodies, Senile Plaques, and Neurofibrillary Tangles in Dementia with Lewy Bodies

The spatial patterns of Lewy bodies (LB), senile plaques (SP), and neurofibrillary tangles (NFT) were studied in ubiquitin-stained sections of the temporal lobe in cases of dementia with Lewy bodies (DLB), which varied in the degree of associated Alzheimer's disease (AD) pathology. In all patients, LB, SP, and NFT developed in clusters and in a significant proportion of brain areas, the clusters exhibited a regular periodicity parallel to the tissue boundary. In the lateral occipitotemporal gyrus (LOT) and parahippocampal gyrus (PHG), the clusters of LB were larger than those of the SP and NFT but in the hippocampus, clusters of the three lesions were of similar size. Mean cluster size of the LB, SP, and NFT was similar in cases of DLB with and without significant associated AD pathology. LB density was positively correlated with SP and NFT density in 42 and 17% of brain areas analyzed, respectively, while SP and NFT densities were positively correlated in 7% of brain areas. The data suggest that LB in DLB exhibit similar spatial patterns to SP and NFT in AD and that SP and NFT exhibit similar spatial patterns in DLB and AD. In addition, in some instances, clusters of LB appeared to be more closely related spatially to the clusters of SP than to NFT.

β-Amyloid (A β) deposition in the medial temporal lobe of patients with dementia with Lewy bodies

The distribution and density of diffuse, primitive and classic β-amyloid (A β) deposits in the medial temporal lobe (MTL) was studied in cases of dementia with Lewy bodies (DLB) with and without associated Alzheimer's disease (AD) and 15 cases of sporadic AD. In the `pure' DLB cases, virtually no A β deposits were observed in the CA regions of the hippocampus or dentate gyrus whereas deposits were distributed throughout the MTL in DLB/AD and AD cases. Densities of diffuse and primitive A β deposits were similar in AD and DLB/AD cases but density was significantly reduced in the `pure' DLB cases. The density of the classic deposits was significantly reduced in DLB cases with or without associated AD compared with AD cases. These results suggest that A β deposition in the (MTL) in `pure' DLB cases is similar to that of elderly non-demented patients while, with the exception of the classic deposits, A β deposition in DLB/AD cases is similar to that in cases of AD alone.