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Despite an established link between depression and higher Alzheimer's disease (AD) risk, it is unclear whether the conditions share pathophysiology. Here, we investigated whether depression manifesting after age 50 is associated with a genetic predisposition to AD.From the population-based Health and Retirement Study cohort with biennial assessments of depressive symptoms and cognitive performance, we studied 6656 individuals of European ancestry with whole-genome genotyping. Polygenic risk scores (PRSs) for AD were estimated and examined for an association with depression in cognitively normal participants using regression modeling.Among cognitively normal participants, those with a higher AD PRS were more likely to experience depression after age 50 after accounting for the effects of genetic predisposition to depression, sex, age, and education.Genetic predisposition to AD may be one of the factors contributing to the pathogenesis of mid-life depression. Whether there is a shared genetic basis between mid-life depression and AD merits further study.

The number of people living with dementia is growing and most patients go years without receiving a specific diagnosis or support services, leading to suboptimal care, negative impacts on the quality of life, and increased costs of care. To address these gaps, the State of Georgia Department of Human Services collaborated with academic and community partners to create the Georgia Memory Net (GMN).GMN is a hub and spoke model partnered with Emory University's Cognitive Neurology Clinic and Emory Goizueta Alzheimer's Disease Research Center to provide training and support for best practices in diagnosis and management to Memory Assessment Clinics (MACs) throughout the state.Communities across the State of Georgia.GMN is a mix of academic and community providers, hospital systems, state and community agencies. Patients and families are evaluated at the MACs and connected to community services.A dedicated clinic workflow: primary care providers (PCPs) identify a memory problem and refer to the MACs for diagnostic evaluation; meeting with a community services educator, and development of a care plan. The patient is reconnected with the PCP for continuity of care.Initial metrics include numbers of unique patients, total patient visits, and referrals to state agency partners for community services.GMN established five MACs across Georgia with annual state funding. Partners at Emory University provided initial training; refined patient workflows for best practices; and provide ongoing support, guidance, and continuing education for MAC teams. Local PCPs and community services partners demonstrated strong engagement with the new model.GMN is an innovative care model to improve access to accurate and timely diagnosis in patients with memory loss. GMN may help improve the quality of life for patients and families through preventive and early care.

The importance of mitogen-activated protein kinase (MAPK) pathway signaling in regulating microglia-mediated neuroinflammation in Alzheimer’s disease (AD) remains unclear. We examined the role of MAPK signaling in microglia using a preclinical model of AD pathology and quantitative proteomics studies of postmortem human brains. In multiplex immunoassay analyses of MAPK phosphoproteins in acutely isolated microglia and brain tissue from 5xFAD mice, we found phosphorylated extracellular signal-regulated kinase (ERK) was the most strongly upregulated phosphoprotein within the MAPK pathway in acutely isolated microglia, but not whole-brain tissue from 5xFAD mice. The importance of ERK signaling in primary microglia cultures was next investigated using transcriptomic profiling and functional assays of amyloid-β and neuronal phagocytosis, which confirmed that ERK is a critical regulator of IFNγ-mediated pro-inflammatory activation of microglia, although it was also partly important for constitutive microglial functions. Phospho-ERK was an upstream regulator of disease-associated microglial gene expression (Trem2, Tyrobp), as well as several human AD risk genes (Bin1, Cd33, Trem2, Cnn2), indicative of the importance of microglial ERK signaling in AD pathology. Quantitative proteomic analyses of post-mortem human brain showed that ERK1 and ERK2 were the only MAPK proteins with increased protein expression and positive associations with neuropathological grade. In a human brain phosphoproteomic study, we found evidence for increased flux through the ERK signaling pathway in AD. Overall, our analyses strongly suggest that ERK phosphorylation, particularly in microglia in mouse models, is a regulator of pro-inflammatory immune responses in AD pathogenesis.

Introduction The retina and brain exhibit similar pathologies in patients diagnosed with neurodegenerative diseases. The ability to access the retina through imaging techniques opens the possibility for non‐invasive evaluation of Alzheimer's disease (AD) pathology. While retinal amyloid deposits are detected in individuals clinically diagnosed with AD, studies including preclinical individuals are lacking, limiting assessment of the feasibility of retinal imaging as a biomarker for early‐stage AD risk detection. Methods In this small cross‐sectional study we compare retinal and cerebral amyloid in clinically normal individuals who screened positive for high amyloid levels through positron emission tomography (PET) from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial as well as a companion cohort of individuals who exhibited low levels of amyloid PET in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. We quantified the number of curcumin‐positive fluorescent retinal spots from a small subset of participants from both studies to determine retinal amyloid deposition at baseline. Results The four participants from the A4 trial showed a greater number of retinal spots compared to the four participants from the LEARN study. We observed a positive correlation between retinal spots and brain amyloid, as measured by the standardized uptake value ratio (SUVr). Discussion The results of this small pilot study support the use of retinal fundus imaging for detecting amyloid deposition that is correlated with brain amyloid PET SUVr. A larger sample size will be necessary to fully ascertain the relationship between amyloid PET and retinal amyloid both cross‐sectionally and longitudinally.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlap in clinical presentation, neuropathology, and genetic underpinnings. The molecular basis for the overlap of these disorders is not well established. We performed a comparative unbiased mass spectrometry‐based proteomic analysis of frontal cortical tissues from postmortem cases clinically defined as ALS, FTD, ALS and FTD (ALS/FTD), and controls. We also included a subset of patients with the C9orf72 expansion mutation, the most common genetic cause of both ALS and FTD. Our systems‐level analysis of the brain proteome integrated both differential expression and co‐expression approaches to assess the relationship of these differences to clinical and pathological phenotypes. Weighted co‐expression network analysis revealed 15 modules of co‐expressed proteins, eight of which were significantly different across the ALS‐FTD disease spectrum. These included modules associated with RNA binding proteins, synaptic transmission, and inflammation with cell‐type specificity that showed correlation with TDP‐43 pathology and cognitive dysfunction. Modules were also examined for their overlap with TDP‐43 protein–protein interactions, revealing one module enriched with RNA‐binding proteins and other causal ALS genes that increased in FTD/ALS and FTD cases. A module enriched with astrocyte and microglia proteins was significantly increased in ALS cases carrying the C9orf72 mutation compared to sporadic ALS cases, suggesting that the genetic expansion is associated with inflammation in the brain even without clinical evidence of dementia. Together, these findings highlight the utility of integrative systems‐level proteomic approaches to resolve clinical phenotypes and genetic mechanisms underlying the ALS‐FTD disease spectrum in human brain.

Introduction It is unclear whether abnormalities in brain glucose homeostasis are associated with Alzheimer's disease (AD) pathogenesis. Methods Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, we measured brain glucose concentration and assessed the ratios of the glycolytic amino acids, serine, glycine, and alanine to glucose. We also quantified protein levels of the neuronal (GLUT3) and astrocytic (GLUT1) glucose transporters. Finally, we assessed the relationships between plasma glucose measured before death and brain tissue glucose. Results Higher brain tissue glucose concentration, reduced glycolytic flux, and lower GLUT3 are related to severity of AD pathology and the expression of AD symptoms. Longitudinal increases in fasting plasma glucose levels are associated with higher brain tissue glucose concentrations. Discussion Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to AD pathogenesis. Abnormalities in brain glucose homeostasis may begin several years before the onset of clinical symptoms.

Abnormal phosphorylation contributes to the formation of neurofibrillary tangles in Alzheimer Disease (AD), but may play other signaling roles during AD pathogenesis. In this study, we employed immobilized metal affinity chromatography (IMAC) followed by liquid chromatography-tandem mass spectrometry to identify phosphopeptides from 8 individual AD and 8 age-matched control postmortem human brain tissues. Using this approach, we identified 5,569 phosphopeptides in frontal cortex across all 16 cases in which phosphopeptides represented 80 percent of all peptide spectral counts collected following IMAC enrichment. Marker selection identified 253 significantly altered phosphopeptides by precursor intensity, changed by at least 1.75 fold relative to controls, with an empirical false discovery rate below 7 percent. Approximately 21 percent of all significantly altered phosphopeptides in AD tissue were derived from tau. Of the other 142 proteins hyperphosphorylated in AD, membrane, synapse, cell junction, and alternatively spliced proteins were overrepresented. Of these, we validated differential phosphorylation of heat-shock protein-beta-1 (HSPB1) and crystallin-alpha-B (CRYAB) as hyperphosphorylated by western blotting. We further identified a network of phosphorylated kinases, which co-enriched with phosphorylated small heat shock proteins. This supports a hypothesis that a number of kinases are regulating and/or regulated by the small heat shock protein folding network.

We recently discovered that protein components of the ribonucleic acid (RNA) spliceosome form cytoplasmic aggregates in Alzheimer's disease (AD) brain, resulting in widespread changes in RNA splicing. However, the involvement of small nuclear RNAs (snRNAs), also key components of the spliceosome complex, in the pathology of AD remains unknown. Using immunohistochemical staining of post-mortem human brain and spinal cord, we identified cytoplasmic tangle-shaped aggregates of snRNA in both sporadic and familial AD cases but not in aged controls or other neurodegenerative disorders. Immunofluorescence using antibodies reactive with the 2,2,7-trimethylguanosine cap of snRNAs and transmission electron microscopy demonstrated snRNA localization with tau and paired helical filaments, the main component of neurofibrillary tangles. Quantitative real-time polymerase chain reaction (PCR) showed U1 snRNA accumulation in the insoluble fraction of AD brains whereas other U snRNAs were not enriched. In combination with our previous results, these findings demonstrate that aggregates of U1 snRNA and U1 small nuclear ribonucleoproteins represent a new pathological hallmark of AD.

TAR DNA-binding protein 43 (TDP-43) is a nuclear protein involved in RNA splicing and a major protein component in ubiquitin-positive, tau-negative inclusions of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Under disease conditions, TDP-43 redistributes to the cytoplasm where it can be phosphorylated, ubiquitinated, and proteolytically cleaved. Enzymes responsible for TDP-43 proteolytic processing in brain remain largely unreported. Using a MS approach, we identified two truncated TDP-43 peptides, terminating C-terminal to asparagines 291 (N291) and 306 (N306). The only documented mammalian enzyme capable of cleaving C-terminal to asparagine is asparaginyl endopeptidase (AEP). TDP-43-immunoreactive fragments (~35 and 32 kDa) predicted to be generated by AEP cleavage at N291 and N306 were observed by Western blot analyses of postmortem frontotemporal lobar degeneration brain tissue and cultured human cells over-expressing TDP-43. Studies in vitro determined that AEP can directly cleave TDP-43 at seven sites, including N291 and N306. Western blots of brain homogenates isolated from AEP-null mice and wild-type littermate controls revealed that TDP-43 proteolytic fragments were substantially reduced in the absence of AEP in vivo. Taken together, we conclude that TDP-43 is cleaved by AEP in brain. Moreover, these data highlight the utility of combining proteomic strategies in vitro and in vivo to provide insight into TDP-43 biology that will fuel the design of more detailed models of disease pathogenesis.

The present study is a discovery mode proteomics analysis of the membrane-enriched fraction of postmortem brain tissue from Alzheimer's disease (AD) and control cases. This study aims to validate a method to identify new proteins that could be involved in the pathogenesis of AD and potentially serve as disease biomarkers.Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyze the membrane-enriched fraction of human postmortem brain tissue from five AD and five control cases of similar age. Biochemical validation of specific targets was performed by immunoblotting.One thousand seven hundred and nine proteins were identified from the membrane-enriched fraction of frontal cortex. Label-free quantification by spectral counting and G-test analysis identified 13 proteins that were significantly changed in disease. In addition to Tau (MAPT), two additional proteins found to be enriched in AD, ubiquitin carboxy-terminal hydrolase 1 (UCHL1), and syntaxin-binding protein 1 (Munc-18), were validated through immunoblotting. DISCUSSION AND CLINICAL RELEVANCE: Proteomic analysis of the membrane-enriched fraction of postmortem brain tissue identifies proteins biochemically altered in AD. Further analysis of this subproteome may help elucidate mechanisms behind AD pathogenesis and provide new sources of biomarkers.