Biological and Clinical Implications of Sex-Specific Differences in Alzheimer's Disease.

Mounting evidence indicates that the female sex is a risk factor for Alzheimer's disease (AD), the most common cause of dementia worldwide. Decades of research suggest that sex-specific differences in genetics, environmental factors, hormones, comorbidities, and brain structure and function may contribute to AD development. However, although significant progress has been made in uncovering specific genetic factors and biological pathways, the precise mechanisms underlying sex-biased differences are not fully characterized. Here, we review several lines of evidence, including epidemiological, clinical, and molecular studies addressing sex differences in AD. In addition, we discuss the challenges and future directions in advancing personalized treatments for AD.

Co-Expression Network Analysis Identifies Molecular Determinants of Loneliness Associated with Neuropsychiatric and Neurodegenerative Diseases.

Loneliness and social isolation are detrimental to mental health and may lead to cognitive impairment and neurodegeneration. Although several molecular signatures of loneliness have been identified, the molecular mechanisms by which loneliness impacts the brain remain elusive. Here, we performed a bioinformatics approach to untangle the molecular underpinnings associated with loneliness. Co-expression network analysis identified molecular 'switches' responsible for dramatic transcriptional changes in the nucleus accumbens of individuals with known loneliness. Loneliness-related switch genes were enriched in cell cycle, cancer, TGF-ß, FOXO, and PI3K-AKT signaling pathways. Analysis stratified by sex identified switch genes in males with chronic loneliness. Male-specific switch genes were enriched in infection, innate immunity, and cancer-related pathways. Correlation analysis revealed that loneliness-related switch genes significantly overlapped with 82% and 68% of human studies on Alzheimer's (AD) and Parkinson's diseases (PD), respectively, in gene expression databases. Loneliness-related switch genes, BCAM, NECTIN2, NPAS3, RBM38, PELI1, DPP10, and ASGR2, have been identified as genetic risk factors for AD. Likewise, switch genes HLA-DRB5, ALDOA, and GPNMB are known genetic loci in PD. Similarly, loneliness-related switch genes overlapped in 70% and 64% of human studies on major depressive disorder and schizophrenia, respectively. Nine switch genes, HLA-DRB5, ARHGAP15, COL4A1, RBM38, DMD, LGALS3BP, WSCD2, CYTH4, and CNTRL, overlapped with known genetic variants in depression. Seven switch genes, NPAS3, ARHGAP15, LGALS3BP, DPP10, SMYD3, CPXCR1, and HLA-DRB5 were associated with known risk factors for schizophrenia. Collectively, we identified molecular determinants of loneliness and dysregulated pathways in the brain of non-demented adults. The association of switch genes with known risk factors for neuropsychiatric and neurodegenerative diseases provides a molecular explanation for the observed prevalence of these diseases among lonely individuals.

Physical Activity Rewires the Human Brain against Neurodegeneration.

Physical activity may offset cognitive decline and dementia, but the molecular mechanisms by which it promotes neuroprotection remain elusive. In the absence of disease-modifying therapies, understanding the molecular effects of physical activity in the brain may be useful for identifying novel targets for disease management. Here we employed several bioinformatic methods to dissect the molecular underpinnings of physical activity in brain health. Network analysis identified 'switch genes' associated with drastic hippocampal transcriptional changes in aged cognitively intact individuals. Switch genes are key genes associated with dramatic transcriptional changes and thus may play a fundamental role in disease pathogenesis. Switch genes are associated with protein processing pathways and the metabolic control of glucose, lipids, and fatty acids. Correlation analysis showed that transcriptional patterns associated with physical activity significantly overlapped and negatively correlated with those of neurodegenerative diseases. Functional analysis revealed that physical activity might confer neuroprotection in Alzheimer's (AD), Parkinson's (PD), and Huntington's (HD) diseases via the upregulation of synaptic signaling pathways. In contrast, in frontotemporal dementia (FTD) its effects are mediated by restoring mitochondrial function and energy precursors. Additionally, physical activity is associated with the downregulation of genes involved in inflammation in AD, neurogenesis in FTD, regulation of growth and transcriptional repression in PD, and glial cell differentiation in HD. Collectively, these findings suggest that physical activity directs transcriptional changes in the brain through different pathways across the broad spectrum of neurodegenerative diseases. These results provide new evidence on the unique and shared mechanisms between physical activity and neurodegenerative diseases.

Network Analysis Identifies Sex-Specific Gene Expression Changes in Blood of Amyotrophic Lateral Sclerosis Patients.

Understanding the molecular mechanisms underlying the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is a major challenge. We used co-expression networks implemented by the SWitch Miner software to identify switch genes associated with drastic transcriptomic changes in the blood of ALS patients. Functional analyses revealed that switch genes were enriched in pathways related to the cell cycle, hepatitis C, and small cell lung cancer. Analysis of switch genes by sex revealed that switch genes from males were associated with metabolic pathways, including PI3K-AKT, sphingolipid, carbon metabolism, FOXO, and AMPK signaling. In contrast, female switch genes related to infectious diseases, inflammation, apoptosis, and atherosclerosis. Furthermore, eight switch genes showed sex-specific gene expression patterns. Collectively, we identified essential genes and pathways that may explain sex differences observed in ALS. Future studies investigating the potential role of these genes in driving disease disparities between males and females with ALS are warranted.

Key Disease Mechanisms Linked to Alzheimer's Disease in the Entorhinal Cortex.

Alzheimer's disease (AD) is a chronic, neurodegenerative brain disorder affecting millions of Americans that is expected to increase in incidence with the expanding aging population. Symptomatic AD patients show cognitive decline and often develop neuropsychiatric symptoms due to the accumulation of insoluble proteins that produce plaques and tangles seen in the brain at autopsy. Unexpectedly, some clinically normal individuals also show AD pathology in the brain at autopsy (asymptomatic AD, AsymAD). In this study, SWItchMiner software was used to identify key switch genes in the brain's entorhinal cortex that lead to the development of AD or disease resilience. Seventy-two switch genes were identified that are differentially expressed in AD patients compared to healthy controls. These genes are involved in inflammation, platelet activation, and phospholipase D and estrogen signaling. Peroxisome proliferator-activated receptor γ (PPARG), zinc-finger transcription factor (YY1), sterol regulatory element-binding transcription factor 2 (SREBF2), and early growth response 1 (EGR1) were identified as transcription factors that potentially regulate switch genes in AD. Comparing AD patients to AsymAD individuals revealed 51 switch genes; PPARG as a potential regulator of these genes, and platelet activation and phospholipase D as critical signaling pathways. Chemical-protein interaction analysis revealed that valproic acid is a therapeutic agent that could prevent AD from progressing.

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders.

BACKGROUND: Dementia is a growing public health concern with an estimated prevalence of 50 million people worldwide. Alzheimer's disease (AD) and vascular and frontotemporal dementias (VaD, FTD), share many clinical, genetical, and pathological features making the diagnosis difficult. METHODS: In this study, we compared the transcriptome from the frontal cortex of patients with AD, VaD, and FTD to identify dysregulated pathways. RESULTS: Upregulated genes in AD were enriched in adherens and tight junctions, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase and protein kinase B/Akt signaling pathways, whereas downregulated genes associated with calcium signaling. Upregulated genes in VaD were centered on infectious diseases and nuclear factor kappa beta signaling, whereas downregulated genes are involved in biosynthesis of amino acids and the pentose phosphate pathway. Upregulated genes in FTD were associated with ECM receptor interactions and the lysosome, whereas downregulated genes were involved in glutamatergic synapse and MAPK signaling. The transcription factor KFL4 was shared among the 3 types of dementia. CONCLUSIONS: Collectively, we identified similarities and differences in dysregulated pathways and transcription factors among the dementias. The shared pathways and transcription factors may indicate a potential common etiology, whereas the differences may be useful for distinguishing dementias.

Bioinformatic Analysis Reveals Phosphodiesterase 4D-Interacting Protein as a Key Frontal Cortex Dementia Switch Gene.

: The mechanisms that initiate dementia are poorly understood and there are currently no treatments that can slow their progression. The identification of key genes and molecular pathways that may trigger dementia should help reveal potential therapeutic reagents. In this study, SWItch Miner software was used to identify phosphodiesterase 4D-interacting protein as a key factor that may lead to the development of Alzheimer's disease, vascular dementia, and frontotemporal dementia. Inflammation, PI3K-AKT, and ubiquitin-mediated proteolysis were identified as the main pathways that are dysregulated in these dementias. All of these dementias are regulated by 12 shared transcription factors. Protein-chemical interaction network analysis of dementia switch genes revealed that valproic acid may be neuroprotective for these dementias. Collectively, we identified shared and unique dysregulated gene expression, pathways and regulatory factors among dementias. New key mechanisms that lead to the development of dementia were revealed and it is expected that these data will advance personalized medicine for patients.

Meta-Analysis of Gene Expression Changes in the Blood of Patients with Mild Cognitive Impairment and Alzheimer's Disease Dementia.

BACKGROUND: Dementia is a major public health concern affecting approximately 47 million people worldwide. Mild cognitive impairment (MCI) is one form of dementia that affects an individual's memory with or without affecting their daily life. Alzheimer's disease dementia (ADD) is a more severe form of dementia that usually affects elderly individuals. It remains unclear whether MCI is a distinct disorder from or an early stage of ADD. METHODS: Gene expression data from blood were analyzed to identify potential biomarkers that may be useful for distinguishing between these two forms of dementia. RESULTS: A meta-analysis revealed 91 genes dysregulated in individuals with MCI and 387 genes dysregulated in ADD. Pathway analysis identified seven pathways shared between MCI and ADD and nine ADD-specific pathways. Fifteen transcription factors were associated with MCI and ADD, whereas seven transcription factors were specific for ADD. Mir-335-5p was specific for ADD, suggesting that it may be useful as a biomarker. Diseases that are associated with MCI and ADD included developmental delays, cognition impairment, and movement disorders. CONCLUSION: These results provide a better molecular understanding of peripheral changes that occur in MCI and ADD patients and may be useful in the identification of diagnostic and prognostic biomarkers.

Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson's disease.

Environmental and genetic factors are likely to be involved in the pathogenesis of Parkinson's disease (PD), the second most prevalent neurodegenerative disease among the elderly. Network-based metaanalysis of four independent microarray studies identified the hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor associated with gluconeogenesis and diabetes, as a central regulatory hub gene up-regulated in blood of PD patients. In parallel, the polypyrimidine tract binding protein 1 (PTBP1), involved in the stabilization and mRNA translation of insulin, was identified as the most down-regulated gene. Quantitative PCR assays revealed that HNF4A and PTBP1 mRNAs were up- and down-regulated, respectively, in blood of 51 PD patients and 45 controls nested in the Diagnostic and Prognostic Biomarkers for Parkinson's Disease. These results were confirmed in blood of 50 PD patients compared with 46 healthy controls nested in the Harvard Biomarker Study. Relative abundance of HNF4A mRNA correlated with the Hoehn and Yahr stage at baseline, suggesting its clinical utility to monitor disease severity. Using both markers, PD patients were classified with 90% sensitivity and 80% specificity. Longitudinal performance analysis demonstrated that relative abundance of HNF4A and PTBP1 mRNAs significantly decreased and increased, respectively, in PD patients during the 3-y follow-up period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale for the altered insulin signaling observed in PD patients. The longitudinally dynamic biomarkers identified in this study may be useful for monitoring disease-modifying therapies for PD.

System-based approaches to decode the molecular links in Parkinson's disease and diabetes.

A growing body of evidence indicates an increased risk for developing Parkinson's disease (PD) among people with type 2 diabetes (T2DM). The relationship between the etiology and development of both chronic diseases is beginning to be uncovered and recent studies show that PD and T2DM share remarkably similar dysregulated pathways. It has been proposed that a cascade of events including mitochondrial dysfunction, impaired insulin signaling, and metabolic inflammation trigger neurodegeneration in T2DM models. Network-based approaches have elucidated a potential molecular framework linking both diseases. Further, transcriptional signatures that modulate the neurodegenerative phenotype in T2DM have been identified. Here we contextualize the current experimental approaches to dissect the mechanisms underlying the association between PD and T2DM and discuss the existing challenges toward the understanding of the coexistence of these devastating aging diseases.

A network approach to diagnostic biomarkers in progressive supranuclear palsy.

Diagnosis of progressive supranuclear palsy (PSP) remains challenging because of the clinical overlap with Parkinson's disease (PD). To date, disease-specific biomarkers have yet to be identified. In the absence of reliable biomarkers, we used an integrated network approach to identify genes and related biological pathways associated with PSP. We tested a highly ranked gene in cellular whole-blood samples from 122 patients enrolled in the Prognostic Biomarker Study. Biological and functional analysis identified 13 modules related to activation of leukocytes and lymphocytes, protein dephosphorylation, and phosphatase activity. Integration of these results with those from microarrays identified ptpn1 as a potential biomarker for PSP. Assessment of biomarker performance revealed that ptpn1 could be used to distinguish PSP patients from PD patients with 86% diagnostic accuracy. Ptpn1 may be a diagnostic marker useful for distinguishing PSP and PD. Further evaluation in a larger well-characterized prospective study is warranted.

Specific splice variants are associated with Parkinson's disease.

BACKGROUND: Diagnosis of Parkinson's disease (PD) currently relies on assessment of motor symptoms. Recently, sensitive, specific, and readily available splice variant-specific biomarkers were identified in peripheral blood from participants in the Diagnostic and Prognostic Biomarkers in Parkinson Disease study. METHODS: Here we test for an association between candidate splice variant biomarkers and PD in blood of an independent population of cases and controls nested in the Harvard NeuroDiscovery Center Biomarker Study. RESULTS: Expression of 7 out of 13 candidate biomarkers was dysregulated in whole cellular blood of patients with PD. CONCLUSIONS: These results support the view that differential expression of a subset of splice-variant markers in blood is associated with PD. Further evaluation in untreated, de novo patients and at-risk subjects is warranted.

Physical activity and lifestyle modifications in the treatment of neurodegenerative diseases.

Neurodegenerative diseases have reached alarming numbers in the past decade. Unfortunately, clinical trials testing potential therapeutics have proven futile. In the absence of disease-modifying therapies, physical activity has emerged as the single most accessible lifestyle modification with the potential to fight off cognitive decline and neurodegeneration. In this review, we discuss findings from epidemiological, clinical, and molecular studies investigating the potential of lifestyle modifications in promoting brain health. We propose an evidence-based multidomain approach that includes physical activity, diet, cognitive training, and sleep hygiene to treat and prevent neurodegenerative diseases.

Diabetes: a tipping point in neurodegenerative diseases.

Diabetes is associated with an increased risk and progression of Alzheimer's (AD) and Parkinson's (PD) diseases. Conversely, diabetes may confer neuroprotection against amyotrophic lateral sclerosis (ALS). It has been posited that perturbations in glucose and insulin regulation, cholesterol metabolism, and mitochondrial bioenergetics defects may underlie the molecular underpinnings of diabetes effects on the brain. Nevertheless, the precise molecular mechanisms remain elusive. Here, we discuss the evidence from molecular, epidemiological, and clinical studies investigating the impact of diabetes on neurodegeneration and highlight shared dysregulated pathways between these complex comorbidities. We also discuss promising antidiabetic drugs, molecular diagnostics currently in clinical trials, and outstanding questions and challenges for future pursuit.

Diet and lifestyle impact the development and progression of Alzheimer's dementia.

Dementia is a growing public health concern, with an estimated prevalence of 57 million adults worldwide. Alzheimer's disease (AD) accounts for 60-80% of the cases. Clinical trials testing potential drugs and neuroprotective agents have proven futile, and currently approved drugs only provide symptomatic benefits. Emerging epidemiological and clinical studies suggest that lifestyle changes, including diet and physical activity, offer an alternative therapeutic route for slowing and preventing cognitive decline and dementia. Age is the single most common risk factor for dementia, and it is associated with slowing cellular bioenergetics and metabolic processes. Therefore, a nutrient-rich diet is critical for optimal brain health. Furthermore, type 2 diabetes (T2D) is a risk factor for AD, and diets that reduce the risk of T2D may confer neuroprotection. Foods predominant in Mediterranean, MIND, and DASH diets, including fruits, leafy green vegetables, fish, nuts, and olive oil, may prevent or slow cognitive decline. The mechanisms by which these nutrients promote brain health, however, are not yet completely understood. Other dietary approaches and eating regimes, including ketogenic and intermittent fasting, are also emerging as beneficial for brain health. This review summarizes the pathophysiology, associated risk factors, and the potential neuroprotective pathways activated by several diets and eating regimes that have shown promising results in promoting brain health and preventing dementia.

Sex-specific transcriptional rewiring in the brain of Alzheimer's disease patients.

Sex-specific differences may contribute to Alzheimer's disease (AD) development. AD is more prevalent in women worldwide, and female sex has been suggested as a disease risk factor. Nevertheless, the molecular mechanisms underlying sex-biased differences in AD remain poorly characterized. To this end, we analyzed the transcriptional changes in the entorhinal cortex of symptomatic and asymptomatic AD patients stratified by sex. Co-expression network analysis implemented by SWItchMiner software identified sex-specific signatures of switch genes responsible for drastic transcriptional changes in the brain of AD and asymptomatic AD individuals. Pathway analysis of the switch genes revealed that morphine addiction, retrograde endocannabinoid signaling, and autophagy are associated with both females with AD (F-AD) and males with (M-AD). In contrast, nicotine addiction, cell adhesion molecules, oxytocin signaling, adipocytokine signaling, prolactin signaling, and alcoholism are uniquely associated with M-AD. Similarly, some of the unique pathways associated with F-AD switch genes are viral myocarditis, Hippo signaling pathway, endometrial cancer, insulin signaling, and PI3K-AKT signaling. Together these results reveal that there are many sex-specific pathways that may lead to AD. Approximately 20-30% of the elderly have an accumulation of amyloid beta in the brain, but show no cognitive deficit. Asymptomatic females (F-asymAD) and males (M-asymAD) both shared dysregulation of endocytosis. In contrast, pathways uniquely associated with F-asymAD switch genes are insulin secretion, progesterone-mediated oocyte maturation, axon guidance, renal cell carcinoma, and ErbB signaling pathway. Similarly, pathways uniquely associated with M-asymAD switch genes are fluid shear stress and atherosclerosis, FcγR mediated phagocytosis, and proteoglycans in cancer. These results reveal for the first time unique pathways associated with either disease progression or cognitive resilience in asymptomatic individuals. Additionally, we identified numerous sex-specific transcription factors and potential neurotoxic chemicals that may be involved in the pathogenesis of AD. Together these results reveal likely molecular drivers of sex differences in the brain of AD patients. Future molecular studies dissecting the functional role of these switch genes in driving sex differences in AD are warranted.

Key Disease Mechanisms Linked to Amyotrophic Lateral Sclerosis in Spinal Cord Motor Neurons.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no modifying treatments available. The molecular mechanisms underpinning disease pathogenesis are not fully understood. Recent studies have employed co-expression networks to identify key genes, known as "switch genes", responsible for dramatic transcriptional changes in the blood of ALS patients. In this study, we directly investigate the root cause of ALS by examining the changes in gene expression in motor neurons that degenerate in patients. Co-expression networks identified in ALS patients' spinal cord motor neurons revealed 610 switch genes in seven independent microarrays. Switch genes were enriched in several pathways, including viral carcinogenesis, PI3K-Akt, focal adhesion, proteoglycans in cancer, colorectal cancer, and thyroid hormone signaling. Transcription factors ELK1 and GATA2 were identified as key master regulators of the switch genes. Protein-chemical network analysis identified valproic acid, cyclosporine, estradiol, acetaminophen, quercetin, and carbamazepine as potential therapeutics for ALS. Furthermore, the chemical analysis identified metals and organic compounds including, arsenic, copper, nickel, and benzo(a)pyrene as possible mediators of neurodegeneration. The identification of switch genes provides insights into previously unknown biological pathways associated with ALS.

The Impact of Disease Comorbidities in Alzheimer's Disease.

A wide range of comorbid diseases is associated with Alzheimer's disease (AD), the most common neurodegenerative disease worldwide. Evidence from clinical and molecular studies suggest that chronic diseases, including diabetes, cardiovascular disease, depression, and inflammatory bowel disease, may be associated with an increased risk of AD in different populations. Disruption in several shared biological pathways has been proposed as the underlying mechanism for the association between AD and these comorbidities. Notably, inflammation is a common dysregulated pathway shared by most of the comorbidities associated with AD. Some drugs commonly prescribed to patients with diabetes and cardiovascular disease have shown promising results in AD patients. Systems-based biology studies have identified common genetic factors and dysregulated pathways that may explain the relationship of comorbid disorders in AD. Nonetheless, the precise mechanisms for the occurrence of disease comorbidities in AD are not entirely understood. Here, we discuss the impact of the most common comorbidities in the clinical management of AD patients.