Plasma high-density lipoprotein cargo is altered in Alzheimer's disease and is associated with regional brain volume.

Cholesterol levels have been repeatedly linked to Alzheimer's Disease (AD), suggesting that high levels could be detrimental, but this effect is likely attributed to Low-Density Lipoprotein (LDL) cholesterol. On the other hand, High-Density Lipoproteins (HDL) cholesterol levels have been associated with reduced brain amyloidosis and improved cognitive function. However, recent findings have suggested that HDL-functionality, which depends upon the HDL-cargo proteins associated with HDL, rather than HDL levels, appears to be the key factor, suggesting a quality over quantity status. In this report, we have assessed the HDL-cargo (Cholesterol, ApoA-I, ApoA-II, ApoC-I, ApoC-III, ApoD, ApoE, ApoH, ApoJ, CRP, and SAA) in stable healthy control (HC), healthy controls who will convert to MCI/AD (HC-Conv) and AD patients (AD). Compared to HC we observed an increased cholesterol/ApoA-I ratio in AD and HC-Conv, as well as an increased ApoD/ApoA-I ratio and a decreased ApoA-II/ApoA-I ratio in AD. Higher cholesterol/ApoA-I ratio was also associated with lower cortical grey matter volume and higher ventricular volume, while higher ApoA-II/ApoA-I and ApoJ/ApoA-I ratios were associated with greater cortical grey matter volume (and for ApoA-II also with greater hippocampal volume) and smaller ventricular volume. Additionally, in a clinical status-independent manner, the ApoE/ApoA-I ratio was significantly lower in APOE ε4 carriers and lowest in APOE ε4 homozygous. Together, these data indicate that in AD patients the composition of HDL is altered, which may affect HDL functionality, and such changes are associated with altered regional brain volumetric data.

Diagnostic and prognostic plasma biomarkers for preclinical Alzheimer's disease.

INTRODUCTION: This study involved a parallel comparison of the diagnostic and longitudinal monitoring potential of plasma glial fibrillary acidic protein (GFAP), total tau (t-tau), phosphorylated tau (p-tau181 and p-tau231), and neurofilament light (NFL) in preclinical Alzheimer's disease (AD). METHODS: Plasma proteins were measured using Simoa assays in cognitively unimpaired older adults (CU), with either absence (Aß-) or presence (Aß+) of brain amyloidosis. RESULTS: Plasma GFAP, t-tau, p-tau181, and p-tau231 concentrations were higher in Aß+ CU compared with Aß- CU cross-sectionally. GFAP had the highest effect size and area under the curve (AUC) in differentiating between Aß+ and Aß- CU; however, no statistically significant differences were observed between the AUCs of GFAP, p-tau181, and p-tau231, but all were significantly higher than the AUC of NFL, and the AUC of GFAP was higher than the AUC of t-tau. The combination of a base model (BM), comprising the AD risk factors, age, sex, and apolipoprotein E gene (APOE) ε4 status with GFAP was observed to have a higher AUC (>90%) compared with the combination of BM with any of the other proteins investigated in the current study. Longitudinal analyses showed increased GFAP and p-tau181 in Aß+ CU and increased NFL in Aß- CU, over a 12-month duration. GFAP, p-tau181, p-tau231, and NFL showed significant correlations with cognition, whereas no significant correlations were observed with hippocampal volume. DISCUSSION: These findings highlight the diagnostic and longitudinal monitoring potential of GFAP and p-tau for preclinical AD.

High-density lipoprotein-related cholesterol metabolism in Alzheimer's disease.

High-density lipoproteins (HDL) are a heterogeneous class of molecules whose main function is to remove excess cholesterol through a mechanism called reverse transport, in which cholesterol is transported from peripheral organs and from arterial foam cells to the liver, where it is subsequently eliminated with bile. While its ability to eliminate excess cholesterol has always been viewed as its main feature, its beneficial effects go beyond this single effect. Many of the proteins that are associated with HDL are responsible for anti-oxidant and anti-inflammatory properties. These proteins that are associated with HDL during its generation and remodelling, are referred to as 'protein cargo', which has been extensively analysed by mass spectrometry analysis in healthy and diseased individuals. In this review, we discuss the pathway that leads to HDL formation and its subsequent remodelling and catabolism with regards to the possible involvement of HDL 'protein cargo' in Alzheimer's disease.

Plasma metabolites associated with biomarker evidence of neurodegeneration in cognitively normal older adults.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that currently has no cure. Identifying biochemical changes associated with neurodegeneration prior to symptom onset, will provide insight into the biological mechanisms associated with neurodegenerative processes, that may also aid in identifying potential drug targets. The current study therefore investigated associations between plasma neurofilament light chain (NF-L), a marker of neurodegeneration, with plasma metabolites that are products of various cellular processes. Plasma NF-L, measured by ultrasensitive Single molecule array (Simoa) technology (Quanterix) and plasma metabolites, measured by mass-spectrometry (AbsoluteIDQ® p400HR kit, BIOCRATES), were assessed in the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohort comprising 100 cognitively normal older adults. Metabolites belonging to biogenic amine (creatinine, symmetric dimethylarginine, asymmetric dimethylarginine; ADMA, kynurenine, trans-4-hydroxyproline), amino acid (citrulline, proline, arginine, asparagine, phenylalanine, threonine) and acylcarnitine classes were observed to have positive correlations with plasma NF-L, suggesting a link between neurodegeneration and biological pathways associated with neurotransmitter regulation, nitric oxide homoeostasis, inflammation and mitochondrial function. Additionally, after stratifying participants based on low/high brain amyloid-ß load (Aß ±) assessed by positron emission tomography, while creatinine, SDMA and citrulline correlated with NF-L in both Aß- and Aß+ groups, ADMA, proline, arginine, asparagine, phenylalanine and acylcarnitine species correlated with NF-L only in the Aß+ group after adjusting for confounding variables, suggesting that the association of these metabolites with neurodegeneration may be relevant to AD-related neuropathology. Metabolites identified to be associated with plasma NF-L may have the potential to serve as prognostic markers for neurodegenerative diseases, however, further studies are required to validate the current findings in an independent cohort, both cross-sectionally and longitudinally.

Autophagy Modulation as a Treatment of Amyloid Diseases.

Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, but the connection between amyloid accumulation and tissue degeneration is not clear. Common examples of amyloid diseases are Alzheimer's disease (AD), Parkinson's disease (PD) and tauopathies, which are the most common forms of neurodegenerative diseases, as well as polyglutamine disorders and certain peripheral metabolic diseases. In these diseases, increased accumulation of toxic amyloid proteins is suspected to be one of the main causative factors in the disease pathogenesis. It is therefore important to more clearly understand how these toxic amyloid proteins accumulate as this will aide in the development of more effective preventive and therapeutic strategies. Protein homeostasis, or proteostasis, is maintained by multiple cellular pathways-including protein synthesis, quality control, and clearance-which are collectively responsible for preventing protein misfolding or aggregation. Modulating protein degradation is a very complex but attractive treatment strategy used to remove amyloid and improve cell survival. This review will focus on autophagy, an important clearance pathway of amyloid proteins, and strategies for using it as a potential therapeutic target for amyloid diseases. The physiological role of autophagy in cells, pathways for its modulation, its connection with apoptosis, cell models and caveats in developing autophagy as a treatment and as a biomarker is discussed.

Hyperspectral Retinal Imaging as a Non-Invasive Marker to Determine Brain Amyloid Status.

Background: As an extension of the central nervous system (CNS), the retina shares many similarities with the brain and can manifest signs of various neurological diseases, including Alzheimer's disease (AD). Objective: To investigate the retinal spectral features and develop a classification model to differentiate individuals with different brain amyloid levels. Methods: Sixty-six participants with varying brain amyloid-ß protein levels were non-invasively imaged using a hyperspectral retinal camera in the wavelength range of 450-900 nm in 5 nm steps. Multiple retina features from the central and superior views were selected and analyzed to identify their variability among individuals with different brain amyloid loads. Results: The retinal reflectance spectra in the 450-585 nm wavelengths exhibited a significant difference in individuals with increasing brain amyloid. The retinal features in the superior view showed higher inter-subject variability. A classification model was trained to differentiate individuals with varying amyloid levels using the spectra of extracted retinal features. The performance of the spectral classification model was dependent upon retinal features and showed 0.758-0.879 accuracy, 0.718-0.909 sensitivity, 0.764-0.912 specificity, and 0.745-0.891 area under curve for the right eye. Conclusions: This study highlights the spectral variation of retinal features associated with brain amyloid loads. It also demonstrates the feasibility of the retinal hyperspectral imaging technique as a potential method to identify individuals in the preclinical phase of AD as an inexpensive alternative to brain imaging.

Sorghum Grain Polyphenolic Extracts Demonstrate Neuroprotective Effects Related to Alzheimer's Disease in Cellular Assays.

Sorghum grain contains high levels and a diverse profile of polyphenols (PPs), which are antioxidants known to reduce oxidative stress when consumed in the diet. Oxidative stress leading to amyloid-ß (Aß) aggregation, neurotoxicity, and mitochondrial dysfunction is implicated in the pathogenesis of Alzheimer's disease (AD). Thus, PPs have gained attention as possible therapeutic agents for combating AD. This study aimed to (a) quantify the phenolic compounds (PP) and antioxidant capacities in extracts from six different varieties of sorghum grain and (b) investigate whether these PP extracts exhibit any protective effects on human neuroblastoma (BE(2)-M17) cells against Aß- and tau-induced toxicity, Aß aggregation, mitochondrial dysfunction, and reactive oxygen species (ROS) induced by Aß and tert-butyl hydroperoxide (TBHP). PP and antioxidant capacity were quantified using chemical assays. Aß- and tau-induced toxicity was determined using the 3-(4,5-dimenthylthiazol-2-yl)-2,5-dimethyltetrazolium bromide (MTS) assay. The thioflavin T (Th-T) assay assessed anti-Aß aggregation. The dichlorodihydrofluorescein diacetate (DCFDA) assay determined the levels of general ROS and the MitoSOX assay determined the levels of mitochondrial superoxide. Sorghum varieties Shawaya short black-1 and IS1311C possessed the highest levels of total phenolics, total flavonoids, and antioxidant capacity, and sorghum varieties differed significantly in their profile of individual PPs. All extracts significantly increased cell viability compared to the control (minus extract). Variety QL33 (at 2000 µg sorghum flour equivalents/mL) showed the strongest protective effect with a 28% reduction in Aß-toxicity cell death. The extracts of all sorghum varieties significantly reduced Aß aggregation. All extracts except that from variety B923296 demonstrated a significant (p ≤ 0.05) downregulation of Aß-induced and TBHP-induced ROS and mitochondrial superoxide relative to the control (minus extract) in a dose- and variety-dependent manner. We have demonstrated for the first time that sorghum polyphenolic extracts show promising neuroprotective effects against AD, which indicates the potential of sorghum foods to exert a similar beneficial property in the human diet. However, further analysis in other cellular models and in vivo is needed to confirm these effects.

Fluid biomarkers in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis. Additionally, they can be used as primary outcome markers in prospective clinical trials. Among fluid biomarkers, blood-based biomarkers offer a distinct advantage over cerebrospinal fluid biomarkers as they do not require a procedure as invasive as a lumbar puncture. This article aimed to provide an overview of the present clinical data concerning fluid biomarkers associated with CAA and point out the direction of future studies. Among all the biomarkers discussed, amyloid ß, neurofilament light chain, matrix metalloproteinases, complement 3, uric acid, and lactadherin demonstrated the most promising evidence. However, the field of fluid biomarkers for CAA is an under-researched area, and in most cases, there are only one or two studies on each of the biomarkers mentioned in this review. Additionally, a small sample size is a common limitation of the discussed studies. Hence, it is hard to reach a solid conclusion on the clinical significance of each biomarker at different stages of the disease or in various subpopulations of CAA. In order to overcome this issue, larger longitudinal and multicentered studies are needed.

Association of Plasma Neurofilament Light Chain With Glycaemic Control and Insulin Resistance in Middle-Aged Adults.

Aims: This study aimed to determine the association of plasma neurofilament light (NfL), a marker of neurodegeneration, with diabetes status and glycaemic parameters in people with normal glycaemia (NG), pre-diabetes (PD) and type 2 diabetes (T2D). Methods: Clinical and descriptive data for the diagnostic groups, NG (n=30), PD (n=48) and T2D (n=29), aged between 40 and 75 years were included in this cross-sectional analysis. Plasma NfL levels were analyzed using the ultra-sensitive single-molecule array (Simoa) platform. Results: A positive correlation was evident between plasma NfL and fasting glucose (r = 0.2824; p = 0.0032). Plasma NfL levels were not correlated with fasting insulin and insulin resistance. Plasma Nfl levels were significantly different across the diabetes groups (T2D >PD >NG, p=0.0046). Post-hoc analysis indicated significantly higher plasma NfL levels in the T2D [12.4 (5.21) pg/mL] group than in the PD [10.2 (4.13) pg/mL] and NG [8.37 (5.65) pg/mL] groups. The relationship between diabetes status and NfL remained significant after adjusting for age, sex, BMI, HOMA-IR and physical activity (adjusted r2 = 0.271, p = 0.035). Conclusions: These results show biomarker evidence of neurodegeneration in adults at risk or with T2D. Larger sample size and longitudinal analysis are required to better understand the application of NfL in people with risk and overt T2D.

A Synergistic Combination of DHA, Luteolin, and Urolithin A Against Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common form of dementia worldwide. The classical AD brain is characterized by extracellular deposition of amyloid-ß (Aß) protein aggregates as senile plaques and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated forms of the microtubule-associated protein Tau. There has been limited success in clinical trials for some proposed therapies for AD, so attention has been drawn toward using alternative approaches, including prevention strategies. As a result, nutraceuticals have become attractive compounds for their potential neuroprotective capabilities. The objective of the present study was to derive a synergistic nutraceutical combination in vitro that may act as a potential preventative therapy for AD. The compounds of interest were docosahexaenoic acid (DHA), luteolin (LUT), and urolithin A (UA). The cell viability and cytotoxicity assays MTS and LDH were used to evaluate the compounds individually and in two-compound combinations, for their ability to inhibit Aß1-42-induced toxicity in human neuroblastoma BE(2)-M17 cells. The LDH-derived% protection values were used in the program CompuSyn v.1.0 to calculate the combination index (CI) of the two-compound combinations. The software-predicted potentially synergistic (CI < 1) two-compound combinations were validated using CellTiter Glo assay. Finally, a three-compound combination was predicted (D5L5U5) and shown to be the most effective at inhibiting Aß1-42-induced toxicity. The synergistic combination, D5L5U5 warrants further research for its mechanism of action; however, it can serve as a basis to develop an advanced functional food for the prevention or co-treatment of AD.

The Association Between Alzheimer's Disease-Related Markers and Physical Activity in Cognitively Normal Older Adults.

Previous studies have indicated that physical activity may be beneficial in reducing the risk for Alzheimer's disease (AD), although the underlying mechanisms are not fully understood. The goal of this study was to evaluate the relationship between habitual physical activity levels and brain amyloid deposition and AD-related blood biomarkers (i.e., measured using a novel high-performance mass spectrometry-based assay), in apolipoprotein E (APOE) ε4 carriers and noncarriers. We evaluated 143 cognitively normal older adults, all of whom had brain amyloid deposition assessed using positron emission tomography and had their physical activity levels measured using the International Physical Activity Questionnaire (IPAQ). We observed an inverse correlation between brain amyloidosis and plasma beta-amyloid (Aß)1-42 but found no association between brain amyloid and plasma Aß1-40 and amyloid precursor protein (APP)669-711. Additionally, higher levels of physical activity were associated with lower plasma Aß1-40, Aß1-42, and APP669-711 levels in APOE ε4 noncarriers. The ratios of Aß1-40/Aß1-42 and APP669-711/Aß1-42, which have been associated with higher brain amyloidosis in previous studies, differed between APOE ε4 carriers and non-carriers. Taken together, these data indicate a complex relationship between physical activity and brain amyloid deposition and potential blood-based AD biomarkers in cognitively normal older adults. In addition, the role of APOE ε4 is still unclear, and more studies are necessary to bring further clarification.

Mitoprotective Effects of a Synergistic Nutraceutical Combination: Basis for a Prevention Strategy Against Alzheimer's Disease.

Evidence to date suggests the consumption of food rich in bioactive compounds, such as polyphenols, flavonoids, omega-3 fatty acids may potentially minimize age-related cognitive decline. For neurodegenerative diseases, such as Alzheimer's disease (AD), which do not yet have definitive treatments, the focus has shifted toward using alternative approaches, including prevention strategies rather than disease reversal. In this aspect, certain nutraceuticals have become promising compounds due to their neuroprotective properties. Moreover, the multifaceted AD pathophysiology encourages the use of multiple bioactive components that may be synergistic in their protective roles when combined. The objective of the present study was to determine mechanisms of action underlying the inhibition of Aß1-42-induced toxicity by a previously determined, three-compound nutraceutical combination D5L5U5 for AD. In vitro experiments were carried out in human neuroblastoma BE(2)-M17 cells for levels of ROS, ATP mitophagy, and mitobiogenesis. The component compounds luteolin (LUT), DHA, and urolithin A (UA) were independently protective of mitochondria; however, the D5L5U5 preceded its single constituents in all assays used. Overall, it indicated that D5L5U5 had potent inhibitory effects against Aß1-42-induced toxicity through protecting mitochondria. These mitoprotective activities included minimizing oxidative stress, increasing ATP and inducing mitophagy and mitobiogenesis. However, this synergistic nutraceutical combination warrants further investigations in other in vitro and in vivo AD models to confirm its potential to be used as a preventative therapy for AD.

Potential of Sorghum Polyphenols to Prevent and Treat Alzheimer's Disease: A Review Article.

Alzheimer's disease (AD) is characterized by the excessive deposition of extracellular amyloid-beta peptide (Aß) and the build-up of intracellular neurofibrillary tangles containing hyperphosphorylated tau proteins. This leads to neuronal damage, cell death and consequently results in memory and learning impairments leading to dementia. Although the exact cause of AD is not yet clear, numerous studies indicate that oxidative stress, inflammation, and mitochondrial dysfunction significantly contribute to its onset and progression. There is no effective therapeutic approach to stop the progression of AD and its associated symptoms. Thus, early intervention, preferably, pre-clinically when the brain is not significantly affected, is a better option for effective treatment. Natural polyphenols (PP) target multiple AD-related pathways such as protecting the brain from Aß and tau neurotoxicity, ameliorating oxidative damage and mitochondrial dysfunction. Among natural products, the cereal crop sorghum has some unique features. It is one of the major global grain crops but in the developed world, it is primarily used as feed for farm animals. A broad range of PP, including phenolic acids, flavonoids, and condensed tannins are present in sorghum grain including some classes such as proanthocyanidins that are rarely found in others plants. Pigmented varieties of sorghum have the highest polyphenolic content and antioxidant activity which potentially makes their consumption beneficial for human health through different pathways such as oxidative stress reduction and thus the prevention and treatment of neurodegenerative diseases. This review summarizes the potential of sorghum PP to beneficially affect the neuropathology of AD.

Therapeutic Potential of Mitophagy-Inducing Microflora Metabolite, Urolithin A for Alzheimer's Disease.

Mitochondrial dysfunction including deficits of mitophagy is seen in aging and neurodegenerative disorders including Alzheimer's disease (AD). Apart from traditionally targeting amyloid beta (Aß), the main culprit in AD brains, other approaches include investigating impaired mitochondrial pathways for potential therapeutic benefits against AD. Thus, a future therapy for AD may focus on novel candidates that enhance optimal mitochondrial integrity and turnover. Bioactive food components, known as nutraceuticals, may serve as such agents to combat AD. Urolithin A is an intestinal microbe-derived metabolite of a class of polyphenols, ellagitannins (ETs). Urolithin A is known to exert many health benefits. Its antioxidant, anti-inflammatory, anti-atherogenic, anti-Aß, and pro-mitophagy properties are increasingly recognized. However, the underlying mechanisms of urolithin A in inducing mitophagy is poorly understood. This review discusses the mitophagy deficits in AD and examines potential molecular mechanisms of its activation. Moreover, the current knowledge of urolithin A is discussed, focusing on its neuroprotective properties and its potential to induce mitophagy. Specifically, this review proposes potential mechanisms by which urolithin A may activate and promote mitophagy.

Targeting Mitophagy in Alzheimer's Disease.

Mitochondria perform many essential cellular functions including energy production, calcium homeostasis, transduction of metabolic and stress signals, and mediating cell survival and death. Maintaining viable populations of mitochondria is therefore critical for normal cell function. The selective disposal of damaged mitochondria, by a pathway known as mitophagy, plays a key role in preserving mitochondrial integrity and quality. Mitophagy reduces the formation of reactive oxygen species and is considered as a protective cellular process. Mitochondrial dysfunction and deficits of mitophagy have important roles in aging and especially in neurodegenerative disorders such as Alzheimer's disease (AD). Targeting mitophagy pathways has been suggested to have potential therapeutic effects against AD. In this review, we aim to briefly discuss the emerging concepts on mitophagy, molecular regulation of the mitophagy process, current mitophagy detection methods, and mitophagy dysfunction in AD. Finally, we will also briefly examine the stimulation of mitophagy as an approach for attenuating neurodegeneration in AD.

Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer's disease.

INTRODUCTION: This study assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) in Alzheimer's disease (AD) diagnosis, its association with amyloid and tau pathology, as well as its potential to predict brain atrophy, cognition, and amyloid accumulation. METHODS: CSF NfL concentration was measured in 221 participants from the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL). RESULTS: CSF NfL levels as well as NfL/amyloid ß (Aß42) were significantly elevated in AD compared to healthy controls (HC; P < .001), and in mild cognitive impairment (MCI) compared to HC (P = .008 NfL; P < .001 NfL/Aß42). CSF NfL and NfL/Aß42 differentiated AD from HC with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.84 and 0.90, respectively. CSF NfL and NfL/Aß42 predicted cortical amyloid load, brain atrophy, and cognition. DISCUSSION: CSF NfL is a biomarker of neurodegeneration, correlating with cognitive impairment and brain neuropathology.

Plasma High Density Lipoprotein Small Subclass is Reduced in Alzheimer's Disease Patients and Correlates with Cognitive Performance.

BACKGROUND: The link between cholesterol and Alzheimer's disease (AD) has received much attention, as evidence suggests high levels of cholesterol might be an AD risk factor. The carriage of cholesterol and lipids through the body is mediated via lipoproteins, some of which, particularly apolipoprotein E (ApoE), are intimately linked with AD. In humans, high density lipoprotein (HDL) is regarded as a "good" lipid complex due to its ability to enable clearance of excess cholesterol via 'cholesterol reverse transport', although its activities in the pathogenesis of AD are poorly understood. There are several subclasses of HDL; these range from the newly formed small HDL, to much larger HDL. OBJECTIVE: We examined the major subclasses of HDL in healthy controls, mild cognitively impaired, and AD patients who were not taking statins to determine whether there were HDL profile differences between the groups, and whether HDL subclass levels correlated with plasma amyloid-ß (Aß) levels or brain Aß deposition. METHODS: Samples from AIBL cohort were used in this study. HDL subclass levels were assessed by Lipoprint while Aß1-42 levels were assessed by ELISA. Brain Aß deposition was assessed by PET scan. Statistical analysis was performed using parametric and non-parametric tests. RESULTS: We found that small HDL subclass is reduced in AD patients and it correlates with cognitive performance while plasma Aß concentrations do not correlate with lipid profile or HDL subfraction levels. CONCLUSION: Our data indicate that AD patients exhibit altered plasma HDL profile and that HDL subclasses correlate with cognitive performances.

A plasma protein classifier for predicting amyloid burden for preclinical Alzheimer's disease.

A blood-based assessment of preclinical disease would have huge potential in the enrichment of participants for Alzheimer's disease (AD) therapeutic trials. In this study, cognitively unimpaired individuals from the AIBL and KARVIAH cohorts were defined as Aß negative or Aß positive by positron emission tomography. Nontargeted proteomic analysis that incorporated peptide fractionation and high-resolution mass spectrometry quantified relative protein abundances in plasma samples from all participants. A protein classifier model was trained to predict Aß-positive participants using feature selection and machine learning in AIBL and independently assessed in KARVIAH. A 12-feature model for predicting Aß-positive participants was established and demonstrated high accuracy (testing area under the receiver operator characteristic curve = 0.891, sensitivity = 0.78, and specificity = 0.77). This extensive plasma proteomic study has unbiasedly highlighted putative and novel candidates for AD pathology that should be further validated with automated methodologies.

Decrease in p3-Alcß37 and p3-Alcß40, products of Alcadein ß generated by γ-secretase cleavages, in aged monkeys and patients with Alzheimer's disease.

INTRODUCTION: Neuronal p3-Alcß peptides are generated from the precursor protein Alcadein ß (Alcß) through cleavage by α- and γ-secretases of the amyloid ß (Aß) protein precursor (APP). To reveal whether p3-Alcß is involved in Alzheimer's disease (AD) contributes for the development of novel therapy and/or drug targets. METHODS: We developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcß in the cerebrospinal fluid (CSF). RESULTS: In monkeys, CSF p3-Alcß decreases with age, and the aging is also accompanied by decreased brain expression of Alcß. In humans, CSF p3-Alcß levels decrease to a greater extent in those with AD than in age-matched controls. Subjects carrying presenilin gene mutations show a significantly lower CSF p3-Alcß level. A cell study with an inverse modulator of γ-secretase remarkably reduces the generation of p3-Alcß37 while increasing the production of Aß42. DISCUSSION: Aging decreases the generation of p3-Alcß, and further significant decrease of p3-Alcß caused by aberrant γ-secretase activity may accelerate pathogenesis in AD.

Gonadotropins and cognition in older women.

Recent research studies associate elevated gonadotropin levels with dementia. Specifically, an age associated increase in levels of luteinizing hormone has been linked to an increased risk of Alzheimer's disease. The objective of this study was to investigate the association between gonadotropin levels and cognition in older, healthy postmenopausal women. Cognitive functioning was compared with plasma levels of estradiol, luteinizing hormone, follicle stimulating hormone, Abeta40 and APOE genetic status in 649 community-dwelling, non-demented older women residing in Western Australia. High endogenous luteinizing hormone levels were associated with a lower cognitive score, especially in older women and in those women that were depressed. Unexpectedly, disproportionately well preserved cognitive functioning was found for the oldest women who had high endogenous levels of follicle stimulating hormone. The findings indicate that gonadotropins can impact upon cognitive functioning in older postmenopausal women, and that luteinizing hormone and follicle stimulating hormone may exert contrasting effects. Taken together, the findings have important implications for the development of possible preventive strategies for dementia.