Abstract A growing body of evidence links type-2 diabetes (T2D) with dementia and neurodegenerative diseases such as Alzheimer's disease (AD). AD is the most common form of dementia and is ...characterised neuropathologically by the accumulation of extracellular beta amyloid (Aβ) peptide aggregates and intracellular hyper-phosphorylated tau protein, which are thought to drive and/or accelerate inflammatory and oxidative stress processes leading to neurodegeneration. Although the precise mechanism remains unclear, T2D can exacerbate these neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism and CNS insulin resistance are features of both AD and T2D. Cell culture and animal studies have indicated that the early accumulation of Aβ may play a role in CNS insulin resistance and impaired insulin signalling. From the viewpoint of insulin resistance and impaired insulin signalling in the brain, these are also believed to initiate other aspects of brain injury, including inflammatory and oxidative stress processes. Here we review the clinical and experimental pieces of evidence that link these two chronic diseases of ageing, and discuss underlying mechanisms. The evaluation of treatments for the management of diabetes in preclinical, and clinical studies and trials for AD will also be discussed.
Glial fibrillary acidic protein (GFAP), an astrocytic cytoskeletal protein, can be measured in blood samples, and has been associated with Alzheimer's disease (AD). However, plasma GFAP has not been ...investigated in cognitively normal older adults at risk of AD, based on brain amyloid-β (Aβ) load. Cross-sectional analyses were carried out for plasma GFAP and plasma Aβ1-42/Aβ1-40 ratio, a blood-based marker associated with brain Aβ load, in participants (65-90 years) categorised into low (Aβ-, n = 63) and high (Aβ+, n = 33) brain Aβ load groups via Aβ positron emission tomography. Plasma GFAP, Aβ1-42, and Aβ1-40 were measured using the Single molecule array (Simoa) platform. Plasma GFAP levels were significantly higher (p < 0.00001), and plasma Aβ1-42/Aβ1-40 ratios were significantly lower (p < 0.005), in Aβ+ participants compared to Aβ- participants, adjusted for covariates age, sex, and apolipoprotein E-ε4 carriage. A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished Aβ+ from Aβ- (area under the curve, AUC = 0.78), but was outperformed when plasma GFAP was added to the base model (AUC = 0.91) and further improved with plasma Aβ1-42/Aβ1-40 ratio (AUC = 0.92). The current findings demonstrate that plasma GFAP levels are elevated in cognitively normal older adults at risk of AD. These observations suggest that astrocytic damage or activation begins from the pre-symptomatic stage of AD and is associated with brain Aβ load. Observations from the present study highlight the potential of plasma GFAP to contribute to a diagnostic blood biomarker panel (along with plasma Aβ1-42/Aβ1-40 ratios) for cognitively normal older adults at risk of AD.
Type 2 diabetes (T2DM), Alzheimer’s disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin ...resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer’s disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD.
Alzheimer’s disease (AD) is a multifactorial age-related brain disease. Numerous pathological events run forth in the brain leading to AD. There is an initial long, dormant phase before the clinical ...symptoms become evident. There is a need to diagnose the disease at the preclinical stage since therapeutic interventions are most likely to be effective if initiated early. Undoubtedly, the core cerebrospinal fluid (CSF) biomarkers have a good diagnostic accuracy and have been used in clinical trials as end point measures. However, looking into the multifactorial nature of AD and the overlapping pathology with other forms of dementia, it is important to integrate the core CSF biomarkers with a broader panel of other biomarkers reflecting different aspects of pathology. The review is focused upon a panel of biomarkers that relate to different aspects of AD pathology, as well as various studies that have evaluated their diagnostic potential. The panel includes markers of neurodegeneration: neurofilament light chain and visinin-like protein (VILIP-1); markers of amyloidogenesis and brain amyloidosis: apolipoproteins; markers of inflammation: YKL-40 and monocyte chemoattractant protein 1; marker of synaptic dysfunction: neurogranin. These markers can highlight on the state and stage-associated changes that occur in AD brain with disease progression. A combination of these biomarkers would not only aid in preclinical diagnosis, but would also help in identifying early brain changes during the onset of disease. Successful treatment strategies can be devised by understanding the contribution of these markers in different aspects of disease pathogenesis.
Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer's disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating ...detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM
gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation.
Summary Background Brain amyloid β (Aβ) deposition and neurodegeneration have been documented in about 50–60% of cognitively healthy elderly individuals (aged 60 years or older). The long-term ...cognitive consequences of the presence of Alzheimer's disease pathology and neurodegeneration, and whether they have an independent or synergistic effect on cognition, are unclear. We aimed to characterise the long-term clinical and cognitive trajectories of healthy elderly individuals using a two-marker (Alzheimer's disease pathology and neurodegeneration) imaging construct. Methods Between Nov 3, 2006, and Nov 25, 2014, 573 cognitively healthy individuals in Melbourne and Perth, Australia, (mean age 73·1 years SD 6·2; 58% women) were enrolled in the Australian Imaging, Biomarker and Lifestyle (AIBL) study. Alzheimer's disease pathology (A) was determined by measuring Aβ deposition by PET, and neurodegeneration (N) was established by measuring hippocampal volume using MRI. Individuals were categorised as A− N− , A+ N− , A+ N+ , or suspected non-Alzheimer's disease pathophysiology (A− N+ , SNAP). Clinical progression, hippocampal volume, standard neuropsychological tests, and domain-specific and global cognitive composite scores were assessed over 6 years of follow-up. Linear mixed effect models and a Cox proportional hazards model of survival were used to evaluate, compare, and contrast the clinical, cognitive, and volumetric trajectories of patients in the four AN categories. Findings 50 (9%) healthy individuals were classified as A+ N+ , 87 (15%) as A+ N− , 310 (54%) as A− N− , and 126 (22%) as SNAP. APOE ε4 was more frequent in participants in the A+ N+ (27; 54%) and A+ N− (42; 48%) groups than in the A− N− (66; 21%) and SNAP groups (23; 18%). The A+ N− and A+ N+ groups had significantly faster cognitive decline than the A− N− group (0·08 SD per year for AIBL-Preclinical AD Cognitive Composite PACC; p<0·0001; and 0·25; p<0·0001; respectively). The A+ N+ group also had faster hippocampal atrophy than the A− N− group (0·04 cm3 per year; p=0·02). The SNAP group generally did not show significant decline over time compared with the A− N− group (0·03 SD per year p=0·19 for AIBL-PACC and a 0·02 cm3 per year increase p=0·16 for hippocampal volume), although SNAP was sometimes associated with lower baseline cognitive scores (0·20 SD less than A− N− for AIBL-PACC). Within the follow-up, 24% (n=12) of individuals in the A+ N+ group and 16% (n=14) in the A+ N− group progressed to amnestic mild cognitive impairment or Alzheimer's disease, compared with 9% (n=11) in the SNAP group. Interpretation Brain amyloidosis, a surrogate marker of Alzheimer's disease pathology, is a risk factor for cognitive decline and for progression from preclinical stages to symptomatic stages of the disease, with neurodegeneration acting as a compounding factor. However, neurodegeneration alone does not confer a significantly different risk of cognitive decline from that in the group with neither brain amyloidosis or neurodegeneration. Funding CSIRO Flagship Collaboration Fund and the Science and Industry Endowment Fund (SIEF), National Health and Medical Research Council, the Dementia Collaborative Research Centres programme, McCusker Alzheimer's Research Foundation, and Operational Infrastructure Support from the Government of Victoria.
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 (Aβ−) or presence (Aβ+) of brain amyloidosis.
Results
Plasma GFAP, t‐tau, p‐tau181, and p‐tau231 concentrations were higher in Aβ+ CU compared with Aβ− CU cross‐sectionally. GFAP had the highest effect size and area under the curve (AUC) in differentiating between Aβ+ and Aβ− 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 Aβ+ CU and increased NFL in Aβ− 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.
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.
Remodeling of high‐density lipoprotein (HDL) during disease onset and progression, in which cholesterol and Apolipoprotein D levels are increased while Apolipoprotein A‐II levels are decreased on HDL (left). Additionally, increased cholesterol levels on HDL are associated with increased ventricular volume and decreased grey matter volume, while increased levels of Apolipoprotein A‐II and Apolipoprotein J are associated with increased hippocampal and grey matter volume and reduced ventricular volume (right).
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.
In this review, we focused on the involvement of HDL in Alzheimer's disease and the protective effects of HDL and HDL‐protein cargo with particular regard to the downstream effects on Aβ processing, catabolism and Aβ oligomer formation.
Age-related hearing loss (ARHL), presbycusis, is a chronic health condition that affects approximately one-third of the world's population. The peripheral and central hearing alterations associated ...with age-related hearing loss have a profound impact on perception of verbal and non-verbal auditory stimuli. The high prevalence of hearing loss in the older adults corresponds to the increased frequency of dementia in this population. Therefore, researchers have focused their attention on age-related central effects that occur independent of the peripheral hearing loss as well as central effects of peripheral hearing loss and its association with cognitive decline and dementia. Here we review the current evidence for the age-related changes of the peripheral and central auditory system and the relationship between hearing loss and pathological cognitive decline and dementia. Furthermore, there is a paucity of evidence on the relationship between ARHL and established biomarkers of Alzheimer's disease, as the most common cause of dementia. Such studies are critical to be able to consider any causal relationship between dementia and ARHL. While this narrative review will examine the pathophysiological alterations in both the peripheral and central auditory system and its clinical implications, the question remains unanswered whether hearing loss causes cognitive impairment or vice versa.
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