Alex E Roher

• Banner Health System

Amyloid imaging demonstrates the in vivo presence of amyloid-β (Aβ) deposits in the aging human brain but it is still unknown which structural forms and modifications of Aβ are detected. In Alzheimer’s disease, most amyloid deposits are predominantly composed of Aβ ending at amino acid residues Val40 or Ala42. It has been reported that Aβ40 is larg...

Introduction: Based on the amyloid cascade hypothesis of Alzheimer's disease (AD) pathogenesis, a series of clinical trials involving immunotherapies have been undertaken including infusion with the IgG1 monoclonal anti-Aβ antibody solanezumab directed against the middle of the soluble Aβ peptide. In this report, we give an account of the clinical...

Tau becomes excessively phosphorylated in Alzheimer’s disease (AD) and is widely studied within the brain. Further examination of the extent and types of tau present in peripheral tissues and their relation to AD is warranted given recent publications on pathologic spreading. Cases were selected based on the presence of pathological tau spinal cord...

Studies of presenilin (PSEN) gene mutations producing early onset Alzheimer’s disease (AD) have helped elucidate the pathogenic mechanisms of dementia and guided clinical trials of potential therapeutic interventions. Although familial and sporadic forms of AD share features, it is unclear if the two are precisely equivalent. In addition, PSEN muta...

Introduction: Epidemiologic data show strong link between cardiovascular risk factors and dementia-related illnesses (DRI) such as Alzheimer’s disease (AD) with evidence that the earliest changes in AD involve vascular dysfunction. The mechanisms behind vascular impairment in DRI remain poorly understood, and lack of a human model to study them imp...

β-Amyloid peptide (Aβ) plaques are a cardinal neuropathologic feature of Alzheimer disease (AD), yet more than one-third of apolipoprotein E ε4 (APOE4) noncarriers with the clinical diagnosis of mild to moderate Alzheimer dementia may not meet positron emission tomographic criteria for significant cerebral amyloidosis. To clarify the percentage of...

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of th...

Amyloid deposition has been implicated as the key determinant of Alzheimer's disease (AD) pathogenesis. Interventions to antagonize amyloid accumulation and mitigate dementia are now under active investigation. We conducted a combined clinical, biochemical and neuropathological assessment of a participant in a clinical trial of the γ-secretase inhi...

Defining the biochemical alterations that occur in the brain during "normal" aging is an important part of understanding the pathophysiology of neurodegenerative diseases and of distinguishing pathological conditions from aging-associated changes. Three groups were selected based on age and on having no evidence of neurological or significant neuro...

Background: Evidence point to vascular dysfunction and hypoperfusion as early abnormalities in Alzheimer's disease (AD); probing their mechanistic bases can lead to new therapeutic approaches. We tested the hypotheses that β-amyloid peptide induces endothelial dysfunction and oxidative stress in human microvasculature and that response will be sim...

We have previously shown that the natural alkaloid anatabine displays some anti-inflammatory and Alzheimer amyloid (Aß) lowering properties in the central nervous system associated with reduced STAT3 and NFkB activation. We investigated here the impact of a chronic oral treatment with anatabine in a model of tauopathy. We found that anatabine reduc...

Transgenic (Tg) mouse models of Alzheimer's disease (AD) have been extensively used to study the pathophysiology of this dementia and to test the efficacy of drugs to treat AD. The 5XFAD Tg mouse, which contains two presenilin-1 and three amyloid precursor protein (APP) mutations, was designed to rapidly recapitulate a portion of the pathologic alt...

Alzheimer's disease (AD) dementia impacts all facets of higher order cognitive function and is characterized by the presence of distinctive pathological lesions in the gray matter (GM). The profound alterations in GM structure and function have fostered the view that AD impacts are primarily a consequence of GM damage. However, the white matter (WM...

The characteristic neuropathological changes associated with Alzheimer's disease (AD) and other lines of evidence support the amyloid cascade hypothesis. Viewing amyloid deposits as the prime instigator of dementia has now led to clinical trials of multiple strategies to remove or prevent their formation. We performed neuropathological and biochemi...

Identifying biomarkers that distinguish Parkinson's disease (PD) from normal control (NC) individuals has the potential to increase diagnostic sensitivity for the detection of early-stage PD. A previous proteomic study identified potential biomarkers in postmortem ventricular cerebrospinal fluid (V-CSF) from neuropathologically diagnosed PD subject...

s Disease consortium 1 The Longtine center for neurodegenerative Biochemistry, Banner Sun health research Institute, Sun city, AZ, USA. 2 civin Laboratory for neuropathology, Banner Sun health research Institute, Sun city, AZ, USA. 3 Department of neurology, Mayo clinic, Scottsdale, AZ, USA. 4 cleo roberts center for clinical research, Banner Sun h...

Dementia pugilistica (DP) is a suite of neuropathological and cognitive function declines following chronic traumatic brain injury (TBI) present in approximately 20% of retired boxers. Epidemiological studies indicate TBI is a risk factor for neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). Some biochemic...

The white matter (WM) represents approximately half the cerebrum volume and is profoundly affected in Alzheimer's disease (AD). However, both the WM responses to AD as well as potential influences of this compartment to dementia pathogenesis remain comparatively neglected. Neuroimaging studies have revealed WM alterations are commonly associated wi...

Alzheimer's disease (AD) dementia is a consequence of heterogeneous and complex interactions of age-related neurodegeneration and vascular-associated pathologies. Evidence has accumulated that there is increased atherosclerosis/arteriosclerosis of the intracranial arteries in AD and that this may be additive or synergistic with respect to the gener...

Parkinson's disease (PD) afflicts approximately 1-2% of the population over 50 years of age. No cures or effective modifying treatments exist and clinical diagnosis is currently confounded by a lack of definitive biomarkers. We sought to discover potential biomarkers in the cerebrospinal fluid (CSF) of neuropathologically confirmed PD cases. We com...

Key pathological hallmarks of Alzheimer's disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes tha...

Abbreviations and explanations. AD = Alzheimer’s disease; ND-HPC = non-demented high pathology control; OO-NPC = oldest-old no plaque control; YO = young-old no plaque control; ID = Case identification number, y = years. String vessels indicates the average number of string vessels from numerous images, TH = tyrosine hydroxylase and TH density indi...

J. Neurochem. (2012) 121, 985–995. The extension of processes of oligodendrocyte (OLG) and their precursor cells are crucial for migration, axonal contact and myelination. Here we show that a non-lethal oxidative stress induced by 3-nitropropionic acid (3-NP) elicited a rapid shortening of processes (∼24%) in primary OLGs and in oligodendroglial ce...

The amyloid cascade hypothesis provides an economical mechanistic explanation for Alzheimer's disease (AD) dementia and correlated neuropathology. However, some nonagenarian individuals (high pathology controls, HPC) remain cognitively intact while enduring high amyloid plaque loads for decades. If amyloid accumulation is the prime instigator of ne...

Here, we synthesize several lines of evidence supporting the hypothesis that at least one function of amyloid-β is to serve as a part of the acute response to brain hemodynamic disturbances intended to seal vascular leakage. Given the resilient and adhesive physicochemical properties of amyloid, an abluminal hemostatic repair system might be highly...

Transgenic (Tg) mouse models of Alzheimer's disease (AD) have been genetically altered with human familial AD genes driven by powerful promoters. However, a Tg model must accurately mirror the pathogenesis of the human disease, not merely the signature amyloid and/or tau pathology, as such hallmarks can arise via multiple convergent or even by path...

Amyloid-β (Aβ) peptides are intimately involved in the inflammatory pathology of atherosclerotic vascular disease (AVD) and Alzheimer's disease (AD). Although substantial amounts of these peptides are produced in the periphery, their role and significance to vascular disease outside the brain requires further investigation. Amyloid-β peptides prese...

The field of Alzheimer's disease (AD) research eagerly awaits the results of a large number of Phase III clinical trials that are underway to investigate the effectiveness of anti-amyloid-β (Aβ) immunotherapy for AD. In this case report, we review the pertinent clinical history, examine the neuropathology, and characterize the Aβ profile of an AD p...

Multiple lines of evidence suggest that cardiovascular co-morbidities hasten the onset of Alzheimer's disease (AD) or accelerate its course. To evaluate the utility of cerebral vascular physical function and/or condition parameters as potential systemic indicators of AD, transcranial Doppler (TCD) ultrasound was used to assess cerebral blood flow a...

A substantial body of evidence collected from epidemiologic, correlative, and experimental studies strongly associates atherosclerotic vascular disease (AVD) with Alzheimer's disease (AD). Depending on the precise interrelationship between AVD and AD, systematic application of interventions used to maintain vascular health and function as a compone...

Epidemiological studies indicate a statistical linkage between atherosclerotic vascular disease (ATH) and Alzheimer's disease (AD). Autopsy studies of cardiac disease in AD have been few and inconclusive. In this report, clinical and gross anatomic measures of cardiac disease were compared in deceased human subjects with and without AD. Clinically...

Background: Active and passive immunotherapy in both amyloid-beta precursor protein (APP) transgenic mice and Alzheimer's Disease (AD) patients have resulted in remarkable reductions in amyloid plaque accumulation, although the degree of amyloid regression has been highly variable. Nine individuals with a clinical diagnosis of AD dementia were act...

In vivo PET imaging studies of young-adult carriers of the apolipoprotein E ε4 allele (APOEε4), the major Alzheimer's disease (AD) susceptibility gene, have demonstrated declines in glucose metabolism in brain areas later vulnerable to AD, such as posterior cingulate cortex, decades before the possible onset of symptoms. We have previously shown in...

Besides its association with Alzheimer's disease (AD), the apolipoprotein E (APOE) ε4 allele may be associated with a higher risk of cardiovascular disease, parasitic, bacterial, and viral infections, hastened progression of AIDS and multiple sclerosis, worse outcome after traumatic brain injury, and shorter lifespan. Here we raise the possibility...

There is considerable epidemiologic evidence that Alzheimer disease (AD) is linked to cardiovascular risk factors and associated with an increased risk of symptomatic left ventricular (LV) dysfunction. Formation of a vortex alongside a diastolic jet signifies an efficient blood transport mechanism. The vortex formation time (VFT) is an index of opt...

The diagnostic performance of several candidate cerebrospinal fluid (CSF) protein biomarkers in neuropathologically confirmed Alzheimer's disease (AD), non-demented (ND) elderly controls and non-AD dementias (NADD) was assessed. Candidate markers were selected on the basis of initial two-dimensional gel electrophoresis studies or by literature revi...

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder with incidence expected to increase four-fold over the next decade. Extensive research efforts are focused upon identifying new treatments, and early diagnosis is considered key to successful intervention. Although imaging and cerebrospinal fluid biomarkers have shown promise in...

A crucial need exists for reliable Alzheimer's disease (AD) diagnostic and prognostic tests. Given its intimate communication with the brain, the cerebrospinal fluid (CSF) has been surveyed intensively for reliable AD biomarkers. The heterogeneity of AD pathology and the unavoidable difficulties associated with the clinical diagnosis and differenti...

Transgenic (Tg) mice that overexpress mutant familial Alzheimer's disease (AD) amyloid precursor protein (APP) genes have contributed to an understanding of dementia pathology, and support the amyloid cascade hypothesis. Although many sophisticated mice APP models exist, none recapitulates AD cellular and behavioral pathology. The morphological res...

The diagnostic performance of several candidate cerebrospinal fluid (CSF) protein biomarkers in neuropathologically confirmed Alzheimer's disease (AD), non-demented (ND) elderly controls and non-AD dementias (NADD) was assessed. Candidate markers were selected on the basis of initial two-dimensional gel electrophoresis studies or by literature revi...

In the last decade, we have witnessed an avalanche of information about the morphological and biochemical changes that occur in Alzheimer disease (AD). This knowledge has provided new strategies for treatment and identified possible approaches for prevention. Because AD pathology is relentlessly progressive, occurring over years or decades, success...

Complement activation and its deposition on β-amyloid plaques in Alzheimer's Disease (AD) brains correlates with the development of AD dementia. Results from immunocytochemical studies suggest that the appearance of complement activation in AD brains results in part from a direct interaction with the β-amyloid (Aβ) peptide Aβ–42, the major peptide...

Post mortem examinations of AN-1792-vaccinated humans revealed this therapy produced focal senile plaque disruption. Despite the dispersal of substantial plaque material, vaccination did not constitute even a partial eradication of brain amyloid as water soluble amyloid-beta (Abeta) 40/42 increased in the gray matter compared to sporadic Alzheimer'...

Post mortem examinations of AN-1792-vaccinated humans revealed this therapy produced focal senile plaque disruption. Despite the dispersal of substantial plaque material, vaccination did not constitute even a partial eradication of brain amyloid as water soluble amyloid-β (Aβ) 40/42 increased in the gray matter compared to sporadic Alzheimer's dise...

We evaluated the amounts of amyloid beta (Abeta)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Abeta plasma levels and Alzheimer's disease (AD) pathology. Amyloid beta levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of...

The Brain Donation Program at Sun Health Research Institute has been in continual operation since 1987, with over 1000 brains banked. The population studied primarily resides in the retirement communities of northwest metropolitan Phoenix, Arizona. The Institute is affiliated with Sun Health, a nonprofit community-owned and operated health care pro...

Alzheimer's disease (AD) is characterized by the accumulation of extracellular insoluble amyloid, primarily derived from polymerized amyloid-beta (Abeta) peptides. We characterized the chemical composition of the Abeta peptides deposited in the brain parenchyma and cerebrovascular walls of triple transgenic Tg-SwDI mice that produce a rapid and pro...

Insulin-degrading enzyme (IDE) is central to the turnover of insulin and degrades amyloid beta (Abeta) in the mammalian brain. Biochemical and genetic data support the notion that IDE may play a role in late onset Alzheimer disease (AD), and recent studies suggest an association between AD and diabetes mellitus type 2. Here we show that a natively...

Insulin-degrading enzyme (IDE) is central to the turnover of insulin and degrades amyloid β (Aβ) in the mammalian brain. Biochemical and genetic data support the notion that IDE may play a role in late onset Alzheimer disease (AD), and recent studies suggest an association between AD and diabetes mellitus type 2. Here we show that a natively folded...

Presenilin (PS) mutations enhance the production of the Abeta42 peptide that is derived from the amyloid precursor protein (APP). The pathway(s) by which the Abeta42 species is preferentially produced has not been elucidated, nor is the mechanism by which PS mutations produce early-onset dementia established. Using a combination of histological, im...

There are 4 million Americans with Alzheimer’s disease (AD), and the cost of the disease to the United States is estimated at $100 billion annually (Alzheimer’s Association). Finding a cure or prevention for AD is therefore an important goal. To do this, however, the cause(s) of AD must first be determined.

We investigated the morphology and biochemistry of the amyloid-beta (Abeta) peptides produced in TgCRND8 Tg mice carrying combined amyloid precursor protein (APP) Swedish (K670M/N671L) and Indiana (V717F) mutations. Histological analyses employing amyloid-specific staining and electron microscopy revealed that the TgCRND8 Tg mice produce an aggress...

A convenient lecture demonstration of the Fenton reaction is presented with references to applications in medicine and environmental engineering. Keywords (Audience): Graduate Education / Research

The role of intracranial atherosclerosis in Alzheimer's disease (AD) has been a subject of debate since the first decade of the last century. The initial "vascular hypothesis" of AD was rejected after a series of mid-twentieth century gross anatomical postmortem studies that showed an inconstant relationship between intracranial atherosclerosis and...

The processes of learning and storage of the results of learning were studied in a model of Alzheimer's disease in two groups of rhesus macaques (three individuals in each group). Studies were performed after injection of neurotoxins (group I) and physiological saline (group II, controls). Two months after injections (stage C1), learning parameters...

Experiments with amyloid-beta (Abeta)-42-immunized transgenic mouse models of Alzheimer's disease have revealed amyloid plaque disruption and apparent cognitive function recovery. Neuropathological examination of patients vaccinated against purified Abeta-42 (AN-1792) has demonstrated that senile plaque disruption occurred in immunized humans as we...

Recent post-mortem studies have reported that the severity of atheromatous deposits in the circle of Willis is significantly greater, relative to non-demented (ND) elderly persons, in subjects with neuropathologically diagnosed Alzheimer's disease (AD). Additionally, the severity of intracranial atherosclerosis correlates significantly with the den...

Diagnostic tests able to reveal Alzheimer's disease (AD) in living patients before cognitive ability is destroyed are urgently needed. Such tests must distinguish AD from other dementia causes, as well as differentiate subtle changes associated with normal aging from true pathology emergence. A single biomarker offering such diagnostic and prognost...

Extracellular fibrillar amyloid deposits are prominent and universal Alzheimer's disease (AD) features, but senile plaque abundance does not always correlate directly with the degree of dementia exhibited by AD patients. The mechanism(s) and dynamics of Abeta fibril genesis and deposition remain obscure. Enhanced Abeta synthesis rates coupled with...

Central to the pathology of Alzheimer's disease (AD) is the profuse accumulation of amyloid-beta (Abeta) peptides in the brain of affected individuals, and several amyloid precursor protein (APP) transgenic (Tg) mice models have been created to mimic Abeta deposition. Among these, the PDAPP Tg mice carrying the familial AD APP 717 Val --> Phe mutat...

Processes of novelty learning and keeping the results in Alzheimer's disease in two groups of rhesus-monkeys (three monkeys in each group), were studied: following neurotoxins administrati- on (I group) and saline administration (II group). In two months after the injections (the C1 stage), considerable differences between the groups were revealed...

Cotton wool plaques (CWPs) are round lesions that lack a central amyloid core. CWPs have been observed in individuals affected by early-onset familial Alzheimer disease (FAD) associated with mutations in the presenilin 1 (PSEN1) gene. Here we present the characterization of the amyloid-beta (Abeta) peptides deposited in the brain of an individual a...

In the AD brain, there are elevated amounts of soluble and insoluble Abeta peptides which enhance the expression of membrane bound and soluble receptor for advanced glycation end products (RAGE). The binding of soluble Abeta to soluble RAGE inhibits further aggregation of Abeta peptides, while membrane bound RAGE-Abeta interactions elicit activatio...

A growing body of evidence suggests that vascular disease underlies Alzheimer dementia. Atherosclerotic lesions in the circle of Willis and large leptomeningeal vessels were quantified and found to correlate with Alzheimer disease (AD) clinical diagnosis and neuropathology. We hypothesize that AD pathology is the complex end result of slowly evolvi...

We postulate that severe atherosclerotic occlusion of the circle of Willis and leptomeningeal arteries is an important factor in the pathogenesis of some sporadic Alzheimer's disease (AD) cases. These arterial stenoses are complicated by an overwhelming amyloid accumulation in the walls of leptomeningeal and cortical arteries resulting in a signifi...

One of the familial forms of Alzheimer's disease (AD) encodes the amyloid-beta precursor protein (AbetaPP) substitution mutation V717F. This mutation is relevant to AD research, since it has been utilized to generate transgenic mice models to study AD pathology and therapeutic interventions. Amyloid beta (Abeta) peptides were obtained from the cere...

We conducted a quantitative investigation of brain arterial atherosclerotic damage and its relationship to sporadic Alzheimer's disease (AD). Fifty-four consecutive autopsy cases, 32 AD and 22 nondemented control subjects, were examined to establish the degree of arterial stenosis. Vessel external and lumenal area measurements were taken from 3-mm...

In this paper we explore the potential functional role of the A beta peptides in the context of Alzheimer's disease (AD). We begin by defining the morphology of the amyloid deposits in relation to surrounding glial cells and, more importantly, in relation to the brain vasculature. Amyloid accumulation in the brain's microvasculature causes disturba...

The neurophysiological interplay of sensory and cognitive processes determines the formation of an outer-world model and, consequently, behavior of the organism. Alzheimer’s disease is a severe human disorder caused by extensive degeneration of various neuronal structures of the brain. Analysis of its causes and mechanisms is not only of clinical i...

APP transgenic mice replicate some aspects of Alzheimer's disease pathology. Despite some similarities, significant biochemical and physical differences exist between the amyloid deposits characteristic of transgenic animals and AD patients. These differences may account for the fact that the promising results obtained by amyloid vaccination of APP...

Indisputable evidence indicates that an inflammatory response is associated with neuron and neurite damage and the deposition of amyloid ß (Aß) and neurofibrillary tangles (NFT) in Alzheimer disease (AD) (see, ref. 1 for a comprehensive review). Just as in the periphery, where degenerating tissue and insoluble materials (resulting from trauma, embo...

Alzheimer's disease (AD) is characterized by neurofibrillary tangles and by the accumulation of beta-amyloid (Abeta) peptides in senile plaques and in the walls of cortical and leptomeningeal arteries as cerebral amyloid angiopathy (CAA). There also is a significant increase of interstitial fluid (ISF) in cerebral white matter (WM), the pathologica...

The β-amyloid peptides, Aβ1-42 and Aβ1-40, were quantified in ventricular CSF taken daily for up to 3 weeks from six individuals with severe traumatic brain injury (TBI). There was considerable interindividual variability in the levels of Aβ peptides, but in general Aβ1-42 levels equalled or exceeded those of Aβ1-40. Averaging the daily totals of o...

Relative to the gray matter, there is a paucity of information regarding white matter biochemical alterations and their contribution to Alzheimer's disease (AD). Biochemical analyses of AD white matter combining size-exclusion, normal phase, and gas chromatography, immunoassays, and Western blotting revealed increased quantities of Abeta40 and Abet...

A key commonality of most age-related neurodegenerative diseases is the accumulation of aggregation-prone proteins in the brain. Except for the prionoses, the initiation and propagation of these proteopathies in vivo remains poorly understood. In a previous study, we found that the deposition of the amyloidogenic peptide Abeta can be induced by inj...

A key commonality of most age-related neurodegenerative diseases is the accumulation of aggregation-prone proteins in the brain. Except for the prionoses, the initiation and propagation of these proteopathies in vivo remains poorly understood. In a previous study, we found that the deposition of the amyloidogenic peptide Aβ can be induced by inject...

Overproduction of the peptide amyloid β (Aβ) is thought to be a critical pathogenic event in Alzheimer's disease (AD), leading to the formation of senile (amyloid) plaques, which in turn lead to neurofibrillary tangles, neuronal and synaptic loss, and dementia. Mendelian inheritance of AD, which occurs in a very small proportion of cases, is caused...

The study of the causes and mechanisms of Alzheimer’s disease, one of the most debilitating human diseases in which neuronal structures of the brain undergo extensive degeneration, is not only of clinical interest, but may also provide a clue to an understanding of the neurophysiological principles of how cognitive processes are organized. Alzheime...

The amyloid (Abeta) peptides generated in Hsiao's APP Tg2576 transgenic (Tg) mice are physically and chemically distinct from those characteristic of Alzheimer's disease (AD). Transgenic mouse Abeta peptides were purified using sequential size-exclusion and reverse-phase chromatographic systems and subjected to amino acid sequencing and mass spectr...