Deciphering Alzheimer's Disease Pathogenic Pathway: Role of Chronic Brain Hypoperfusion on p-Tau and mTOR.

This review examines new biomolecular findings that lend support to the hemodynamic role played by chronic brain hypoperfusion (CBH) in driving a pathway to Alzheimer's disease (AD). CBH is a common clinical feature of AD and the current topic of intense investigation in AD models. CBH is also the basis for the vascular hypothesis of AD which we originally proposed in 1993. New biomolecular findings reveal the interplay of CBH in increasing tau phosphorylation (p-Tau) in the hippocampus and cortex of AD mice, damaging fast axonal transport, increasing signaling of mammalian target of rapamycin (mTOR), impairing learning-memory function, and promoting the formation of neurofibrillary tangles, a neuropathologic hallmark of AD. These pathologic elements have been singularly linked with neurodegeneration and AD but their abnormal, collective participation during brain aging have not been fully examined. The format for this review will provide a consolidated analysis of each pathologic phase contributing to cognitive decline and AD onset, summarized in nine chronological steps. These steps galvanize each factor's active participation and contribution in constructing a biomolecular pathway to AD onset generated by CBH.

Hemodynamic Instability in Heart Failure Intensifies Age-Dependent Cognitive Decline.

This review attempts to examine two key elements in the evolution of cognitive impairment in the elderly who develop heart failure. First, major left side heart parts can structurally and functionally deteriorate from aging wear and tear to provoke hemodynamic instability where heart failure worsens or is initiated; second, heart failure is a major inducer of cognitive impairment and Alzheimer's disease in the elderly. In heart failure, when the left ventricular myocardium of an elderly person does not properly contract, it cannot pump out adequate blood to the brain, raising the risk of cognitive impairment due to the intensification of chronic brain hypoperfusion. Chronic brain hypoperfusion originates from chronically reduced cardiac output which progresses as heart failure worsens. Other left ventricular heart parts, including atrium, valves, myocardium, and aorta can contribute to the physiological shortfall of cardiac output. It follows that hemodynamic instability and perfusion changes occurring from the aging heart's blood pumping deficiency will, in time, damage vulnerable brain cells linked to specific cognitive regulatory sites, diminishing neuronal energy metabolism to a level where progressive cognitive impairment is the outcome. Could cognitive impairment progress be reversed with a heart transplant? Evidence is presented detailing the errant hemodynamic pathways leading to cognitive impairment during aging as an offshoot of inefficient structural and functional heart parts and their contribution to heart failure.

Can mild cognitive impairment be stabilized by showering brain mitochondria with laser photons?

There is now substantial evidence that cerebral blood flow (CBF) declines with age. From age 20 to 60, CBF is estimated to dip about 16% and continues to drop at a rate of 0.4%/year. This CBF dip will slowly reduce oxygen/glucose delivery to brain thus lowering ATP energy production needed by brain cells to perform normal activities. Reduced ATP production from mitochondrial loss or damage in the wear-and-tear of aging worsens when vascular risk factors (VRF) to Alzheimer's disease develop that can accelerate both age-decline CBF and mitochondrial deficiency to a level where mild cognitive impairment (MCI) develops. To date, no pharmacological or any other treatment has been successful in reversing, stabilizing or delaying MCI. For the first time in medical interventions, a non-pharmacological, non-invasive, well-tolerated, easy to perform, free of significant side effects and cost-effective treatment may achieve what virtually all AD treatments in the past have been unable to accomplish. This intervention uses transcranial infrared brain stimulation (TIBS), a form of photobiomodulation (PBM). PBM is a bioenergetic non-ionizing, therapeutic approach using low level light emission from laser or light emitting diodes. PBM has been used in a number of neurological conditions including Parkinson's disease, depression, traumatic brain injury, and stroke with diverse reported benefits. This brief review examines the impact of reduced energy supply stemming from chronic brain hypoperfusion in the aging brain. In this context, the use of TIBS is planned in a randomized, placebo-controlled study of MCI patients to be done at our University Clinic. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.

Treating cognitive impairment with transcranial low level laser therapy.

This report examines the potential of low level laser therapy (LLLT) to alter brain cell function and neurometabolic pathways using red or near infrared (NIR) wavelengths transcranially for the prevention and treatment of cognitive impairment. Although laser therapy on human tissue has been used for a number of medical conditions since the late 1960s, it is only recently that several clinical studies have shown its value in raising neurometabolic energy levels that can improve cerebral hemodynamics and cognitive abilities in humans. The rationale for this approach, as indicated in this report, is supported by growing evidence that neurodegenerative damage and cognitive impairment during advanced aging is accelerated or triggered by a neuronal energy crisis generated by brain hypoperfusion. We have previously proposed that chronic brain hypoperfusion in the elderly can worsen in the presence of one or more vascular risk factors, including hypertension, cardiac disease, atherosclerosis and diabetes type 2. Although many unanswered questions remain, boosting neurometabolic activity through non-invasive transcranial laser biostimulation of neuronal mitochondria may be a valuable tool in preventing or delaying age-related cognitive decline that can lead to dementia, including its two major subtypes, Alzheimer's and vascular dementia. The technology to achieve significant improvement of cognitive dysfunction using LLLT or variations of this technique is moving fast and may signal a new chapter in the treatment and prevention of neurocognitive disorders.

Are Major Dementias Triggered by Poor Blood Flow to the Brain? Theoretical Considerations.

There is growing evidence that chronic brain hypoperfusion plays a central role in the development of Alzheimer's disease (AD) long before dyscognitive symptoms or amyloid-ß accumulation in the brain appear. This commentary proposes that dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD) may also develop from chronic brain hypoperfusion following a similar but not identical neurometabolic breakdown as AD. The argument to support this conclusion is that chronic brain hypoperfusion, which is found at the early stages of the three dementias reviewed here, will reduce oxygen delivery and lower oxidative phosphorylation promoting a steady decline in the synthesis of the cell energy fuel adenosine triphosphate (ATP). This process is known to lead to oxidative stress. Virtually all neurodegenerative diseases, including FTD, DLB, and CJD, are characterized by oxidative stress that promotes inclusion bodies which differ in structure, location, and origin, as well as which neurological disorder they typify. Inclusion bodies have one thing in common; they are known to diminish autophagic activity, the protective intracellular degradative process that removes malformed proteins, protein aggregates, and damaged subcellular organelles that can disrupt neuronal homeostasis. Neurons are dependent on autophagy for their normal function and survival. When autophagic activity is diminished or impaired in neurons, high levels of unfolded or misfolded proteins overwhelm and downregulate the neuroprotective activity of unfolded protein response which is unable to get rid of dysfunctional organelles such as damaged mitochondria and malformed proteins at the synapse. The endpoint of this neuropathologic process results in damaged synapses, impaired neurotransmission, cognitive decline, and dementia.

Cerebral Perfusion Enhancing Interventions: A New Strategy for the Prevention of Alzheimer Dementia.

Cardiovascular and cerebrovascular diseases are major risk factors in the development of cognitive impairment and Alzheimer's disease (AD). These cardio-cerebral disorders promote a variety of vascular risk factors which in the presence of advancing age are prone to markedly reduce cerebral perfusion and create a neuronal energy crisis. Long-term hypoperfusion of the brain evolves mainly from cardiac structural pathology and brain vascular insufficiency. Brain hypoperfusion in the elderly is strongly associated with the development of mild cognitive impairment (MCI) and both conditions are presumed to be precursors of Alzheimer dementia. A therapeutic target to prevent or treat MCI and consequently reduce the incidence of AD aims to elevate cerebral perfusion using novel pharmacological agents. As reviewed here, the experimental pharmaca include the use of Rho kinase inhibitors, neurometabolic energy boosters, sirtuins and vascular growth factors. In addition, a compelling new technique in laser medicine called photobiomodulation is reviewed. Photobiomodulation is based on the use of low level laser therapy to stimulate mitochondrial energy production non-invasively in nerve cells. The use of novel pharmaca and photobiomodulation may become important tools in the treatment or prevention of cognitive decline that can lead to dementia.

Do We Try Mending Humpty Dumpty or Prevent His Fall? An Alzheimer's Disease Dilemma.

In the popular nursery rhyme, Humpty Dumpty's great fall and the inability to put him together again has been used to demonstrate the second law of thermodynamics. An oversimplification of this law states that all things in the universe tend to move from order to disorder, an occurrence that can be applied allegorically to the development and clinical outcome of Alzheimer's disease (AD). An important argument relevant to the future use of resources and primary focus of AD research arises from the question, do we make it a priority to mend the shattered brain of AD patients or attempt to prevent the brain from shattering? If the former approach continues to be the priority it has become, how exactly do we mend the irreparable neuronal loss and associated cognitive failure in advanced cases of AD? Or, must we change direction and make prevention the primary goal of AD research? The latter approach would identify asymptomatic or mildly symptomatic patients with high risk of developing dementia by means of establishing multidisciplinary heart-brain clinics that would provide either close observation or a tailored therapeutic intervention. This is an important challenge that needs to be achieved if the AD incidence, societal costs and suffering, is to be significantly reduced.

In-house heart-brain clinics to reduce Alzheimer's disease incidence.

The incidence rate in Alzheimer's disease (AD) is expected to quadruple worldwide by 2050. To limit this impending socio-medical calamity, a fulcrum change from how AD is presently managed is crucial. The present approach has not averted the stress of AD on medical resources nor reduced the already cost-strained government health care programs. Since substantial evidence indicates that sporadic AD is directly associated with vascular risk factors, a strategic plan is proposed to target this association and markedly reduce the onset of AD. This plan would establish in-house heart-brain clinics devoted to identifying, detecting, and preventing the progression of vascular risk factors that predispose to cognitive impairment and development of AD. The heart-brain clinics would be staffed with a multidisciplinary group of neurologists, psychologists, neuroradiologists, cardiovascular specialists, and technical personnel Their goal would be to apply and interpret non-invasive, cost-effective multidiagnostic testing of heart and brain function in outpatient asymptomatic and symptomatic patients at risk of dementia. Multidiagnostic testing would permit better risk stratification, medical decision-making, and a tailored intervention of patients at-risk of dementia than the present monotherapeutic approach. Personalized intervention, moreover, should achieve better patient compliance and outcome through periodic follow-up visits to the clinics where the medical plan of action could be monitored and modified as needed. Multidisciplinary heart-brain clinics will be costly at first but eventually should become cost-effective while providing an invaluable medical service to an aging population and possibly extending years of full-health lived in those at risk of dementia.

Vascular risk factors: a ticking time bomb to Alzheimer's disease.

Evidence is growing that vascular risk factors (VRFs) for Alzheimer's disease (AD) affect cerebral hemodynamics to launch a cascade of cellular and molecular changes that initiate cognitive deficits and eventual progression of AD. Neuroimaging studies have reported VRFs for AD to be accurate predictors of cognitive decline and dementia. In regions that participate in higher cognitive function, middle temporal, posterior cingulate, inferior parietal and precuneus regions, and neuroimaging studies indicate an association involving VRFs, cerebral hypoperfusion, and cognitive decline in elderly individuals who develop AD. The VRF can be present in cognitively intact individuals for decades before mild cognitive deficits or neuropathological signs are manifested. In that sense, they may be "ticking time bombs" before cognitive function is demolished. Preventive intervention of modifiable VRF may delay or block progression of AD. Intervention could target cerebral blood flow (CBF), since most VRFs act to lower CBF in aging individuals by promoting cerebrovascular dysfunction.

Cardiovascular risk factors promote brain hypoperfusion leading to cognitive decline and dementia.

Heart disease is the major leading cause of death and disability in the world. Mainly affecting the elderly population, heart disease and its main outcome, cardiovascular disease, have become an important risk factor in the development of cognitive decline and Alzheimer's disease (AD). This paper examines the evidence linking chronic brain hypoperfusion induced by a variety of cardiovascular deficits in the development of cognitive impairment preceding AD. The evidence indicates a strong association between AD and cardiovascular risk factors, including ApoE(4), atrial fibrillation, thrombotic events, hypertension, hypotension, heart failure, high serum markers of inflammation, coronary artery disease, low cardiac index, and valvular pathology. In elderly people whose cerebral perfusion is already diminished by their advanced age, additional reduction of cerebral blood flow stemming from abnormalities in the heart-brain vascular loop ostensibly increases the probability of developing AD. Evidence also suggests that a neuronal energy crisis brought on by relentless brain hypoperfusion may be responsible for protein synthesis abnormalities that later result in the classic neurodegenerative lesions involving the formation of amyloid-beta plaques and neurofibrillary tangles. Insight into how cardiovascular risk factors can induce progressive cognitive impairment offers an enhanced understanding of the multifactorial pathophysiology characterizing AD and ways at preventing or managing the cardiovascular precursors of this dementia.

Cerebral hemodynamics and vascular risk factors: setting the stage for Alzheimer's disease.

Considerable information is currently available from neuroimaging, pathological, and population-based prospective studies showing that vascular risk factors are independently associated with an increased risk of Alzheimer's disease (AD). Many of these studies indicate that vascular risk factors can predict the clinical development of cognitive dysfunction and AD onset. This review examines the role of cerebral hemodynamics and vasoactive molecules that contribute to the regulation of cerebral perfusion and how three common vascular risk factors to AD, namely, hypertension, diabetes type 2, and atherosclerosis, can alter cerebral blood flow (CBF) regulation and generate perfusion pressure deficits. It is proposed that these vascular risk factors (and presumably other vascular risk factors) initiate chronic brain hypoperfusion that ultimately impair signaling from neurons, astrocytes, and endothelial cells to vascular smooth muscle controlling vessel diameter. Impaired signaling involving vascular pathways in the elderly can attenuate vessel tone and deregulate CBF. Noxious cerebral hemodynamic responses to vascular risk factors and chronic brain hypoperfusion are partly explained by Poiseuille's Law which states that miniscule changes in vessel diameter can have a dramatic effect on vessel resistance and on the rate of blood flow. Using Poiseuille's model, even minor narrowing of arteriolar diameter can lead to major reductions in CBF and in suboptimal delivery of high energy nutrients to the brain, with lethal consequences to brain cells that participate in cognitive function. Regional brain cell loss sets the stage for age-related cognitive impairment and AD onset. Keeping cerebral hemodynamic homeostasis by careful management of vascular risk factors could be a decisive therapeutic target in the prevention of AD.

A turning point for Alzheimer's disease?

Despite an archive of over 73,000 research papers published in the last two decades on the subject of Alzheimer's disease (AD), little clinical progress has been made relative to how people get sporadic AD and what can be done to help them avoid it. This review spotlights strategic steps that could be a turning point in the dramatic lowering of Alzheimer prevalence. The main strategy includes application of four pillars of prevention: 1) early identification of AD vascular risk factors; 2) early detection of AD vascular risk factors; 3) early intervention of AD vascular risk factors based on evidence-based medical decisions; 4) patient follow-up to assess and modify interventions as needed. Tandem to these four pillars of prevention, a proactive lifestyle consisting of a healthy diet coupled to physical and mental activity should be applied as part of any therapeutic intervention. We are persuaded by mounting and compelling evidence that AD is a multifactorial disorder kindled by vascular risk factors that generate chronic brain hypoperfusion (CBH) during advanced aging. A pathobiological cascade of biochemical events in the presence of CBH that leads to oxidative stress and neurodegeneration appears to involve multiple biofactors including micronutrients, trace metals, lipids, and pro-oxidants, as reviewed in this special issue of BioFactors. Modulation of these biofactors may help prevent or control incipient AD. © 2012 International Union of Biochemistry and Molecular Biology, Inc.

Three postulates to help identify the cause of Alzheimer's disease.

Two centuries ago, the German bacteriologist Robert Koch proposed three postulates to support a causal relationship between a specific microbe and an infectious disease. Similarly, three postulates are formulated here to help evaluate hypothetical proposals attempting to explain the pathogenesis of Alzheimer's disease (AD). The first postulate requires that the cause of AD precedes the cognitive decline and neurodegenerative pathology that characterize AD. This rule identifies a primary event from a neuropathological effect generated by the disease process. The second postulate stipulates that interventions aimed at the proposed causal event should prevent or reverse the cognitive and neurodegenerative pathology associated with AD prior to disease onset. This postulate emphasizes prevention or reversal of emerging neurocognitive pathology considerably before AD onset. If the first and second postulate requirements are met, the third postulate follows that interventions targeting the causal event should significantly lower the incidence of AD. For a causal hypothesis to be considered "likely" pathogenic to AD, support from all three postulates is a requisite. The pragmatic potential of the three postulates was applied to seven proposals using evidence-based meta-analysis mainly from randomized controlled trials. Proposals included the amyloid-ß, cell cycle, cholinergic, inflammatory, oxidative stress, tau, and vascular hypotheses. Clinical evidence derived from each proposal formed the basis for an inferential conclusion based on the level of confidence provided by the trial data. The three postulates may challenge or help validate a proposed cause-effect relationship to AD and serve as a useful model for designing more intelligent therapeutic interventions aimed at preventing AD.