The Catastrophe of Intracerebral Hemorrhage Drives the Capillary-Hemorrhage Dementias,Including Alzheimer’s Disease

Abstract

This review advances an understanding of several dementias, based on four premises. One is that capillary hemorrhage is prominent in the pathogenesis of the dementias considered (dementia pugilistica, chronic traumatic encephalopathy, traumatic brain damage, Alzheimer’s disease). The second premise is that hemorrhage introduces four neurotoxic factors into brain tissue: hypoxia of the tissue that has lost its blood supply, hemoglobin and its breakdown products, excitotoxic levels of glutamate, and opportunistic pathogens that can infect brain cells and induce a cytotoxic immune response. The third premise is that where organisms evolve molecules that are toxic to itself, like the neurotoxicity ascribed to hemoglobin, amyloid- (A), and glutamate, there must be some role for the molecule that gives the organism a selection advantage. The fourth is the known survival-advantage roles of hemoglobin (oxygen transport), of A (neurotrophic, synaptotrophic, detoxification of heme, protective against pathogens) and of glutamate (a major neurotransmitter). From these premises, we propose 1) that the brain has evolved a multi-factor response to intracerebral hemorrhage, which includes the expression of several protective molecules, including haptoglobin, hemopexin and A; and 2) that it is logical, given these premises, to posit that the four neurotoxic factors set out above, which are introduced into the brain by hemorrhage, drive the progression of the capillary-hemorrhage dementias. In this view, A expressed at the loci of neuronal death in these dementias functions not as a toxin but as a first responder, mitigating the toxicity of hemoglobin and the infection of the brain by opportunistic pathogens.

Keywords

Acquired resilience Alzheimer’s disease brain protection capillary hemorrhage dementia glutamate excitotoxicity hypoxia immune-mediated cytotoxicity neurotoxicity of hemoglobin vascular aging

INTRODUCTION

Capillary-hemorrhage dementias

The loss of cognitive ability (memory, awareness, executive ability) can be caused by a wide range of circumstances—drugs, general anesthetics, dehydration, sleep deprivation, toxins, fever and infections, chromosomal abnormalities (as in Down syndrome) or the single mutations of amyloid- (A)-related genes that cause familial dementia, and by trauma to the head or brain; and, it would seem, just by getting old [1]. As argued previously [2], capillary hemorrhage is prominent in the sporadic and early-onset forms of Alzheimer’s disease (AD), and in chronic traumatic encephalopathy (CTE), dementia pugilistica (DP), traumatic brain injury (TBI), and probably Down-related dementia.

The idea that capillary hemorrhage might be an important element in the formation of senile plaques goes back to Alzheimer’s original papers [3, 4] and Kraepelin’s coverage of these ideas in his 1910 textbook [4]. Both noted vascular degeneration in brains studied post-dementia but considered the dementias distinct (eigenartige) from the vascular dementias. Through the 20th century, a series of investigators (reviewed [5, 6]) returned to this issue—of the role of vascular dysfunction in these dementias—noting the relationship of senile plaques to small cerebral vessels, and interpreting it sometimes as ‘A-induced damage to vessels’ in AD, or as amyloid angiopathy [6, 7]. Miyakawa [6 , 8–11] contributed strong ultrastructural evidence that plaques form around damaged capillaries, interpreting the damage to capillaries as caused by the accumulation of A. Even so, Miyakawa, in his summarizing 2010 review [6], suggested that vascular damage is important in the pathogenesis of AD. During those years, Hachinski and Munoz [12] reviewed epidemiological, genetic, and neuropathological evidence to assess whether blood vessel damage in AD was ‘cause, effect or epiphenomenon’. Their conclusion was cautiously written: The apparent improvement of patients with Alzheimer’s and vascular dementia who received agents that affect the microcirculation again suggests possible common mechanisms. But its meaning is clear: the idea that the pathogenesis of AD includes a vascular cause warranted study. de la Torré [13] set out a clear view, summarizing extensive evidence that this dementia is a ‘vasocognopathy’, caused by capillary dysfunction.

Over the next decade, with the availability of antibody techniques and amyloid-specific dyes to tag A, this relationship was re-examined in humans with early-onset familial dementia and in mouse models of these dementias [14, 15], and in post-dementia human brains and age-matched controls [16, 17]. These authors confirmed the plaque-vessel relationship and added [16] the observation that heme colocalizes with A in plaques, together with—in a minority of plaques, presumably those formed not long before death—blood specific cells and proteins (red cells, fibrinogen, von Willebrandt’s factor). They suggested, with growing confidence, based on growing understanding of the expression of A by CNS tissue (its expression is hypoxia-induced [18]), that the vascular event in the pathogenesis of AD is capillary hemorrhage [5, 17]. Philbert and colleagues [19] reported the upregulation of two hypoxia-inducible proteins, haptoglobin and hemopexin (known to be protective against the toxicity of hemoglobin) in the post-AD brain and argued that this upregulation is evidence of a ‘pervasive microvasculopathy’. In addition, epidemiological studies showed, for example, that hypertension is a strong risk factor for dementia (reviewed [20 –23]) and conversely that good-for-circulation lifestyle measures (exercise, saunas, healthful diets) delay the onset of dementia; and further that head trauma, which induces small cerebral bleeds, can hasten that onset (reviewed [2]).

Our suggestion that several dementias result from capillary hemorrhage could be seen as counter-intuitive. The onset and progress of these dementias are slow and insidious, making it natural to expect that the cause will be continuous, a slow build-up of some pathology. In the analysis of vascular dementia, for comparison, Hachinski [24] argued that vascular dementias, which by definition occur after symptoms of cerebrovascular dysfunction, should be regarded a ‘quantal and episodic rather than continuous and chronic’ in their genesis, the episodes being strokes—thrombosis in or hemorrhage from vessels large enough for their dysfunction to create symptoms. In arguing for the idea of capillary-hemorrhage dementias, we are suggesting that these dementias, too, are quantal and episodic in their progress, each episode being a hemorrhage from a capillary. Capillary-level hemorrhage, in this view, causes too little damage for their dysfunction to create symptoms, so that the phenotypical development of the dementia seems continuous. How big does an infarct have to be to create symptoms? Clinicians have detected small vascular lesions in vivo, using MRI, in patients that have reported no symptoms (in the ‘healthy aging brain’ [25]), calling them ‘silent’ or ‘asymptomatic’ microbleeds [25 –27]. They are 2–10 mm in diameter, orders of magnitude larger that the plaques that form at the sites of capillary bleeds; plaques measure 0.1 mm in diameter or less, presumably too small to be detected by MRI.

The question why capillaries hemorrhage with increasing frequency with age has been explored in [28], whose authors suggest that the age-related loss of cognition (dementia) has its origin in age-related stiffening of the great arteries of the body, and the rise in pulse pressure consequent on that stiffening. Several reviewers have suggested that senescent changes (weakening) of small cerebral vessels may contribute to the pace of capillary hemorrhage (reviewed in [13]). Finally, in this line of argument, there is evidence that alleles of APOE that regulate the risk of AD regulate the risk of CTE, TBI and DP in the same way. These four forms of dementia seem to share a common pathology, whether assessed by neuropathology, by genetic regulation, by relation to age (all show progression with age [2]) or by relationship to lifestyle factors like blood pressure, exercise, or diet. The question posed by Hachinski and Munoz ([12] in the title of their review (Cerebrovascular pathology in Alzheimer’s disease: cause, effect or epiphenomenon?) may have been answered.

Why this focus?

In all scientific fields some of the time, and in some fields (it seems) all of the time, ideas clash. For science, the clash of ideas can be healthy, a sign of vigor; but, for those suffering, or wondering whether they will suffer, dementia (all of us [1]), dispute can delay optimal treatment. So, what is the clash of ideas? Consider the ‘mainstream’ of the pathogenesis of AD hypothesized in Fig. 1. There is no controversy in its suggestion that, with age, the great arteries stiffen and pulse pressure increases, or that increased pulse pressure can cause hemorrhage from cerebral vessels. Even the further suggestion that the ageing of the great vessels of the body may induce bleeding from smaller cerebral vessels (arterioles or capillaries) creates no clash of ideas. Raised blood pressure is long established as a causal factor in stroke (large bleeds from large vessels, with symptoms and signs); why not for small bleeds from small vessels? With no symptoms nor signs?

Fig. 1

The pathogenesis of dementias like dementia pugilistica (DP), traumatic encephalopathy (CTE), traumatic brain injury (TBI), and Alzheimer’s disease begins with vascular aging, the hardening of the great arteries (Step 1) causing an increase in pulse intensity (2), then in late age, small bleeds from capillaries, which introduce the four forms of toxicity discussed in the text (Step 3). The ‘upstream’ cause of the dementia is then the increase with age in the elastic modulus (stiffness) of the aortic wall; the causes of neuronal death, at the level of each microbleed and plaque, are the focus of this review. In DP, CTE and TBI, the rate at which capillary hemorrhages occur is accelerated by external trauma to the head, bringing the dementia on early. The reason that these trauma-related dementias do not begin immediately on concussion may lie in the brain’s cognitive reserve; the reason that the trauma-related dementias nevertheless appear some years, even decades, after the head trauma is that the pulse continues to damage capillaries [2].

Controversy arises only when one adds—‘and the ageing-induced bleeding from small cerebral vessels leads to dementia’, especially ‘including Alzheimer’s’. It is controversial because the cause-of-Alzheimer’s ‘space’ is already occupied by other ideas, brilliantly researched, but with little reference to the cerebral vasculature, aging or otherwise. And, empirically, scientists share the very human trait of affection for the ideas we have grown up with or have ourselves created. Such controversy still would have little import outside this field, except that understanding of this limited issue—exactly what kills neuron in the dementias?—determines a great deal about treatment and research funding, even the formal approval of drugs for clinical use. Because dementia threatens us all, and arguably can be avoided only by dying before it ‘gets’ us [1], this small issue is a big deal.

SHAPING THE ARGUMENT

The argument of this review is in three parts. In the first, we argue by deduction, from stated premises; and then the devil lies in the premises. In a second, we argue by heuristic power, comparing the explanatory potential of competing ideas of the cause of dementia. In the third section, we consider whether the present debate can be understood, and perhaps will be decided, by a change of paradigms, the slow, often irrational shift of thinking in a field of science, from one set of premises to another.

ARGUMENT BY DEDUCTION FROM PREMISES

The hypothesis in Fig. 1 was developed, in our analysis, from four premises.

1. AD, CTE, DP, and TBI are small-vessel hemorrhagic dementias

We have argued above and previously [5 , 28] that AD, and dementias related to external trauma to the head and brain (DP, TBI, CTE), are small-vessel vascular dementias [2], mentioned above as ‘capillary-hemorrhage dementias’. This premise includes the hypothesis that each senile plaque forms at the site of a small bleed from a capillary-size vessel. The idea that plaques form in relation to capillary-sized vessels was argued by Miyakawa and colleagues [6 , 8–11] from ultrastructural evidence, by Kumar-Singh and colleagues [14, 15] and Cullen and colleagues [16, 17] from studies using molecule-specific labels, in human brain post-dementia and in animal models of early-onset AD. Cullen and colleagues added evidence that senile plaques show evidence of being sites of hemorrhage (the presence in them of heme and, in a minority, of red cells and blood specific proteins). In a separate line of evidence, Robinson and colleagues [29, 30] reported that scavenging microglia loaded with the iron-storage protein ferritin are found at the center of senile plaques of aging human brains, with or without a diagnosis of dementia. They interpreted the ferritin as a cause of A deposition; three decades on it seems more likely that the microglia are loaded with iron scavenged from capillary bleeds, and stored as ferritin, in which form the iron is not toxic. Considered in this way, these findings anticipate Cullen and colleagues’ interpretation of the presence of heme in plaques, just noted above, that A+ plaques form at the site of small hemorrhages. Hachinski and Munoz [24] noted that treatments that protect microvasculature delay dementia; while Stone and colleagues [28] noted that the alleles of APOE regulate the four forms of dementia considered here in the same way. Other reviewers had proposed that failure of the blood-brain barrier (BBB) of capillaries is critical in the genesis of plaque pathology [6, 13]; we confirm this and add that capillary hemorrhage seems particularly important.

2. Even small bleeds are catastrophic: The four toxicities that follow small bleeds

It has for some decades been recognized that intracerebral hemorrhage (ICH) is a severe form of stroke [31, 32] and considerable research has been directed to understanding this severity. Initially, the analysis of the severity focused on the rise in intracranial pressure caused or threatened by intracranial bleeding. Subsequently, the analysis was extended by a distinction between the damage caused in the acute stages of the hemorrhage and a later, ‘secondary’ damage. The idea of secondary brain damage was influenced by the clinical reality that the fast-moving, acute events of ICH could only be managed. Perhaps there was therapeutic opportunity (better recovery, less mortality) if treatment could be devised for a slower-developing, ‘secondary’ stage of survival, after the primary event had been stabilized. Expressed in these terms, the death of neurons after capillary hemorrhage could be regarded as damage secondary to the bleed. The death of neurons at the site of a bleed arises, arguably, from at least four causes [33], one that might be considered primary damage, the other three secondary:

Hypoxia

The capillaries of the cerebral circulation (∼400 miles of them in the adult human brain (reviewed [34])) are the major site of oxygen delivery to the brain. ‘Collapse’ or ‘stickiness’ or ‘failure’ of capillaries would interfere with oxygen delivery, by restricting blood flow through them. Our starting point, however, is that the major pathology of capillaries underlying the dementias considered here is hemorrhage (above) and that the hemorrhage of a capillary causes immediate (primary) hypoxia in its target tissue.

The ‘exquisite neurotoxicity’ [35] of hemoglobin and its breakdown products

In the last decade and more, considerable effort to understand secondary brain damage has focused on the neurotoxicity of blood [32 , 35–37]. In brief summary of a detailed literature, there seems to be agreement that the neurotoxicity of blood is a significant cause of secondary brain damage; that several elements of blood are neurotoxic but the major part of the toxicity of blood arises from hemoglobin and its breakdown products [35], including ‘free’ hemoglobin (intact hemoglobin but outside red cell), free heme (heme free from its usual combination with globin), hemin (an oxidized form of heme), and free iron (Fe^+2/+3). All are considered neurotoxic [35] and it is understood that their toxicity is normally contained by two mechanisms: tight control of hemoglobin within red cells and the timely removal of ‘spent’ red cells by erythrophagocytes in the liver and spleen [38 –40]. The toxicity of these breakdown products becomes evident when this containment fails, as in hemorrhage but also in the hemolytic anemias (thalassemia, sickle cell disease [41]) and in cerebral malaria [42, 43]. The hemolysis of the hemolytic anemias results from genetic malformations of hemoglobin, severe enough that the breakdown of red cells and then of hemoglobin occurs, abnormally, in the circulating blood, with toxic sequelae, including excess iron storage and hemoglobin-induced kidney damage. The hemolysis in cerebral malaria results from the infection of red cells by the pathogen, and causes severe damage in the brain, including breakdown of the BBB and consequent infection of brain cells.

As that understanding grew, it became clear that the toxicity of hemoglobin becomes an issue not only after intra-vascular hemolysis, but also after any hemorrhage [41]. Extravasated red cells break down, releasing hemoglobin into the tissue, and the hemoglobin breaks down ‘freeing’ toxic moieties like heme and Fe² ⁺ ^/3 ⁺ . Several investigators have therefore suggested, but in the context of stroke rather than dementia, that a major component of secondary brain damage is the hemoglobin-driven death of neurons [32 , 35–37]. We now extend this idea to suggest that a major component of the neurodegeneration that causes insidious-onset, capillary dementias is also secondary brain damage, the hemoglobin-driven death of neurons occurring at the sites of bleeds from the smallest of vessels, capillaries. In the brain, we have argued previously [5 , 44], capillary bleeds lead to the formation of senile plaques, which contain both A and heme; these are the foci (German –Herde) that Alzheimer described in the brains, examined postmortem, of patients who had suffered dementia [3].

Finally in this line of thought, investigators have brought together evidence that tissues, including the brain, do not passively suffer hemoglobin-driven secondary brain damage after a bleed. The affected tissue responds, at the local level, to mitigate the toxicity of extravasated blood. In the brain, this response includes (Fig. 1, following [45]) the stress-induced upregulation, at the hemorrhage site, of haptoglobin and hemopexin and the transcription factor HIF-1 [46 –48]. In a mouse model in which hemorrhage was induced by exogenous hemoglobin, for example, deletion of the hemopexin gene aggravated the hemorrhage [49]. Other authors (e.g., [41]) include the heat shock protein heme oxygenase-1 among the detoxifying first responders. Vallelian and colleagues [45] conceptualized a ‘hierarchical defense’ against hemoglobin toxicity, comprising the internalization of disintegrated red cells by erythrophages, then the binding and detoxification of dimeric hemoglobin by haptoglobin, then of free heme by hemopexin. Correspondingly, microglia loaded with ferritin, the body’s major iron-sequestering protein, are prominent within or adjacent to A⁺ (senile) plaques [29, 30], supporting the idea that, as argued above, each plaque is the locus of a small hemorrhage, and microglia react to internalize free iron that enters with the blood, using ferritin to store it in a non-toxic form.

Excitotoxicity from blood levels of neurotransmitters, especially glutamate

The most abundant neurotransmitter in the human brain is glutamate, the ionic form of glutamic acid [50, 51]. Arguably, the selection advantage that drove the evolution of the BBB was the need to control the microenvironment of the brain [52], especially the levels of glutamate in the extracellular fluid of the brain, by blocking glutamate diffusion across the barrier [53]. With glutamate in the brain controlled to low levels by this block, and by the glutamate scavenging mechanisms in neurons and neuroglia [50], glutamate could evolve to be a neurotransmitter. In hemorrhage, or just failure of the BBB without the extravasation of blood, glutamate can diffuse into the neuropil with the blood, where it is potentially neurotoxic, over-stimulating the neurons that have receptors for glutamate and, in their normal function, react to it with excitation. Many studies have proposed glutamate excitotoxicity as a significant neuron-killer in AD (reviewed [50, 51]) and, correspondingly, the one drug approved for treatment of the moderate-severe stages of AD is memantine, an NMDA receptor antagonist drug developed for its ability to reduce glutamate-induced excitotoxicity [54].

Opportunistic infections of the brain and immune cytotoxicity

In addition to its control-of-glutamate role, the BBB excludes pathogenic microbes (bacteria, spirochetes, viruses) from the brain [55]. The exclusion of pathogens is obviously protective and we have noted previously [56] that the same barrier properties also prevent entry of the ‘killer’ T-cells, which—if/when they gain entry—would kill brain cells infected by a pathogen. Balin and colleagues have provided extensive evidence that infection of the brain by the bacterium Chlamydophila pneumonia is associated with greatly raised incidence of AD [57], suggesting that the pathogen may gain access to the brain via the nose and olfactory bulbs, or by areas of breakdown of the BBB. Miklossy [58] reviewed evidence that the spirochete that causes syphilis is found in or near senile plaques/sites of hemorrhage, apparently wrapped and sequestered by attendant A. A considerable body of evidence has grown in recent years (reviewed [59]) that neurotropic viruses that persist in the body (most clearly HSV1) contribute to the onset of AD; and that antiviral drugs and even lithium in drinking water [60] can delay dementia, by suppressing those viruses.

The capillary-hemorrhage hypothesis of this dementia (premise 1 above) provides a mechanism for this role of viral and bacterial pathogens in hastening the onset of dementia. It seems possible that hemorrhages allow the influx of blood-borne pathogens, normally excluded from the brain by the BBB, into the neuropil; and that the same hemorrhages can give killer T-cells access to the same area of brain. A cycle of infection and T-cell-mediated killing of infected neurons may then add to the neuronal death caused by hypoxia, the neurotoxicity of hemoglobin and the excitotoxicity of glutamate.

Supporting this suggestion, it is established, without reference to AD, that—where the brain is infected by syphilis [61] or by the HSV-1 [62] and HIV-1 viruses [63]—a form of dementia can result, in our view because of this cycle of infection and immune-mediated cytotoxicity. Correspondingly, there are reports that antiviral treatment against the HSV viruses [64] and antibiotic treatment against bacteria can significantly delay the onset of dementia. Intervention studies, where the anti-pathogens are given after the appearance of cognitive loss have not yet been shown to be effective treatment, perhaps because cognitive reserve has been exhausted. More positively, anti-pathogens, taken prophylactically before cognitive loss, should, the evidence suggests, be seriously considered as a dementia-delaying treatment.

3. If an organism evolves a self-toxic molecule, that molecule must have another role that gives the organism a survival advantage

Our third premise is that, as other reviewers have pointed out [65 –67], the discovery that a molecule produced by the body is toxic to the body raises an evolutionary ‘flag’. One of the tenets of evolutionary theory is that the species that survive are ‘selected’ by their success in adapting their phenotype, via variations in their genome, to their environment. Self-toxicity seems counter to this tenet—why/how would such toxicity evolve? [65].

Nevertheless, some molecules produced by the body are markedly self-toxic, the clearest examples including hemoglobin and glutamate; and the view that A is both produced by the brain and toxic to it adds A to that list. What are their functional roles?

4. The beneficial actions of hemoglobin, A, and glutamate

The key role of hemoglobin in the transport of oxygen is well established. The disabling of hemoglobin in this role, for example by competitors for its oxygen-binding site like carbon monoxide, causes grave toxicity (https://www.ncbi.nlm.nih.gov/books/NBK538336). The peptide A has several beneficial actions [68]. At picomolar concentrations [69 –71], A enhances the long-term potentiation of synaptic potentials in hippocampal neurons, long considered a possible mechanism of synaptic plasticity and memory. Also at low concentrations, A has been shown to accelerate dendrite formation in neurons and the formation of synapses [69]. Further, evidence has grown that A reduces the severity of infections of brain tissue [72 –74], arguably serving as part of the innate immune system of the brain [66 , 76]. Some authors, focusing on its anti-pathogen function, have dubbed it an ‘antimicrobial peptide’ [75, 77]. In this view, A acts as a biofilm [77] or bioflocculant [74], sequestering viruses within the neuropil. Finally on this point, glutamate is now understood to have evolved to be the major excitatory neurotransmitter in the brain; arguably, it is this role that, in evolution, has offset its excitotoxicity [50].

Summary of the argument by deduction

To the extent that these four premises are correct, it would seem that we risk stating (may the reader forgive us) the bleeding obvious, if we now suggest that the four dementias being considered here (DP, CTE, TBI, AD) are driven at the cellular level by capillary hemorrhages, which cause local hypoxia, release hemoglobin into the neuropil and allow the entry of excitotoxic levels of glutamate and of opportunistic pathogens capable of infecting brain cells and inducing a cytotoxic immune response. Given the still-wide acceptance of the view that A is the toxin that drives AD and that vascular factors are irrelevant, there is much for investigators to discuss, and much at stake for the those suffering dementia or at risk of it (really all of us [1]). But if these premises are substantially correct then the causes of neuronal death in the capillary-hemorrhage dementias include the four just mentioned, and the ‘first responders’ found at hemorrhage sites (erythrophagocytes, haptoglobin, hemopexin, A) have evolved to mitigate those toxicities.

ARGUMENT BY EXPLANATORY POWER

It is a commonplace of scientific argument that attention must be given to data—to ‘the facts’. Debate about the power of an idea is distinctive; it is theory-checking rather than fact-checking. It was, for example, Darwin’s and Wallace’s ideas that changed biology, not their observations. One account of heuristic power (https://en.wikipedia.org/wiki/Explanatory_power) proposes that a theory has better heuristic/explanatory power if, inter alia, it accounts for more observations, provides more details of causal relations, has greater predictive power, depends less on authorities or makes fewer assumptions; or all of the above. With any debate, present or past, each participant makes a judgement. And often the data do not help; they can be explained by either theory. There may be guidance for that judgement, like that just quoted; but there seem to be no certain rules.

Writing a decade and a half ago [5], one of us reviewed earlier evidence that small-vessel pathology is central to the pathogenesis of dementia (e.g., [7 , 17]) and listed observations that the vascular idea of the cause of dementia could explain, and on which the more widely accepted amyloid cascade hypothesis was silent:

The premise that the event that initiates plaque formation is vascular explains why the risk factors for (the capillary dementias) and cardiovascular diseases overlap; why drugs and lifestyle changes with vasoprotective effects protect against dementia; and why oxidative stress is prominent early in the genesis of Alzheimer-like dementias. The vascular premise also suggests that the anatomical substrate for the spread of plaque formation is the capillary bed of the cerebral cortex and provides an explanation of why plaque formation is age-related, occurring as the capillary bed becomes fragile with age. The more specific premise, that haemorrhage creates the conditions for plaque formation, explains many of the features of plaques: their small and relatively uniform size, each being the site of a capillary bleed; why plaques form around capillaries; why heme is found in every plaque; why an inflammatory response is prominent where plaques form; why plaque formation and haemorrhagic stroke commonly co-occur in both sporadic and familial dementias; why plaques form around vessels in mouse models of plaque formation induced by transgenes that mimic the mutations that cause familial disease; why the acute petechial bleeding caused by brain trauma can lead to the formation of plaques.

Subsequently, we proposed [78], following others [79 –81], that the link from age to dementia lies in the wall of the aorta, which loses its elasticity with age (as the elastin in the wall’s tunica elastica denatures), increasing the elastic modulus (stiffness) of the wall (Fig. 1). The effect of this increasing aortic stiffness is to increase with age the intensity of the pulse (pulse pressure), causing capillary bleeding in the later decades of life. It is not necessary to postulate age-relate increases in vessel fragility (as we did in 2008 [5]), although such fragility may occur. These vascular ideas provide understanding of why dementia is so robustly age-linked. Two other premises—the toxicity of hemoglobin and the bind-and-detoxify actions of A, haptoglobin and hemopexin—add (we argue) explanatory breadth.

At the clinical level, the vascular-ageing-causes-dementia hypothesis would predict that high pulse pressure would be a risk factor for dementia [82] and that removing A from the brain (using an anti-A antibody, as in the aducanumab and lecanumab trials) would cause damage to the aging brain, by removing the protection provided by A against the toxicity of hemoglobin. In the trials of anti-A treatments of humans facing dementia, serious side effects were reported, so regularly that they gained their own acronym: ARIAs (amyloid-related-imaging abnormalities). Two classes of ARIAs have been distinguished: ARIA-Es, areas of edema, and ARIA-Hs, areas of hemorrhage. This is a way of stating that the anti-A drugs appear to cause, in some trial participants, brain edema and/or intracerebral hemorrhage. The same drugs also accelerate brain shrinkage [83], another clinical measure of brain damage in dementia. Critics of the approval of these drugs by the American Federal Drugs Administration note that these forms of damage are significant setbacks for those affected, while the benefit claimed for the drugs is too small to improve the lot of either sufferers or their carers [68]. We would add that the ARIAs were predictable from the known brain-protective actions of A, so extending the explanatory power of the vascular hypothesis of the cause of dementia. Supporters of the approvals might note that, although the positive effect claimed for these drugs (the slowing of the rate of cognitive decline) is small, it was predictable from their understanding of the toxicity of A and could be the beginning of a process of drug development, some advance at least in the treatment of a condition that has proved resistant to intense efforts to develop treatments.

In complex processes, like the aging of the brain, there seem to be sufficient variables to allow any datum to be interpreted in opposing ways. Judgement is needed and ours is that, in the present debate, the jury is ‘still out’ concerning these competing views of the cause of AD, but that it should have been back quite some time ago, to report the greater explanatory power of the hypothesis that the capillary dementias are small-vessel vascular dementias, in which capillary hemorrhage is driven by the ageing pulse. And that would allow us, in Smith and colleagues’ now decades-old words [67], to ‘move beyond the firemen to identify the arsonist’. We might amend that slightly, to ‘arsonists’, of which—above—we identify four.

ARGUMENT BY PARADIGMS

The view that scientists think and sometimes re-think in paradigms was developed by T.S. Kuhn [85] as a way of understanding ‘scientific revolutions’. His analysis was distinctive in its view that disagreements in science are typically not solved by rational analysis, but by a shift in the minds of those working in the field, from one set of assumptions (paradigm) to another. A canonical example is the shift from the geocentric to the heliocentric view of how the planets move relative to the earth and sun.

Kuhn’s shift-of-paradigms view [85] was much discussed because of this irrational element, that science makes progress without the detail of data and argument resolved. In these terms, the field of dementia seems, as we have argued previously [2] and other authors before that [86], to be approaching a shift in paradigm, from the view that A is the toxin driving dementia and must be cleared from the ageing brain, to the view that AD and several other dementias are vascular in their basis, and that A may be part of a protective response to the toxicities unleashed by intracerebral bleeds [87, 88]. We argue here from an understanding of vascular ageing; other authors have argued for a change of paradigm to understanding A as a protectant against viral or bacterial infection [57 , 89].

The shift we anticipate may or may not come; when it does (or does not) it will not because any authority adopts it or rejects it, or some key point of evidence is found. The process is not simply rational, although it is somehow data-based and sometimes responsive to deductive analysis. Those of us writing in this area (and there are several other concepts of the cause of dementia vying for attention) write in interesting times. Our view is that the shift just discussed is overdue, for scientific and clinical reasons.

CONCLUSIONS: THE CATASTROPHE OF INTRACEREBRAL HEMORRHAGE

At each hemorrhage site (plaque) four neurotoxic factors; A expression is induced by one and mitigates two

When neuropathologists consider sites of small hemorrhage (the senile plaques) in the aging brain, they report evidence of four forms of neurotoxicity unleashed by capillary bleeds: hypoxia, hemoglobin and its breakdown products, blood-borne glutamate, and opportunistic pathogens. They also report evidence of hypoxia-induced expression of protective molecules—haptoglobin, A, and hemopexin and of the presence of ferritin-rich microglia—all able to mitigate the toxicity of hemoglobin; and they have reported also that A is able to reduce the infection of nerve cells by bacteria. In this view, three of these four toxicities cause the secondary brain damage that is considered to account for the relative severity of hemorrhagic stroke, and A acts at a critical point in the pathogenesis of dementia (the capillary hemorrhage/senile plaque), not as a toxin but as a mitigator of three of these four toxic factors. As support for this view, we note above that several investigators have provided evidence that the trophic roles of A are evident at low doses [69 , 91], its toxic actions at higher doses. In toxicology, it is a long established adage that ‘the dose makes the poison’ [92, 93] or, more recently, ‘the dose makes the medicine’ [92].

Implications for treatment: The ‘bad’ of cognitive reserve

One of the enigmas of the dementias considered above is the lack of effective treatment for them. As we have noted previously, the capillary hemorrhages driving their progression are likely caused by the aging pulse [28] and accelerated by head trauma [2]. Although capillary hemorrhage and associated cognitive loss can be slowed in models of human dementia by many interventions (Table 1) in [1], few of these interventions are effective as post-diagnosis treatments in humans. The understanding argued above that neuronal death at the sites of capillary hemorrhages is driven by a combination of toxicities strengthens the likelihood that it may prove impossible to prevent neuronal death, once a hemorrhage has occurred. The ‘best medicine for dementia’ is then the life-long prevention of intracerebral hemorrhage [1], by protecting the brain from external trauma, controlling blood pressure, and preconditioning the brain by the mechanisms of acquired resilience [78].

Cognitive reserve extends our cognitive life, enabling us to ‘bounce back’ to full cognition, for example after concussion, even though—as now we know—concussions damage the brain and the damage is cumulative [2], causing CTE. But cognitive reserve reduces with age [94] and one way of understanding the onset of dementia is that its symptoms appear when cognitive reserve has been exhausted. With no reserve left the symptoms persist and they also progress, because the pulse continues to cause new hemorrhages [28]. This is the tragedy of dementia.

Efforts continue to identify ways of at least slowing the progression of dementias. The US Federal Drug Administration has in recent years approved the use of several antibody-based drugs designed to extract A from the brain, based on the view that A is the toxic driver of the pathology. These approvals have not been matched in other jurisdictions, because of the weakness of the drugs’ effects and the seriousness of their side effects [95 –97]. In addition, several searches for vaso-active drugs that might alter the course of dementia have been disappointing. Grabowska and colleagues, for example, used a drug-repurposing approach [98] to test many candidate drugs, reporting that none warranted further investigation. Further, a randomized trial of a cholesterol-lowering statin drug failed to slow progression in patients with mild-to-moderate AD [99], and a large-scale, Phase III trial of a calcium channel blocker also gave no evidence of an effect on disease progression [100]. On the other hand, older epidemiological evidence (reviewed [28]) that controlling blood pressure before symptoms delays the onset of cognitive loss has been confirmed in more recent studies [101 –104]. Indeed, one study of anti-hypertensive treatment reported a slowing of the progression of patients from mild cognitive impairment to a diagnosis of AD dementia [105], so matching the effects of the A-extraction drugs, without their severe side effects and high cost.

These recent results, the positive and the negative taken together, seem to confirm that 1) it is difficult to prevent neuronal death once a hemorrhage has occurred; 2) the most effective approach in the face of dementia is to prevent capillary hemorrhage, requiring intervention before diagnosis; and 3) post-diagnosis treatment will at best slow progression. The reasons for this grim outlook are several: 4) the pulse continues (else we die), creating new capillary hemorrhages [28]; 5) the neurotoxicity at the site of each hemorrhage is severe (above); and 6) by the time a patient receives a diagnosis, cognitive reserve is exhausted, and there can be no more ‘bouncing back’ to full cognition. The ‘bad’ of cognitive reserve is that it masks accumulating damage in the brain, until it is too late for any intervention to do more than slow the rate of progression.

The hope when facing dementia: where does it lie?

Previously [1], we suggested that, because the pulse plays a major role in the cause of small-vessel intracerebral hemorrhages [28], dementia is a fate, like other aspects of ageing, that we can avoid only by dying before we are affected. That glimpse forward is discouraging; it is one thing to accept as inevitable the weakening of muscles, the clouding of the eyes, the loss of agility that come with age; quite another to accept that our personality and cognition are also certain to break down with age. There is, even so, a more hopeful perspective—that cognitive loss may impact the individual at 70 years of age or at 100 years or more. There are decades of full cognitive life to be hoped and fought for. Understanding the severity of the toxicities that drive the capillary dementias, but also the effectiveness of pre-diagnosis intervention and the first-responder status of molecules like haptoglobin, hemopexin and A should, we argue, be a valuable step toward cognitive longevity.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

The authors have no funding to report.

CONFLICT OF INTEREST

JS is a Director of CSCM Pty Ltd. SRR is a Director of NeuroTest Pty Ltd.

All other authors have no conflict of interest to report.

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