Best Medicine for Dementia: The Life-Long Defense of the Brain

Abstract

This review deals with an unwelcome reality about several forms of dementia, including Alzheimer’s disease— that these dementias are caused, in part or whole, by the aging of the vasculature. Since the vasculature ages in us all, dementia is our fate, sealed by the realit!ies of the circulation; it is not a disease with a cure pending. Empirically, cognitive impairment before our 7th decade is uncommon and considered early, while a diagnosis in our 11th decade is late but common in that cohort (>40%). Projections from earlier ages suggest that the prevalence of dementia in people surviving into their 12th decade exceeds 80%. We address the question why so few of many interventions known to delay dementia are recognized as therapy; and we try to resolve this few-and-many paradox, identifying opportunities for better treatment, especially pre-diagnosis. The idea of dementia as a fate is resisted, we argue, because it negates the hope of a cure. But the price of that hope is lost opportunity. An approach more in line with the evidence, and more likely to limit suffering, is to understand the damage that accumulates with age in the cerebral vasculature and therefore in the brain, and which eventually gives rise to cognitive symptoms in late life, too often leading to dementia. We argue that hope should be redirected to delaying that damage and with it the onset of cognitive loss; and, for each individual, it should be redirected to a life-long defense of their brain.

Keywords

Alzheimer’s disease cerebral vasculature chronic traumatic encephalopathy dementia dementia pugilistica traumatic brain injury

INTRODUCTION: ABOUT DEMENTIAS

This essay concerns a small number of dementias— Alzheimer’s disease (AD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), and dementia pugilistica (DP). These are among the many dementias that have been described and included in the DSM (Diagnostic and Statistical Manual of the American Psychiatric Association) and the ICD (the WHO’s International Classification of Diseases). Attempts to classify mental disturbances go back at least to the middle of the 19th century (for an American history see [1]; for a history in Europe see [2]). Debates continue as to whether dementias should be classified and diagnosed according to patients’ signs and symptoms or by causation, which is more fundamental but still not fully understood. They continue because anomalies and paradoxes arise in either approach, which in turn are symptoms of the limits of our knowledge.

Following either stream of thought (to classify by symptoms or causation), it is hard not to be struck by the enormous variety in the brain dysfunctions that have been described, and by the difficulty of classifying them. Considering just dementias, among those not considered here are dementias associated with genetic syndromes like Down’s syndrome (a triploidy of a full chromosome) or the familial dementias caused by highly penetrative single mutations; deliria and dementias caused by drugs, general anesthetics, dehydration, sleep deprivation, toxins, fever; and dementias caused by uncontrolled infections (syphilis, HIV). The brain is complex, and symptoms of its dysfunction vary well beyond the present scope.

The rationale for focusing on four dementias (AD, CTE, TBI, DP) is that they seem to share a common cause, in the impact of trauma on the cerebral vasculature; they form a group by hypothesis of causation. Further, if the hypothesis [3–5] of a common vascular cause continues to survive empirical testing, then this growing understanding should guide the investment of resources into prevention and management. Finally, at this point, we note that previous authors have argued [6] that cerebrovascular breakdown may play a key role in multiple dementias, including the α-synucleinopathies and frontotemporal dementia. This review extends the idea to CTE and TBI.

THE PARADOX: THE FEW AND MANY WAYS OF MANAGING DEMENTIA

The understanding of dementia, and with it the management of dementia, may be approaching a paradigm change, driven (we suggest) by an emerging paradox. The paradox is presented below, and outlines of a new paradigm are becoming clear. The shift, when it comes, will have implications for those at risk of dementia (so, all of us) and for public health research and practice in dementia. But first, a look at the paradox, and the related data.

The few

For all concerned (sufferer, carer, physician, public health decision maker), one reality of a diagnosis of any of these dementias is the paucity of treatment. The mainstream advice is clear, though often and understandably cloaked in encouraging words: there is no cure; the dementia will likely progress; the drugs approved are few in number and can at best slow progress, and then only in some patients; the tragedy of dementia will unfold.

The drugs presently approved for treatment vary somewhat, from jurisdiction to jurisdiction. The Dementia Australia website lists four drugs available to improve cognition, to enable sufferers to ‘be themselves’ for a while longer but notes that ‘there is no evidence that they slow the progression of the underlying disease’. Three of the drugs (donepezil, rivastigmine, galantamine) are cholinesterase inhibitors, designed to prolong the activity of cholinergic pathways that spread from basal forebrain into the cerebral cortex and are early casualties in the course of dementia. Several other cholinesterase inhibitors have been investigated [7]; these are the three approved in Australia. The same three are approved for use in the USA; advice at a National Library of Medicine site 1 includes:

“(Galantamine) has a positive effect in about 14 out of 100 people who use it”.

“So far the research hasn’t show that cholinesterase inhibitors help people with Alzheimer’s cope better in everyday life” or “can improve disease-related quality of life” or “delay the move to a nursing home”.

The fourth drug listed on the Australian site is memantine, which is described pharmacologically as a low-affinity voltage-dependent uncompetitive antagonist of glutamatergic NMDA receptors. It is considered to act by blocking prolonged influxes of calcium ions into nerve cells, so protecting them from excitotoxicity (death by over-excitation). Memantine is rated as giving no clinical benefit for people suffering early-to middle-stage AD; rather it is commended for the later stages of the dementia. Advice at a National Library of Medicine site 2 is also disappointing:

“Memantine was able to delay the worsening of cognitive performance over a period of six months in about 1 out of 10 people” and “There is also no evidence that this treatment helps to lessen the burden on family members or loved ones, for example by lowering the need for care or lessening emotional stress.”

In the USA, but not in Europe or Australia, approval was recently given for the use of two other drugs, both antibodies designed to reduce the ‘load’ in the brain of a peptide known as amyloid-β (Aβ): the drugs are known as aducanumab and lecanemab. Their approval by the relevant authority (the Federal Drug Administration) was conditional and subject to review.

A 2022 analysis of aducanumab/Aduhelm [8] noted that results of two clinical trials had been presented in the application to the FDA for approval; that in both trials the drug reduced the amount of Aβ in the brain; that, in one trial, a 22% reduction in the rate of cognitive decline over the test period had been reported; while in the other trial, there had been no significant reduction in the rate of cognitive decline. The review authors concluded that:

Pre-clinical studies and clinical trials have suggested the ability of aducanumab to restore neurological function in patients with AD by reducing Aß plaques and re-establishing neuronal calcium permeability. However, discrepancies in post hoc analysis findings have cast doubt on the research and medical community. Some studies suggest the benefits of aducanumab are perhaps limited to statistical significance and lack clinical significance.

Qualified approval was given in early 2023 for a second anti-Aβ drug, lecanemab. A report provided by the team producing the drug [9] gave evidence that the drug reduces Aβ load in the brain and slows the rate of cognitive decline. One independent reviewer [10] commented that “although the findings are encouraging it is not yet known whether the drug will make a real world difference to people who have the condition”. Similar caution was expressed in an Australian review, written soon after the FDA approval of lecanemab [11]. Both drugs were judged safer than anti-Aβ drugs previously reported, but still had detrimental side-effects, particularly swelling of and bleeding in the brain, sufficient for some commentators to question whether the game was worth the candle [12]. The search for still-better drugs for AD, most involving a small molecule targeting Aβ for use post-diagnosis, remains vigorous [13], its vigour arising from the awfulness of the condition, and the clinical ineffectiveness of even the drugs approved.

Further studies will establish the clinical value of these drugs. Even with them, the treatments available to the newly diagnosed sufferer of dementia remain heart-wrenchingly few— a handful of drugs with significant side effects; with some ability to slow cognitive decline in some sufferers; but still no demonstrated ability to stabilize the underlying disease process or lessen the burden on carers.

The many

In laboratory studies (Table 1), many approaches to slowing Alzheimer-like pathology (plaques, tangles, inflammation) have been reported to work robustly, raising the question— why so many in the lab, so few in the clinic?

Table 1

Interventions that slow Alzheimer-like pathology in rodent models

Therapeutic applications of resilience-inducing stress in rodent models of dementia
Intervention/Rationale	Authors	Model
WAYS OF SLOWING PATHOLOGY/COGNITIVE LOSS IN (mostly) TRANSGENIC MICE
Photobiomodulation/low-level light therapy
Upregulation of mesenchymal stem cells	[14]	5x Tg mice
Upregulation of mitochondrial function	[15]	Tg-APP mice
Upregulation of BDNF	[16]	Tg APP/PS1 mouse neurons
Upregulation of resilience mechanisms	[17]	Tg-APP/PS1 and Tg-K3 mice
Upregulation of cellular and indirect mechanisms of resilience	[18]	Wildtype mice injected with amyloid-β_25 - 35
Decrease in JNK3 phosphorylation	[19]	Tg-APP/PS1 mice
Regulation of intestinal flora with gut-flora targeted PBM	[20]	Wildtype mice injected with Aβ_1 - 42
Upregulation of glial cell polarization and inhibition of neuroinflammation, preservation of mitochondrial dynamics by regulating fission and fusion proteins, and suppression of oxidative damage to DNA, proteins, and lipids	[21]	Tg-F344 rats
Upregulation of long-term potentiation	[22]	Tg-APP/PS1 mice
Activation of bone-marrow-derived stem cells, which slow deposition of Aβ	[23–26]	Aβ-induced hippocampal damage
Immune checkpoint blockade	[27]	5x FAD mice and APP/PS1 mice
Exercise (voluntary running)
Upregulations of cholesterol trafficking in lysosomes	[28]	THY-Tau22 mice
Reduction of oxidative stress	[29, 30]	3x Tg-AD mice
Reduction of extracellular soluble Aβ	[31]	Tg2576 mice
Regulation of several pathways, including GDNF and Sirt1	[32]	3xTg-AD mice
Maintenance of APOE function	[33]	APOE-deficient mice
Increase of complement cascade inhibitors including clusterin	[34]	Tg-APP mice
Morphological plasticity in the hippocampus	[35]	Tg-APP/PS1
Maternal exercise (voluntary running)
Epigenetic transmission of upregulated tissue resilience	[36]	TgCRND8 mouse offspring
Conference of Aβ protection in rat offspring’s cerebellum	[37]	Wildtype rats
Learning, spatial training
Training reduces Aβ load	[38]	3xTg-AD mice
Alleviation of Aβ burden and adult hippocampal neurogenesis deficits	[39]	Tg-APP/PS1 mice
Maintenance of estrogen, progesterone, androgens
Estrogens, progesterone	[40]	3xTg-AD mice
Androgens	[41]	3xTg-AD mice
Hunger, Intermittent caloric restriction
Reduction Aβ toxicity, inflammation	[42]	Tg-APP-SwDI mice
Protection of brain tissue from Aβ/tau toxicity	[43]	3xTg mice
Chronic caloric restriction enhanced autophagy and reduced microgliosis, resulting in decrease of Aβ load	[44]	Tg-APP/PS1 mice
Regulation of microglia
Role of in microglia in neuron elimination	[45]	5x Tg mice, receptor KO
Inhibition of microglial activation by blocking CSFR1	[46]	3x TG mice
Transplanted microglia upregulate Aβ clearance	[47]	Aβ injection into rat lateral ventricle
Light flicker recruited neurons and microglia to attenuate Aβ levels	[48]	5x Tg mice
Hydrogen sulfide, reproducing ‘health-giving spa waters’, upregulating H₂S-mediated neurotransmission	[49]	Toxin-damaged rat, 3x Tg mice
Plant toxins
Ingested phenols including resveratrol reduce Aβ levels	[50]	Tg2576 mice
Ingested flavonoids reduce Aβ load, inflammation; improve vascular function	[51]	Tg-APP/PS1 mice
Ingested resveratrol upregulates cell survival pathways	[52]	SAMP8 mice
Ingested phytosterols attenuates inflammation, suppressing inflammatory response of microglia to Aβ₄₂ oligomers	[53]	Tg-APP/PS1 mice
Ingested hexane and ethanolic extracts (in avocado) inhibit acetylcholinesterase activity	[54]	In vitro
Overexpression of APPsα in brain
Upregulation of APPsα with neurotrophic effects	[55–57]	Tg-APP/PS1 mice
Infusion of Aβ₄₂/hormetic effect on synaptic plasticity and memory	[58, 59]	Wildtype (C57BL/6) injected with
Aβ₄₂ and APP/PS1 mice
Ultrasound and microbubbles
US increase Aβ clearance by opening BBB, allowing microglial movement across barrier	[60, 61]	Tg-APP23 mice
Ultrasound
US reduced cognitive loss and Aβ loading, by upregulation of eNOS-mediated pathways.	[62]	5x Tg mice
US with the BBB intact has no effect on Aβ burden.	[63]	Tg-APP23 mice
US reduced Aβ burden, in association with an upregulation of microglia colocalized with Aβ.	[64]	5x Tg mice
US reduced amyloid load in pre- and infra-limbic cortex and in hippocampus. Suggested that US acts by entraining EEG activity.	[65]	5x Tg mice
US long-term potentiation and ameliorated spatial learning deficits in aged rats. Authors suggest that US is ‘a non-invasive, pleiotropic modality’.	[66]	Wildtype (C57BL/6) mice
US slowed Aβ+plaque formation and cognitive loss, by low-level stress on brain tissue	MJA’s PhD dissertation, unpublished	Tg-APP/PS1 mice
Phosphodiesterase 5 inhibitor (Viagra)/Enhances phosphorylation of CREB, a molecule involved in memory through elevation of cGMP levels	[67]	Tg-APP/PS1 mice
HSP induction/Stabilisation of proteins by HSPs	[68]	Tg-APP/PS1 mice
Angiotensin receptor blocker / Mitigates Aβ upregulation, reduces toxic effects	[69]	Tg-APP23 mice
Sodium selenite / Inhibition of tau phosphorylation	[70]	K3 mice (two strains)

Tg, transgenic; BDNF, brain-derived neurotrophic factor; JNK3, c-Jun N-terminal kinase 3; PBM, photobiomodulation; GDNF, glial-derived neurotrophic factor; Sirt1, sirtuin-1; CSFR1, colony-stimulating factor-1; BBB, blood-brain barrier; CREB, cAMP-response element binding protein; cGMP, cyclic guanosine monophosphate; HSPs, heat-shock proteins; 3x, three genes have been transposed into the mouse genome; 5x, five genes have been transposed into the mouse genome; APP, amyloid precursor protein; Aβ, amyloid-β, PS1, presenilin 1.

In animal models of AD

Laboratories pioneering treatments for any disease begin, where they can, with animals— usually, for practical reasons, laboratory mice— in which both genetic and environmental variation can be minimized, reducing the ‘noise’ of individual variation so marked in humans, so that a treatment-induced response can be detected readily. But regular mice (in lab lingo ‘wild-type’) live about 24 months and rarely develop the Aβ+plaque pathology seen in the adult human brain. To create mouse models for dementia research, specialist laboratories developed “Alzheimer transgenics”, drawing on work that had identified the single gene mutations that, in humans, reliably cause Alzheimer-like dementia; these are the ‘early-onset’ or ‘familial’ Alzheimer-like dementias. These groups pioneered how to insert/transfer those mutated human genes into the genome of mice, creating ‘transgenic’ strains of mice, and monitored each strain, each with 1, 2, or 3 of the human early-onset genes. Long story short, 15 or more strains have been described [71], in which pathology very like that which Alzheimer described in humans appears and progresses; and cognitive loss, assessed in mice by memory tasks, appears and progresses in parallel. Their availability stimulated much research.

To the authors, Table 1 was striking, as it came together. Photobiomodulation, activation of bone-marrow stem cells, immune checkpoint blockade, exercise, maternal exercise, active learning, management of sex hormones, hunger, caloric restriction, regulation of microglia, exposure to H₂ S as in a traditional health spa, dietary supplementation with plant toxins (mimicking a Mediterranean diet), ultrasound with or without manipulation of the blood-brain barrier, Viagra, induction of heat shock proteins— all these interventions and more were reported to slow the progress of the plaque/tangle/inflammation pathology and of cognitive loss. It seems that the pathology and cognitive loss considered characteristic of AD can be slowed by almost anything. Yet only the three cholinesterase inhibitors, one anti-excitotoxicity drug, and (in the USA) two immune-based anti-Aβ interventions have been approved, even conditionally, for clinical use; and none has yet to change more than slightly the clinical reality of dementia, for sufferers or carers, or for clinicians.

Each of the many interventions in Table 1 had a rationale— the mechanism the investigators suggested their intervention tapped into— summarized briefly in the table and in more detail in the original papers. Our point for the moment is the contrast between the few treatments that have been approved for dementia in humans and the plethora of ways in which the pathology and cognitive loss caused by human ‘Alzheimer’ genes in transgenic mice can be slowed. And then to ask— what is stopping the translation of these many observations into the clinic? The suggestion developed below is that there is an identifiable block to the translation of the many ways of reducing the pathology of dementia; we then analyze the block.

In humans, but is it really treatment?

With Table 1 in mind, we went back to the literature asking, not which drugs have been approved in various jurisdictions, but what interventions have been shown to be effective in delaying or preventing AD in humans, including ‘lifestyle’ (pre-diagnosis) interventions (Table 2). For this table, for each of five forms of everyday stress that induce acquired resilience (exercise, dietary toxins, photobiomodulation, caloric restriction/hunger, heat [72]), a search was made for reports of whether that stress delayed or slowed cognitive loss in humans. Overall, with perhaps the exception of pre-diagnosis exercise, the number of studies available for humans was less than for transgenic mice. Also, the reports concerned cognitive loss, and not the underlying pathology, which was available for mice. The table is not comprehensive, especially for exercise, but provides significant evidence that these stresses are effective in protecting cognition. A limited number of ‘not effective’ reports were encountered and are listed. There may be a bias against our identifying ‘no effect’ reports, because investigators may take less trouble to publish negative results. We have separated studies that examined the effect of the stress as a lifestyle preventative, from intervention studies in subjects with a diagnosis of cognitive loss.

Table 2

Studies and reviews of 5 stresses known to induce acquired resilience [72], showing their effectiveness/ineffectiveness in slowing or delaying cognitive loss. In broad summary, some but not all were effective as post-diagnosis interventions; but all were reliably effective as pre-diagnosis preventative measures

Stress-induced protection against dementia
Form of stress	As pre-diagnosis/lifestyle preventative Effective/ineffective	As post-diagnosis intervention Effective/ineffective
Exercise	Alty et al. [77] Petersen and Saltin [78] And many others	Fari et al. [65] Archer [79] Karssemeijer et al. [80] Morris et al. [81] Zhang et al. [82] Lamb et al. [83] Ho et al. [84] Ströhler et al.[73]
Phytotherapy/plant toxins/Mediterranean diet	Petersson, Philippou [85] Sofi et al. [86] Berendsen [87] Howes [88] Russo [89] Gregory et al. [90] Cherbuin and Anstey [91]
Photobiomodulation and similar radiations	Vargas [92]	Maksimovich [93] Salehpour et al. [94] Berman et al. [95] Enengl et al. [96] Zhu et al. [97]
Caloric restriction, intermittent hunger	Luchsinger [98] Pasinetti et al. [99]
Heat (as in saunas)	Laukkanen et al. [100] Knekt et al. [101] Hussain and Cohen [102]
Multiple stresses	Tsai et al. [103] Lisko et al. [104] McMaster [105]

For exercise during mid-life, before a diagnosis of cognitive loss, study after study reported positive effects; exercise did not prevent the onset of cognitive loss, but appeared to delay onset, and to improve many other aspects of health. Studies of exercise after diagnosis of cognitive loss reported more mixed outcomes; a minority of the studies that we identified reported no effect, the majority reporting improvements in cognition. One review [73], allowed comparison between the impact of approved drugs (cholinesterase inhibitors, memantine) and the impact of exercise, in patients with early cognitive loss (mild cognitive impairment, MCI) or more severe loss (‘Alzheimer’s’), concluding that the drugs had a ‘small effect’ for AD patients and no effect on MCI; while exercise had a ‘moderate to strong’ effect for AD patients and a ’mild’ effect in MCI. Yet, exercise continues to be a recommendation adjunct to the drugs. With the stronger effect and fewer side effects, exercise, and the other stresses that induce acquired resilience [72], surely deserve full status as treatments for dementia, more important (until evidence suggests otherwise) than the drugs.

More generally, all resilience-inducing stresses, when begun pre-diagnosis as preventative measures, had the effect of delaying the onset of dementia and, where it was reported, in reducing general morbidity. The formally approved drugs were all designed, tested, and approved for use post-diagnosis. And, post-diagnosis, our reading of the literature is, most clearly for exercise, that the lifestyle stress interventions are at least as effective. Further the stresses do not, at the effective doses, produce harmful side-effects such as the brain swelling and bleeding reported for minorities of the participants in the trials of the anti-Aβ immno-drugs [74, 75], effects that critics suggest arise from the physiological functions of the Aβ that is stripped away by the immunotherapy [12]. Indeed, at the effective low doses, for example for saunas a rise in body temperature up to 1°C for tens of minutes per day [76], the ‘side effects’ are positive— low general morbidity and greater longevity.

Perhaps because these interventions are not specific in their effects to dementia, they are mentioned on many advice-to-the-affected sites not as treatments to of dementia, but as ‘healthy habits’. Yet many are effective delayers of dementia and their deployment pre- and post-diagnosis is arguably the best approach available to reduce the suffering of dementia.

RESOLVING THE PARADOX: THE CASE FOR A SHIFT OF PARADIGM

The paradox of the few and the many, set out above, can (we argue) be fruitfully resolved by a shift from thinking of these dementias as diseases with cures pending, to accepting dementia (especially AD) as a fate, caused by the realities of the cardiovascular system. Emotionally, the shift is unwelcome, because it seems to remove the element of hope from advice to sufferers and carers. More positively, however, the shift will, we argue, unblock the translation of ‘the many’ for the prevention and management of dementia, and re-direct hope to delay.

As a last note before attempting the resolution of paradox, we note that several previous authors or groups of authors have called for this shift of understanding, or of ‘paradigm’ (T.S. Kuhn’s term [106]), in thinking about the cause of dementias, to a focus on the cerebral vasculature. These include Bateman [107] and Henry-Feugeas [108] who argued that the pulse plays a causal role in a range of ‘encephalopathies’, including dementia; de la Torre [109] who argued that AD is a ‘vasocognopathy’ caused by small-vessel dysfunction; Kling and colleagues [110], who called for paradigm shifts in thinking about dementia ‘to advance research’; and ourselves [3], who drew on these suggestions and much literature to argue that in AD, ‘the brain is destroyed by the pulse’, and traced the implications of that hypothesis. The shift to a vascular understanding of AD, and of the several other dementias in the present focus, is already two decades, even three, in the making.

What then are the paradigm-imposed issues presently blocking the translation of ‘the many’ ways of slowing and stabilizing the neurodegeneration known as AD into clinical practice? Perhaps five: the rejection of fate; the human need for hope; the downplaying of lifestyle measures; the problem of a predictive biomarker, and the elusive brain property of cognitive reserve.

The rejection of the idea/reality that dementia is a fate

An example of the hopeful view of dementia is the volume Mayo Clinic on Alzheimer’s Disease and other dementias. The first 5 chapters draw a distinction between ‘typical aging’ and the beginnings of the tragedy of dementia. Many authoritative websites, such as Alzheimer’s Australia, argue the same point, that ‘dementia is not a normal part of aging’.

So, what is the argument that dementia is a fate, and therefore a normal part of aging? The argument is in (at least) two parts. One is an argument-by-logic from the understanding that AD is a ‘vasocognopathy’ [109], or a pulse-induced encephalopathy [107, 108] or a pulse-induced small-vessel vascular dementia [3]. With that idea as a premise, it follows that, as long as the heart beats, the damage to the brain will continue, from youthful and mid-age levels at which there are no cognitive symptoms, to levels found in late age, when symptoms emerge and then progress. As long as the heart beats, and therefore in everybody, the damage continues (this argument goes), accumulating to the symptomatic threshold, and beyond.

The second part of the argument is empirical. If dementia is a pulse-driven fate, its prevalence should rise with age towards 100%. A rise towards 100% was reported in the “90+” study of Corrada and colleagues [112] in their Fig. 2. They report 12.7% incidence in a cohort aged 90– 94 years; 21.2% in a cohort aged 95– 99 years, and 40.7% in a cohort aged > 100 years. Further, they estimated that the doubling time of dementia incidence in the 11th decade of life falls to 5.5 years. This suggests that in a cohort aged 110 years or more the incidence would be > 80%. Similarly, Lucca and colleagues [113], in a study of ‘oldest old’, reported prevalence levels of 15.7% at ages 80– 84 years, rising to 76% at 102– 107 years, adding that ‘prevalence rates of dementia do not level off, but … rise gradually even in the extreme ages’. It would seem that those of us who escape dementia do so by dying of something else.

Is the increase of age/pulse-induced damage to the brain linear? Or does the rate of damage vary with age?

The two studies of the very old just mentioned, and the study of Hall and colleagues [114], all report that the incidence of dementia continues to increase in the late decades of life, but each describes a particular time course. Hall and colleagues noted that, although the prevalence of dementia rises monotonically with age and increases at an increasing rate (so ‘exponentially’) in cohorts up to 85 years of age, their observations suggested of an easing in the rate of increase after the age of 90 years. Corrada colleagues [112], concluded somewhat differently, that the prevalence of dementia increases exponentially with age, including in their oldest cohort (>100 years old); while Lucca and colleagues [113] suggested the prevalence of dementia rises linearly with age. More observations will resolve these discrepancies; it remains robustly the case that the prevalence of dementia increases with age, towards 70– 80% in the oldest cohorts studied. At these extreme ages, further data become unavailable, for those who have escape dementia have succumbed to something else.

From what else? As O’Rourke and colleagues noted [115], the one other organ whose failure increases with age as reliably as the brain, is the kidney; because, they argued, the kidney too is a high-blood-flow organ, and the necessarily high compliance of its vascular bed makes the kidney as vulnerable to pulse-induced damage as the brain. Empirically, kidney failure and brain failure (dementia) co-occur commonly and are the two causes of death that currently are rising robustly as the causes of death (reviewed in [3]). Deaths caused by infectious diseases, heart disease, and cancer have held steady or fallen in recent years. Die we must, however, and as more and more of us survive these non-fate killers, deaths from kidney and brain failure (caused in this view by the beat of the heart) rise. Until we can contrive to live without a pulse (and, with the development and success of continuous-flow left ventricular assist devices as destination therapy [116], that can at least be imagined), that trend is likely to continue.

A note on names

Most forms of dementia are referred to as dementias: dementia pugilistica, frontotemporal dementia, Lewy body dementia, vascular dementia, syphilitic dementia. An exception, and it is a big one, is AD; the insidious-onset dementia of late age is commonly called Alzheimer’s disease. The naming goes back to Alzheimer’s mentor Emil Kraepelin who, writing Alzheimer’s ideas into a textbook in 1910, included Alzheimers Krankheit in the Table of Contents (Fig. 1). ‘Alzheimer’s disease’ is an entirely reasonable translation of Alzheimers Krankheit, if only the English word ‘disease’ did not carry the hope of a cure.

Fig. 1

From the Table of Contents of Kraepelin’s Lehrbuch für Studierende und Ärzte [117], showing what must be the first use of ‘Alzheimer’s disease’ or ‘illness’. The Section C heading Der Altersblödsinn translates as ‘derangements in the aged’. The highlighting is ours.

Hope, and the way hope affects the search for a cure

Some fates short of death we already accept, if not happily: that our muscles will weaken as we grow older and our skin will lose its elasticity, the accommodation power of our eyes will reduce, the lenses of the eye will cloud over, and the easy spring of youth will go from our step. But we will still be ourselves. The idea that our brain and personality will crumble in an otherwise viable body is harder to accept as certain fate; and the hope that dementia is a disease with a possible cure is preferred.

But hope has its price as well as its comfort (Fig. 2). If we believe that dementia is a disease then each of us will get on with life; if and when we are diagnosed, we will turn to our physicians, hoping that a cure has emerged in the meantime. Researchers who share that view will devote their careers to the search for a post-diagnosis cure; funding bodies will pour funds into their search; and regulators will be asked to assess what the scientists bring forward— possible post-diagnosis cures.

Fig. 2

Outcomes of a choice in the understanding of dementias considered here, as diseases or a fate. The choice is between paradigms— dementia as a disease caused by proteinopathies versus dementia as a consequence of small-vessel hemorrhages which in turn result from the normal function of the aging vasculature.

Conversely, if we accept that dementia is our fate, avoidable only by dying before it ‘gets’ us, we will focus our research and attention on the life-long, pre-diagnosis measures already known to protect the brain and delay dementia, better than any drug: diet, exercise, weight control, blood pressure control, the radiations, the heat of saunas, caloric restriction. This is part of the story of acquired resilience [72]. We will also avoid situations known to bring on dementia, particularly external trauma to the head (head-knock sports, accidents) and internal trauma to the brain (pulse pressure, and therefore hypertension). Clinical emphasis will be on life-long measures of prevention, as well as post-diagnosis interventions. Researchers who share that view will look for ways to optimize life-long preventatives, funding bodies will support them and regulators, if they are involved (is there a need to regulate exercise?), will be asked to assess these life-long measures.

So, the choice is important. The young have another choice— to enjoy life and just not worry about issues of disease and fate. In every generation, some box or play football with or without a helmet, jump off cliffs trusting parachutes to engage before whatever, climb rock faces untethered, skateboard down hills at lethal speeds or toboggan headfirst, risking ‘sled head’ [118]. The ideas proposed here are for those who would enjoy cognitive health in their later decades. For them, hope can be reformulated. The dementia we call Alzheimer’s can affect us at 70 years of age, or at 110; there are 40 years of clarity of mind to be fought for, with measures already at hand. There lies hope; not in a cure.

The down-playing of ‘lifestyle’ measures

Probably all websites advising on dementia recommend exercise, mental exercise, diet, refraining from smoking, limiting alcohol. But they recommend these choices as good habits, not as therapy, even as therapy adjunct to approved drugs. Yet, as Table 2 shows, some are reliably effective, most clearly when implemented as life-long preventative treatment; some are also effective post-diagnosis. And their side effects are healthful— lower morbidity, greater longevity; very different from the brain swelling and bleeding reported for Aβ-clearance drugs [74].

We argue that these ‘good habits’ should be recognized as mainstream preventative treatments and, for those for which there is evidence, as post-diagnosis treatment. The acquired resilience concept gives them a mechanistic base and a base in evolutionary biology. In practice they are too often downplayed, as part of the hopeful understanding of AD as a disease, with a cure just around the corner.

The choice of a predictive biomarker: mild cognitive loss is a late diagnosis.

If AD is, at diagnosis, the result of accumulated hemorrhagic damage to the brain, then the first symptoms of the dementia— often memory failure— are a decades-late alert of damage that might have been slowed by pre-diagnosis measures protective to the brain. What might serve as a biomarker for damage that has yet to emerge clinically? Here again, paradigm is critical. Biomarkers for AD have been developed, based on the assumption that it is caused by proteinopathies of Aβ or tau, for example [119]. If, conversely, we accept the vascular basis of these dementias, then the established biomarkers of vascular aging (arteriosclerosis, pulse pressure, pulse wave velocity or PWV) should serve better. As one example [120], Chiesa and colleagues showed a significant correlation between PWV and cognitive decline (the greater the PWV, and hence the pulse pressure – pre-diagnosis, the more rapid is later cognitive decline). PWV can be assessed quickly and non-invasively with a probe placed over one of the carotid arteries. In comparable epidemiological studies, Lockhart and colleagues [121] suggested in summary the convergence of multiple vascular and Alzheimer’s processes underlying neurodegeneration and cognitive decline; while Jiang and colleagues [122] concluded that cardiovascular risk factors play critical roles, both through independent and neurodegenerative pathways, on cognition. The ‘association’ of cardiovascular pathology with dementia is robust; we have argued previously that it is causative, specifically that the aging pulse causes the capillary-level damage that eventually creates cognitive loss [3].

Arguably, since they reflect the cause of the central pathology of the dementia (vascular aging) rather than one of the consequences of the bleeding (Aβ⁺-plaque formation and the hyperphosphorylation of tau [3, 123, 124]), the vascular markers should prove more sensitive, better guides. But their adoption, testing and development depend on paradigm.

This plea for an emphasis on pre-diagnosis, preventative treatment for dementia follows a recommendation of Vogt and colleagues [125]. In a review of antibody therapies to AD (including Aduhelm, lecanemab, discussed above), these authors, even without considering the vascular contribution to the pathogenesis of AD (which to us seem central), concluded:

Although many preclinical studies have reported the clearing effects of Aβ deposits by passive as well as active immunotherapy, they could not delay the progression of AD … Therefore, it is urgent to change the diagnostic toward the detection of pre-symptomatic AD.

Cognitive reserve

One of the most elusive yet impressive properties of the brain has been called cognitive reserve. This, and related terms like brain reserve, compensation, and cognitive resilience, refer to the ability of the brain to function normally despite damage [126]. Functional reserve has been described in the kidney (renal reserve) and liver (hepatic reserve) but seems more mysterious in the brain, which is commonly (and reasonably) thought of as an organ of complex circuitry, that malfunctions in specific ways when areas of it are damaged. The liver and kidney are simpler organs, each part functioning in the same way as any other; in them, functional reserve can be understood as redundancy, valuable for survival but not mysterious. In the brain, just in the neocortex, neuroscientists distinguish areas dealing with motor output, the senses, speech (motor and sensory separately), memory, and more. This functional specificity within neocortex was described around the turn of the last Century, based largely on functional-anatomical correlates in cases of stroke; a mid-20th century update was provided by A.S. Luria, after his intensive study of the bullet-in-the-head wounded of World War 2 [127].

It was then something of a mystery to realize how thoroughly shot through with microlesions the aging brain becomes without cognitive symptoms appearing [128]. Neurologists have coined the term ‘silent microbleeds’ to describe their observation of small (a few mm diameter) bleeds in the brain, detectable by high-resolution MRI, with no symptoms nor signs in the patient. It is hard to imagine an engineer-built microprocessor maintaining performance with the level of damage known to accumulate in the human brain without cognitive loss. The brain (it would seem) continuously repairs itself, to function despite large numbers of lesions. One ‘secret’ of this functional repair is, perhaps, the small size of many vascular lesions. Bullet-sized lesions, and infarcts caused by hemorrhage from large cerebral vessels typically create clear clinical deficits; they are too big, apparently, for full repair, though partial recovery of function during convalescence is common. But the brain can, it would seem, ‘repair around’ silent microbleeds (5– 10 mm in diameter as detected by MRI [129]) and the much smaller senile plaques (up to 100μm diameter), which previous workers [124, 130] have argued result from bleeds from the smallest cerebral vessels, the capillaries.

But empirically, there seems to be a limit to brain’s ability to repair around even the smallest lesions and that limit may be set by the amount of neocortex available for recruitment into the repair. That amount presumably reduces as the brain deals with the lesions that continue to occur with age. That ‘amount’ of recruitable neocortex is presumably the physical basis of cognitive reserve.

If we— the individual, the carer, the professional— do not know of, or do not accept, the concept of age-related reduction of cognitive reserve, and the related concept of clinical threshold, then cognitive loss can, when diagnosed, be seen as something that has just happened and surely can be treated. And that understandable misunderstanding slows the translation of the many mechanisms touched on in Table 1 to mainstream preventative therapy.

THE FOUR DEMENTIAS CONSIDERED

To this point, this review has mentioned DP, CTE, TBI, and AD as a group, but has focused on AD. We have argued recently [5] that in DP, CTE, and TBI, external trauma adds to the pace of vascular damage that causes AD, bringing on clinical symptoms earlier than would have occurred without the external trauma. Once symptoms appear, all four progress, because of damage caused by the beating of the heart into vessels stiffening with age. The dementia of old age— AD— is, in this view, unavoidable as long as the heart keeps beating, but its onset is hastened by external trauma and delayed by protective measures taken pre-diagnosis. How much can it be hastened? Perhaps, we have suggested [5], by 15– 20 years. How long can it be delayed? Perhaps by as much as from 70 years of age to 110 years of age. As noted above, therein lies hope.

CONCLUSION

We began this review with the paradox of the few-and-many— why are so many effective ways of delaying dementias still awaiting translation into mainstream treatment? We ended it with an analysis of factors that seem to be blocking that translation (the rejection of fate, the comfort of hope, the downplaying of lifestyle, the choice of a biomarker, the brain’s remarkable cognitive reserve). Between the paradox and the analysis, we argued for a shift of understanding, of paradigm, for the dementias considered here. Dementia, we argue, is a normal part of aging; it is a fate that can be delayed or brought on early by lifestyle choices and genetic factors; and the best clinical and public health outcomes will be achieved if the premises of research and clinical practice include that understanding.

The thought is not new, that age can destroy us before we die. It is there in Shakespeare’s ‘mere oblivion’ as the seventh of the seven stages of human life (in his As You Like It, written late in the 16th century); it is there in the 19th century bravado of ‘live hard, die young’ 3 and in the poet’s gentler language of tribute, early in the 20th Century, for the dead of World War I–‘age shall not weary them, nor the years condemn’ 4 . It may be heartbreakingly difficult to abandon hope of a cure and accept that dementia can be avoided only by dying. But the price of hope is high, in lost opportunity. Better clinical outcomes will be obtained, suffering will be less, when we understand the vascular basis of these dementias, accept the inevitability of the dementia we call AD, make our personal choices and guide research and clinical management to the life-long defense of the brain.

Footnotes

ACKNOWLEDGMENTS

The authors are grateful to Dr. Emily C. Stone for the advice on the clinical aspects of this review.

FUNDING

JS acknowledges support from the Zelman Cowen Associates (Sydney).

CONFLICT OF INTEREST

JS is a Director of CSCM Pty Ltd.

‘Live hard, die young and leave a good-looking corpse’; American, 19th Century, anonymous.

Laurence Binyon’s For the Fallen 1914.

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