Worldwide, an estimated 50 million people are living with dementia (1). Projections (which I believe are conservative) show this rising to 82 million by 2030 and 152 million by 2050 (1, 2); with global costs currently estimated at $1 trillion and rising fast (3). Alzheimer’s disease accounts for approximately 60%–70% of these cases, with vascular dementias making up most of the rest (1).
The risk of dementia can be reduced by controlling blood pressure and clotting parameters, but there are no effective treatments for Alzheimer’s.
One reason for this is that Alzheimer’s is not a disease but a syndrome, in the sense that the same clinical symptoms can be generated by different pathologies. There is evidence of at least four sub-types, namely inflammatory, atrophic, toxic (4) and iatrogenic (5), and each of these requires different therapeutic approaches. There is also persuasive evidence that Alzheimer’s in some patients can be stabilised and partly reversed with intensive nutritional strategies (6, 7), but this approach is not widely known and is certainly not accepted by the main stakeholders.
As the mainstream pharmaceutical approach has been a comprehensive failure we need to develop preventative strategies – and there are some obvious things we could do to reduce risk. Unfortunately, as they require social engineering rather than drugs, they will not be promoted by officialdom. Depressive illness (8-14) and the interlinked trio of diabetes (15-18), obesity (19-24) and hypertension (25, 26) are well-established risk factors; but modifying these would require us to design a society less likely to cause depression, diabetes, obesity and hypertension; in other words, a society where the multinational food companies assumed a degree of social responsibility and re-designed their currently toxic products.
But that’s just a day dream. Depression, diabetes, obesity and hypertension are all increasing.
The pandemics of dementia and Alzheimer’s will therefore continue to grow. The damaging effects are and will be most pronounced in our children (8-13, 19, 23, 24) but there’s no need to worry about it too much. Odds are you’ll forget about it soon enough.
You could go on a diet but in our obesogenic environment most diets fail, repeatedly. This may well be counter-productive because body weight fluctuations, which increase the risk of insulin resistance, NIDDM and cardiovascular disease (26-30), also appear to increase the risk of Alzheimer’s (31). So perhaps we should try to be more specific, and look to key events in the brain.
Microglia are critically important cells in the central nervous system, where they play multiple roles.
During brain development, microglia secrete neurotrophic factors which promote the growth and development of neurons in the hippocampus and cortex. Throughout life they enable synaptic pruning, a constant refinement of the synaptic tree and a process of creative destruction which is at the heart of learning and adaptation. At all times, they are the major regulators of neuroinflammation; and they play a dual role in Alzheimer’s. If programmed in one way they degrade amyloid β (Aβ), reduce plaque formation and protect against Alzheimer’s. If alternately programmed, they release pro-inflammatory and inflammatory factors which drive neuroinflammation and increase both Aβ and tau pathology. This initiates a vicious cycle, because as more synapses are damaged by Aβ and tau accumulation, the microglia increasingly activate one of their repertoire of behaviours, namely the removal of dysfunctional, under-utilised and damaged neuronal tissue. The pruning process is amplified beyond normal bounds and now leads to progressive cognitive loss (32).
The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer’s disease (33). Hippocampal neurogenesis plays an important role in structural plasticity and network maintenance, and when pro-inflammatory and destructive microglia start to damage the hippocampus (34, 35), the stage has been set for global decline. One of the key factors supporting hippocampal health and function is brain-derived neurotrophic factor (BDNF). BDNF synthesis is impaired by the ultra-processed diet (36) and recently, an alarming clinical study found that habitual consumption of such a diet was associated with, and likely caused, hippocampal atrophy (37, 38).
There are various ideas as to what switches microglia from supportive and protective dominance to destructive dominance, and most of these involve inflammatory stress. If this is chronic and excessive, the microglia will tend to go along with this and become themselves chronically pro-inflammatory and destructive (39). As the modern lifestyle and diet have become spectacularly pro-inflammatory, it is not surprising that chronic degenerative conditions, neuroinflammatory disorders, dementia and Alzheimer’s have all increased.
From the mass of available data, it looks as if one way of differentiating between the positive and negative effects of microglia is to divide their functions into innate and adaptive immune responses (38, 39). This might be considered an odd way of considering what are thought to be specialized macrophages, but the microglia play different roles depending on their environment.
Chronic inflammation is harmful in all tissues, including the central nervous system.
By switching microglia away from a damaging chronic inflammatory response back towards an innate (and acute) inflammatory response, they shift towards a protective set of behaviours (39) which enable axonal regeneration (41) and presumably synaptic regeneration also. This can be achieved using yeast-derived 1-3, 1-6 beta glucans (41) which likely act via TREM2, a microglial receptor that identifies both beta amyloid (42) and a number of pathogen-linked molecular patterns found in yeast and other microbes (43, 44).
The evidence indicates that the 1-3, 1-6 beta glucans are best supported by a systemic anti-inflammatory approach (39). This would include the classical omega 3 HUFA / lipophile combination; and as dysbiosis and IBD has recently been found to double the risk of dementia (45), a parallel restoration of the microbiome using blended prebiotic fibers (46-48).
Given the above nutritional factors, it seems overwhelmingly likely that dietary shift since WW2 has driven the increase in Alzheimer’s we see today. The removal of 1-3, 1-6 beta glucans and prebiotic fibers from the food chain and the parallel move from an anti-inflammatory to a pro-inflammatory diet leads directly to neuroinflammation, microglial-mediated damage and rising tides of depression and dementia. Restoring these nutritional inadequacies should push the tides back.
What I am proposing here is no more than an extended version of a nutritional regime that has already been shown to stabilize and reverse early cases of Alzheimer’s (5). Professor Dale Bredesen’s pioneering work has opened a door through which we may all hope to progress.
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