Castillo (2013) notes that the term ‘hypothesis’ is often confused with ‘theory’, explaining that ‘[a] theory is the end result of a previously tested hypothesis, meaning a proved set of principles that explain observed phenomena.’ But he also advises that many consider the scientific method as ‘rigid and constrained in its design and produces results that are isolated from real environments and that only address specific issues.’ So perhaps, as Castillo (2013) posits, there is room for serendipity and an awareness that science is ‘a dynamic process engaging many individuals and activities’ and that data may not always fit into organised and neat conclusions: ‘Science is about discovery, not the justifications it seems to emphasise.’
If nothing else, Castillo's assertions in relation to the scientific method should remind us that, as the historian Marc Bloch put it: ‘The nature of our intelligence is such that it is stimulated far less by the will to know than by the will to understand’ (James, 2007). In this respect, current work on Alzheimer's disease (AD) shows that there is no shortage of hypotheses-generating research attesting to a will to understand.
For example, Agarwal et al (2021) list the amyloid-beta (Aβ) hypothesis, referring to the accumulation of Aβ oligomers in the brain; the Tau protein hypothesis, focusing on Tau's role in the regulation of microtubule function; the cholinergic hypothesis, which identifies a reduced rate of production and transport of the neurotransmitter acetylcholine in the brains of AD-affected individuals; and the dendritic hypothesis, implicating dendrite degeneration and their accompanying structural and functional disturbances.
And now there is a more recent hypothesis that throws light on possible future research directions. Espay et al (2023) indicate that much of AD research and drug development derive from an emphasis on the assumed toxicity of the Aβ peptide, so that ‘when proteins become aggregated into an amyloid state, referred to as pathology, they not only define neurodegenerative diseases but cause them – that pathology is pathogenesis.’ This approach, assert Espay et al (2023), is flawed for two reasons: first, aggregated proteins do not accurately predict functional decline; and second, ‘Amyloid clearance has yielded futility, harm, or, with lecanemab and donanemab, no improvement but statistically significant slowing in cognitive decline of a magnitude below the established threshold for clinical meaningfulness.’
It is known not only that Aβ42 is an evolutionarily conserved neuropeptide with a role in modulating synaptic plasticity, but that as Aβ42 monomers convert into amyloid the concentration of Aβ42 declines. Thus, Espay et al (2023) hypothesise ‘that the loss of soluble Aβ42 to protein aggregation also represents the loss of its neurotrophic properties and is, therefore, more detrimental to the brain than the corresponding accrual of insoluble amyloid.’ It follows, therefore, that ‘[d]eveloping ways to restore soluble Aβ42 via pharmacological induction, enhancement, or replacement represents a testable rescue strategy for slowing disease progression in AD’ (Espay et al, 2023).
‘With Aβ accumulating in the brain through impaired clearance, not overproduction, Berger and Ede (2023) suggest that a possible explanation for this is reduced concentrations of insulin-degrading enzyme’
While Espay et al's hypothesis opens another avenue of exploration, Berger and Ede (2023) provide a different – dietary – perspective on the role of Aβ in the pathology of AD, asserting that the Aβ hypothesis exemplifies how ‘conventional theories about dementia development and pharmaceutical research have largely focused on the anatomical consequences of the disease process rather than its root causes.’ Citing evidence that ‘chronically elevated insulin, even in the context of normal blood glucose concentrations, has emerged as a strong independent risk factor for cognitive decline’, and that hyperinsulinaemia is a prominent lifestyle-related factor increasing the risk of declining cognition in the elderly, Berger and Ede (2023) make an interesting suggestion. With Aβ accumulating in the brain through impaired clearance, not overproduction, Berger and Ede (2023) suggest that a possible explanation for this is reduced concentrations of insulin-degrading enzyme (IDE), ‘which, as its name implies, is also responsible for breaking down insulin molecules’, and since insulin stimulates the production of IDE, a low-insulin environment, such as occurs in the AD brain, may help facilitate the accumulation of amyloid.
Intriguing hypotheses like that of Espay et al (2023) might well indicate future drug-related strategies, but meanwhile it appears that a ketogenic dietary approach that addresses the challenges of AD risk factors like hyperinsulinaemia and insulin resistance represents a potentially empowering therapeutic avenue.