According to Alzheimer's Research UK (Jones, 2024), in 2024 the number of people living with dementia in the UK was estimated to be almost 1 million (982 000), and by 2040 this could rise to 1.4 million; in 2022, the leading cause of death in the UK was dementia, claiming over 74 000 lives; and in 2024 the economic impact of dementia in the UK was an estimated £42.5 billion.
Possible causes of Alzheimer's disease
Among hypotheses listed by Agarwal et al (2021) are:
- The amyloid-beta (Aβ) hypothesis, highlighting the accumulation of Aβ oligomers in the brain
- The tau protein hypothesis, whereby mutations cause tau (present in axons and dendrites to regulate microtubules function) to aggregate and destroy the cytoplasmic functions of the nerve cells
- The cholinergic hypothesis that describes a reduced rate of production and transport of the neurotransmitter acetylcholine in individuals affected by Alzheimer's disease
- The dendritic hypothesis that describes dendrite degeneration and their resultant structural and functional disturbances.
Aβ hypothesis
It appeared promising with the publication of the findings of an 18-month, double-blind, phase 3 trial involving individuals with early Alzheimer's disease in November 2022 (van Dyck et al, 2022). Half of the 1795 participants received lecanemab, a monoclonal antibody that binds to soluble Aβ protofibrils. A BBC News story announced: ‘Alzheimer's drug lecanemab hailed as momentous breakthrough’ (Gallagher, 2022).
However, the findings of the trial should be taken with caution: ‘… lecanemab made a tiny difference to cognitive deterioration on cognition scales over 18 months, which although statistically significant may not be clinically significant …’ Kmietowicz (2022). The researchers themselves stated that the drug gave ‘moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events’ (van Dyck et al, 2022).
Aβ hypothesis questioned
Espay et al (2023) suggested that Alzheimer's disease research and drug development emphasise an 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, asserted Espay et al (2023), is flawed:
- 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’.
Is there a type 3 diabetes?
A fundamental question is why do some people contract Alzheimer's disease and others do not? In 2005, a paradigm change in the understanding of the nature of Alzheimer's disease came with the publication of a paper by Steen et al (2005).
Their work demonstrated that the much-reduced central nervous system expression of genes encoding insulin, insulin-like growth factor type 1(IGF-I) and IGF type 2 (IGF-II) suggested that Alzheimer's disease may represent a neuro-endocrine disorder resembling, but distinct from, diabetes: ‘Therefore, we propose the term, “Type 3 Diabetes” to reflect this newly identified pathogenic mechanism of neurodegeneration’ (Steen et al, 2005).
Citing evidence that 81% of those with Alzheimer's disease are insulin resistant or have type 2 diabetes – a rate twice as high as cognitively healthy counterparts – psychiatrist Georgia Ede has also noted that ‘the younger you are when you are diagnosed with T2D, the greater your chance of developing AD as you age’ (Ede, 2024:131).
And, notwithstanding the relatively recent focus on a relationship between type 2 diabetes and Alzheimer's disease, Kciuk et al (2024) noted that the concept of type 3 diabetes remains theoretical, although ‘[a] recent meta-analysis published in 2024 found a 59% increased risk of dementia in diabetic patients compared to non-diabetics’.
Type 3 diabetes and amyloid/tau hypotheses
Referring to the widespread hypotheses that implicate the accumulation and aggregation of tau/amyloid peptides as causative in Alzheimer's disease, de la Monte et al (2018) suggested that the ‘logical extension of this concept is to conclude that if the brain could be rid of those menacing molecules, AD would be cured. However, the outcomes of clinical trials indicate otherwise’.
Pointing out that Aβ and tau can accumulate in the brains of individuals with type 2 diabetes and Alzheimer's disease, Michailidis et al (2022) asserted that, since patients with type 2 diabetes ‘are not routinely evaluated in terms of their cognitive status, they are rarely treated for cognitive impairment. Similarly, AD patients are not routinely evaluated for high levels of insulin or for T2D’.
It is unsurprising, therefore that studies suggesting that ‘Alzheimer's disease as a metabolic disease caused by insulin resistance in the brain also offer strong support for the hypothesis that AD is T3D’ (Michailidis et al, 2022).
Possible inter-relationships
A review of studies suggesting a possible relationship between type 3 diabetes, Aβ and tau (Michailidis et al, 2022) included one piece of research that found that reduced concentrations of IGF-I combined with insulin resistance may result in reduced IGF-I and insulin uptake in the brain, causing Aβ accumulation and inflammation.
Therefore, insulin dysfunction and inflammation, combined with oxidative stress, enhance the toxicity and concentration of Aβ in a pathological feedback cycle. In relation to tau protein, Michailidis et al (2022) cited evidence demonstrating that the pathology of tau-associated neurofibrillary tangles can occur in the pancreas. However, while tau protein and Aβ were found in pancreatic tissue in the autopsies of 21 patients with type 2 diabetes (Miklossy et al, 2010), ‘in another relevant study, there was no increase in [the incidence of] Aβ in the brain of patients with T2D, but when Aβ was present it increased according to the severity of diabetes’ (Janson et al, 2004; Michailidis et al, 2022).
Implications of a link between type 2 diabetes and Alzheimer's
Pioglitazone
A possible therapeutic approach to meeting the challenge of Alzheimer's disease is one that targets insulin resistance. For example, one drug currently under investigation is pioglitazone, a member of the thiazolidinediones, and often used in the treatment of type 2 diabetes where it enhances insulin sensitivity.
Kciuk et al (2024) cited evidence showing that its ‘mechanism of action involves the activation of peroxisome proliferator-activated receptor gamma, which binds to specific DNA sequences to regulate the expression of genes associated with glucose and lipid metabolism’. They noted that pioglitazone was associated with a reduced risk of developing dementia in diabetic patients with DM.
Given that this effect was especially marked in patients with a history of stroke or ischemic heart disease, these ‘findings suggest that pioglitazone's neuroprotective and anti-inflammatory properties may contribute to cognitive preservation, possibly through improved insulin sensitivity, reduced vascular damage, and the modulation of neuroinflammation’ (Kciuk et al, 2024). However, these authors indicate that, thus far, most clinical trials conducted have been too small or too short in duration to observe significant therapeutic effects.
Bioactive compounds
In terms of the potential of natural bioactive compounds with anti-diabetic properties to treat Alzheimer's disease, it has been suggested that this is ‘mainly based on anti-inflammation, anti-oxidation, regulation of insulin signalling pathway, and intestinal flora’ (Huang et al, 2023).
Yet, despite some encouraging evidence, many challenges remain. These include, for example, the fact that most Alzheimer's disease studies are preclinical and thus clinical research data are sparse. Evidence from several studies ‘is largely derived from non-target effects such as anti-inflammatory and antioxidant effects… and… unavoidable side effects, such as severe hypoglycemia…[that] are even more harmful than AD’ (Huang et al, 2023).
Neurotransmitters
Addressing the neurotransmitter hypothesis cited by Agarwal et al (2021), Ede (2024:135) noted that drugs such as donepezil, rivastigmine and galantamine were developed to prolong the activity of diminishing concentrations of acetylcholine that the brain was able to generate, but they could not restore the cells that had already been killed.
What was killing these cells? ‘Tau and amyloid accumulation are partly to blame, but low brain insulin activity helps pull the plug by reducing the supply of nerve growth factor – a nurturing protein these cells need in order to thrive’ (Ede, 2024:135). However, a commonly prescribed drug that may be of help to Alzheimer's disease patients is memantine, which ‘tones down the activity of glutamate, a neurotransmitter that can spin out of control in AD’ (Ede, 2024:135).
Citing evidence that the problem is exacerbated by insulin resistance due to its interference with glutamate metabolism and function and the promotion of Aβ and tau accumulation, Ede (2024:135) cited evidence demonstrating that this combination ‘can damage the glutamate regulation system over time and allow glutamate to reach dangerously high levels that are capable of triggering cell death’.
Alzheimer's disease is T3D … true or false?
A review to evaluate evidence ‘from bench to bedside’ to determine whether Alzheimer's disease could be described as type 3 diabetes was undertaken by Peng et al (2024). At the outset, they stated that, in contrast to earlier beliefs, it had been ‘well-documented that insulin is a significant neuromodulator, playing a role in neurobiological processes, particularly energy homeostasis and cognition’. Further, they cited studies showing that molecules identical to pancreatic insulin and specific insulin receptors are widely distributed in the central nervous system networks, and that they are related to feeding, reproduction and cognition.
Animal model studies, as cited in Peng et al (2024), have shown that Alzheimer's disease-related pathologies observed in diabetic rats have included decreased hippocampal volume, lower protein concentrations in the cerebral cortex, neurodegeneration, and lowered dendritic spine density.
At a clinical level, Peng et al (2024) stated that the first report of insulin in the brain was published in 1999, where a twofold higher risk of Alzheimer's disease in diabetic patients was documented. A further clinical study (Arvanitakis et al, 2004) demonstrated that type 2 diabetes patients have a 65% greater chance of developing Alzheimer's disease than those with normal blood sugar, and that insulin resistance was associated with poor cognition in people aged more than 60 years.
Ethical considerations
While the search for Alzheimer's disease amyloid-lowering therapies continues, Daly et al (2022) point out that, in research ethics, patients should be enrolled onto clinical randomised controlled trials (RCTs) only if there is uncertainty over the outcome of treatment with an intervention or placebo. They also noted that, ‘if repeated RCTs show that a treatment is inefficacious or unsafe, we are ethically bound to withhold it’.
This statement is important in the context of their observations that ‘to date, 40 Phase II/II RCTs of amyloid-lowering therapies in AD have failed to improve, and often worsen, cognition. It is objectively unlikely that the 41st trial will be successful’ (Daly et al, 2022).
If the suggestion that Alzheimer's disease is fuelled by an insulin-associated nutritional factor gathers pace, it could mean that nutrition-based preventive measure could ameliorate or possibly obviate the drug-related ethical challenges identified by Daly et al (2022).
Conclusion
Suzanne M de la Monte and colleagues (2018) observed that a substantial body of work had originated from a group led by Eric Steen published a ground-breaking study on the potential links between Alzheimer's disease and impaired insulin expression.
Suzanne de la Monte,–who was part of Steen's group – and her team, observed that a substantial body of work had originated from Steen's group. de la Monte et al (2018) stated that it had marked ‘a trail that began with studies of vascular, stress, and mitochondrial factors in AD pathogenesis, exploded into the concept of “type 3 diabetes”, and continued with the characterization of how environmental, exposure, and lifestyle factors promote neurodegeneration and which therapeutic strategies could reverse the neurodegeneration cascade’.
Some researchers contend that the multifactorial nature of Alzheimer's disease is too diverse to ascribe its origin to a single cause. However, an evidence base is accumulating that may make the assertion of Ede (2024:130) that ‘insulin resistance is pre-AD’ a compelling one that cannot be ignored.