Insulin Resistance as a Common Link Between Current Alzheimer’s Disease Hypotheses

Abstract

Almost 115 years ago, Alois Alzheimer described Alzheimer’s disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6%in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses.

Metabolic Disturbances Induced by Sleep Restriction as Potential Triggers for Alzheimer’s Disease

“…This is based on the hypothesis that Aβ decomposition in the CNS initiates a molecular cascade that causes neurodegeneration (Cockerill et al, 2018). Further, some authors have published reviews that integrate the role of insulin in Aβ transport in the brain and the consequences this may have on AD development (Vandal et al, 2015;Mullins et al, 2017;Rhea et al, 2020;Alves et al, 2021;Rhea and Banks, 2021). Based on the evidence presented, we propose that chronic sleep restriction induces peripheral low-grade inflammation and insulin resistance leading to hyperglycemia which together alter the BBB function (Figure 2).…”

A complex systems view on the current hypotheses of epilepsy pharmacoresistance

“…This current halt of the progress in the development of new therapies is not new in neurology/neuropsychiatry/neurosciences since similar cases can be found, for instance, in other conditions, such as depression and Alzheimer's disease. For the latter, there has been, over several decades, huge investment and disappointment, in the production of anti‐Alzheimer´s therapies with a failure rate of 99.6% in clinical trials, which could be attributed to persistence in a single set of hypotheses 18 . In the case of antidepressants, the search for any association between central 19,20 or peripheral 21 biomarkers of depression brought little improvement to patients’ quality of life.…”

“…For the latter, there has been, over several decades, huge investment and disappointment, in the production of anti‐Alzheimer´s therapies with a failure rate of 99.6% in clinical trials, which could be attributed to persistence in a single set of hypotheses. 18 In the case of antidepressants, the search for any association between central 19 , 20 or peripheral 21 biomarkers of depression brought little improvement to patients’ quality of life. Specifically, Insel (2017) 22 refers to the lack of improvement in our ability to decrease the number of depressive patients and suicidality, in spite of the high investment in that kind of research, as reasons why he proposes “digital phenotyping” 23 and the use of technology as a contemporary, more efficient alternative.…”

Dimethyl Fumarate Alleviates Adult Neurogenesis Disruption in Hippocampus and Olfactory Bulb and Spatial Cognitive Deficits Induced by Intracerebroventricular Streptozotocin Injection in Young and Aged Rats

“…sAD has a complex etiology that is still not fully understood. It is believed that sAD is not hereditary and its development is related to interactions between genetic, environmental and metabolic factors [ 1 ]. The most common diagnostic marker in AD is episodic memory impairment; however, the decline in this memory system correlates with age, and is also a symptom of other types of dementia with a different etiology (e.g., frontotemporal dementia, vascular dementia), which significantly complicates and delays diagnosis [ 2 , 3 ].…”

“…Behavioural and neurochemical changes occurring in patients with sAD (e.g., cognitive impairments, insulin signalling disorders, oxidative stress, neuroinflammation, neurodegeneration, Aβ and hyperphosphorylated tau pathology) have also been found with the STZ-ICV model. Moreover, in STZ-ICV animals, the severity of cognitive and neurochemical impairments correlates with age, and such a relationship is also common in human sAD [ 1 , 16 , 17 , 18 , 19 ].…”