Alzheimer’s Disease, the Sweet Trail to Neuroprotection

In Alzheimer’s disease (AD), we are gaining great ground in the field of early diagnosis, but disease-modifying drugs are still missing. While many studies have been focused on the pathogenic role of amyloid-β (Aβ) dysmetabolism, recent preclinical and clinical findings revealed a more complex picture. In AD, we need to embrace a complex view of the disease state as a condition resulting from the converging failure of health-controlling systems and networks; A condition shaped by the combination of our “omic” blueprint and the influence of the environment. AD is, in fact, a multifactorial condition in which, along with Aβ accumulation, the convergence of many genetic, environmental, vascular, metabolic, and inflammatory factors increase the likelihood of developing the disease. All these conditions find fertile ground inside and outside of the central nervous system provided by aging. In that respect, approaches targeting co-morbidity factors are becoming promising as, at least, a third of AD cases are strongly dependent on the concerted activity of modifiable factors (low education, midlife hypertension, midlife obesity, diabetes, physical inactivity, smoking, and depression) [1,2]. One promising area of early intervention concerns the vascular system. Systematic reviews have revealed that cardiovascular factors go out of range in young adulthood or middle age (<65 years), but not necessarily in late life (≥75 years), and studies indicate that such early “early on” alterations are the ones associated with an increased AD risk [3,4].

A very promising area of investigation and intervention is now offered by insulin-related signaling [5]. In the brain, the hormone acts as a neurotrophic factor and critically modulates neuronal survival, synaptic plasticity, and the molecular pathways underlying learning and memory processes [6]. Decreased insulin sensitivity is found upon brain aging, and defective insulin signaling has been reported in subjects affected by mild cognitive impairment and AD patients [7]. An intriguing target of action is now provided by the agonists of the glucagon-like peptide-1 receptor (GLP-1R). Glucagone is an endogenous insulinotropic hormone that participates in the homeostatic regulation of insulin and glucose. Like insulin, the activation of the GLP-1Rs impacts on neuronal excitability, synaptic plasticity, and memory processes [8–11]. These effects are largely obtained through the activation of the cAMP response element-binding protein (CREB), the induction of the expression of the brain-derived neurotrophic factor (BDNF), and the activation of its tropomyosin-related kinase B receptor (TrkB). GLP-1 analogs have been successfully tested in preclinical models of neurodegeneration and in clinical trials. In particular, exenatide, a GLP-1R agonist approved for type 2 diabetes mellitus treatment, is under evaluation in trials targeting AD and was found to produce important beneficial effects in Parkinson’s disease (NCT01255163, NCT01174810, NCT01971242) [12–15].

We have tested a 6-month treatment with exenatide in Presenilin-1 Knock-In (PS1-KI) mice, a preclinical model of amyloid-independent neuronal dysfunction and found that the molecule promotes beneficial effects on short- and long-term memory performances [16]. In a more recent study, we have also found that a 2-month exenatide treatment resulted in enhanced cognitive performances in adult mice. The study is relevant in terms of translational value as the timeframe of intervention (animals at 10-12 month of age) matches the mid-life stage of humans, thereby opening a window of opportunity for preventative intervention in a critical pre-symptomatic phase and may offer the possibility to revert or at least halt the disease progression. In the study, exenatide was found to exert positive effects through the phosphorylation of CREB, that eventually leads to increased expression levels of BDNF and TrkB and downstream activation of BDNF-related signaling [17].

These results pinpoint to the importance of targeting neurotrophic systems and BDNF in particular. Mature BDNF promotes neurogenesis, neurite outgrowth, dendritic arborization, spine formation, and long-term potentiation, and is crucial for shaping synaptic plasticity and to promote neuroprotection upon adulthood and against AD-related neurodegeneration [18,19]. High levels of brain BDNF expression are associated with decreasing rate of cognitive decline and a milder course of AD [20,21]. BNDF levels are increased by physical activity and represent one of the significant beneficial effects of interventions aimed at promoting healthier lifestyles. Intriguingly, serotonergic psychedelics have also been shown in vitro and in vivo, to promote synaptogenesis and structural plasticity through the activation of BDNF signaling. These findings are thereby prompting the search for new serotoninergic compounds devoid of psychotropic effects and engineered to facilitate BDNF-related signaling [22]. It is also conceivable that more focused efforts aimed at the synthesis of human BDNF or affordable TrkB agonists may promote the therapeutic revolution that occurred in diabetes upon the introduction of human insulin. A mix of new or rediscovered BDNF-modulating drugs, like exenatide or GLP1-R agonists, along with exercise and vascular and metabolic interventions may finally offer the therapeutic options that we have been waited for so long.

Are we finally ready to embrace and pursue an amyloid-independent therapeutic strategy?

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Last comment on 11 November 2018 by Paula Moreira, PhD


Prof Sensi is right to highlight the increasing recognition of the importance of insulin signalling in neurodegenerative diseases. Exploring the impact of enhancing insulin signalling through modification of behaviours or through targeted pharmacology should be a high priority for preclinical and clinical scientists. The potential role of neurotrophic factors such as BDNF as the ultimate effectors in the insulin signalling pathway is of great interest, and should be further investigated alongside its relationship with neuroinflammation, mitochondrial and lysosomal function and apoptotic control systems.

When Sherlock Holmes was asked by police how he spotted a bullet hole that others had missed, he replied, “I saw it because I looked”.

This simple but perceptive explanation by the foremost fictional detective of all time is relevant to the problem of AD.

How many researchers have examined an Alzheimer brain and without looking any further, concluded for the last 40 years that only one factor is causal to this disorder? This mindset flies against overwhelming findings that AD is instead, a complex multifactorial disorder.

The Abeta cascade hypothesis of AD was a bright idea that has become a dark obsession. Initially, it postulated that brain plaques and tangles were responsible for the progressive cognitive deterioration and eventual onset of AD. The revelation that these brain plaques were made up mostly of Abeta added support to the predicated assumption that this peptide was an inducer of tangles and a neuron killing machine. This clever exploit drew thousands of investigators around the world to redirect their laboratories, lectures, publications and grant seeking funds towards the new gold standard of medical research.

Mostly ignored was the consistent finding that 30-40% of cognitively healthy elderly individuals have plaques in their brain and many of these display enough plaque density to satisfy AD diagnosis at autopsy [1]. Also brushed away have been dozens of clinical trials showing no evidence that Abeta plaque burden correlates with AD clinical severity, or that brain plaque removal with anti-Abeta agents benefit AD patients in any way.

So, the follow-up question is ripe and behooves an answer. How and why did the Abeta hypothesis become an obsessive Gordian knot among its subscribers and an intractable force incapable of being replaced or seriously eclipsed by other neurological strategies?

If we follow the 4 basic steps posed by the eminent Hungarian mathematician George Polya for solving problems, we might see where the Abeta hypothesis went off the track. These steps are: 1) Understand the problem; 2) Devise a plan to resolve the problem; 3) Carry out the plan; 4) Interpret the results.

I would venture that basic research into the cellular and molecular biology of Abeta, carried out all four steps in an adequate fashion, with some reservations. When Abeta vaulted into dozens of clinical applications, step 4 turned into a monumental failure. Now it’s time to let go and move on.

Fortunately, all is not dark. Dr. Sensi and others like him have been “looking” to better explain the pathophysiology of this dementia. His argument relating to the importance of targeting neurotrophic systems in humans as potential preventive interventions of mild cognitive impairment is persuasive and makes sense (no pun intended). I hope he and his group are joined by many ex-subscribers of Abeta dynamism so we can all look forward to the moment when practical prevention of Alzheimer’s offers a genuine hope to its future victims.

[1] Kepp KP (2017) Ten challenges of the amyloid hypothesis of Alzheimer's disease. J Alzheimers Dis 55, 447-457.

The reason why the "amyloid hypothesis" has dominated the field for so long relies on the more pervasive issue on how modern medicine has failed to produce a full transition from the Oslerian reductionist approach. Medicine really needs a leap forward to embrace a more fruitful systems and networks based understanding of the disease state.  Look for instance at the work of Joseph Loscalzo  (1). In line with a more modern, personalized, and realist view, we also need to put at rest the whole concept of magic "silver bullets".


1) Putting the Patient Back Together - Social Medicine, Network Medicine, and the Limits of Reductionism. Greene JA, Loscalzo JN Engl J Med. 2017 Dec 21;377(25):2493-2499. doi: 10.1056/NEJMms1706744. 


Prof. Sensi has observed the importance of insulin signaling in AD by applying a diabetes-related drug (GLP-1R agonist) to a mouse model of non-Abeta AD which shows positive effects. This and a tremendous amount of other data, as well as metabolic risk factors and biomarkers, imply a central role of metabolism in AD.

The amyloid hypothesis is very simplistic and offers no solutions to the sporadic, aging, and energy problems of AD, which I personally think are the central control variables. Protein misfolding happens in all cells - why does it lead to disease in neurons? Because they are extremely energy requiring. The energy cost of protein turnover limits the energy available for maintaining the ion pumps, which take up 50% of the brain's total energy budget. The associated energy depletion leads to the direct clinical effect of impaired neuronal signalling.

Mitochondrial mutations and quality control for energy efficiency and a variety of risk factors will contribute to the energy balance either positively or negatively, causing the accelrated aging phenotype of the diseases. Any model of AD that ignores aging and energy seems, at this point of knowledge, to be superficial and lacking. Prof. Sensi has shown direct positive effects on energy utilization that supports the model outlined above.

For a multifactor model not to become useless, it must possess a few central control variables. I have been struggling with a mathematical model that combines these features together and can relate energy, risk factors, aging, and amyloid aggregation to the same control variable - energy available for cognitive execution - and will submit it this week. I hope it can be of some interest to the clinicians and cell biologists already welcoming more complete multifactor models.

Thank you for the nice work and blog post, we are many that share your views on this complex disease.

Best wishes,


It is more than time to stop focusing on therapies merely based on the amyloid cascade hypothesis. The continuing failure of these therapies should be the motor to change minds. In the last years, it was become evident that metabolic anomalies play an important role in the development of Alzheimer’s disease. In fact, multiple lines of evidence demonstrate that sporadic Alzheimer’s disease and type 2 diabetes share several common features such as brain glucose dysmetabolism, mitochondrial anomalies and insulin signaling defects. These common features propelled researchers to test the efficacy of antidiabetic drugs such as insulin and GLP-1 analogs. Since the results so far have been optimistic, we must pursuit this line of investigation and explore new therapeutic opportunities for existing drugs aimed at improving metabolic derangements. Besides pharmacologic strategies, we can also decrease the risk of developing metabolic disorders (including Alzheimer’s disease) by changing people’s lifestyle choices. To achieve this goal, the benefits of physical activity and healthy diets must be communicated to students and lay public. Hopefully, these strategies may help us see the light at the end of the tunnel.