Arguing that Alzheimer's is a Mitochondrial Disease
Researchers here advocate one of the many varied theories on Alzheimer's disease, in this case that the mitochondrial dysfunction that occurs with age is an important root cause of the condition. Over the past twenty years, a sufficient understanding of Alzheimer's to make good progress in producing therapies has expanded to include the need to understand a fairly large chunk of the cellular biochemistry of the brain: it is a complex condition, and given the ongoing struggles to make the initial approach of amyloid clearance work in any practical way, alternative hypotheses are springing up. You might take note of the point made in this paper on the dubious relevance of genetic studies to much of the prevalence of Alzheimer's, given the tiny proportion of cases that are familial versus sporadic. It is worth bearing in mind when reading other research reports from the field:
Alzheimer's disease (AD) is a progressive neurodegenerative disease that represents the most common form of dementia among the elderly. Despite the fact that AD was studied for decades, the underlying mechanisms that trigger this neuropathology remain unresolved. Since the onset of cognitive deficits occurs generally within the 6th decade of life, except in rare familial case, advancing age is the greatest known risk factor for AD. To unravel the pathogenesis of the disease, numerous studies use cellular and animal models based on genetic mutations found in rare early onset familial AD (FAD) cases that represent less than 1% of AD patients. However, the underlying process that leads to FAD appears to be distinct from that which results in late-onset AD. As a genetic disorder, FAD clearly is a consequence of malfunctioning/mutated genes, while late-onset AD is more likely due to a gradual accumulation of age-related malfunction.Normal aging and AD are both marked by defects in brain metabolism and increased oxidative stress, albeit to varying degrees. Mitochondria are involved in these two phenomena by controlling cellular bioenergetics and redox homeostasis. In the present review, we compare the common features observed in both brain aging and AD, placing mitochondria in the center of pathological events that separate normal and pathological aging. We emphasize a bioenergetic model for AD including the inverse Warburg hypothesis which postulates that AD is a consequence of mitochondrial deregulation leading to metabolic reprogramming as an initial attempt to maintain neuronal integrity. After the failure of this compensatory mechanism, bioenergetic deficits may lead to neuronal death and dementia. Thus, mitochondrial dysfunction may represent the missing link between aging and sporadic AD, and represent attractive targets against neurodegeneration.
I sure hope it is a mitochondrial disease, because the way in which amyloid beta antibodies have been flaming out in stage 3 over the past few years is suggesting that the amyloid hypothesis is wrong.
The fact that amyloid beta antibodies have been flaming out in stage 3 over the past few years doesn't really suggest that the amyloid hypothesis is wrong: it suggests rather (as the amyloid hypothesis implies) that trying waiting until a person has spent a lifetime undergoing degenerative aging, accumulating substantial levels of plaque for 15-25 years (and an uncertain problem with oligomers for even longer), with ensuing accumulation of malformed tau and cholinergic neuron loss, along with other aging damage in parallel, to the point where they are already clinically demented, and only then swooping in with an Abeta immunotherapy as your sole intervention (and, by the way, with about a third of patients enrolled in your trial not actually having neuropathological Alzheimer's and thus not having Abeta as the main driver of their dementia!), is a fool's errand.
Happily, better-designed trials of beta-amyloid vaccines (that, amongst other things, start with people with only mild or prodromal AD) are currently in the pipes. We are already seeing hints that trials with such improved designs may be far more effective in actually improving patients' lives — and more meaningful tests of the amyloid hypothesis.
To really succeed, however, we're going to need further regulatory reform for rejuvenation biotechnology to allow and incent the testing of ab initio multi-component rejuvenation biotechnology for the aging of the brain (and all of our organs), including clearance of tau and cell therapy, and the initiation of therapies before the "threshold of pathology" of aging damage has been breached.
Thanks for another great explanation Michael.
I guess the next real steps to persuading the FDA and other regulatory bodies to allow the testing and use of medicines in apparently healthy individuals is the establishment of easy to collect biomarkers for Alzheimer. Possibly some way of measuring amyloid Beta, Tau, and cell loss.