In our last post, we walked through some of the canonical hypotheses surrounding Alzheimer’s Disease (AD), but what about all the other hypotheses that are knocking around? Since AD’s discovery over a century ago countless ideas have emerged, yet the exact cause of this disease remains the holy grail for many neuroscientists.
In this post, we will try to spice things up a little by taking a look at one of the less popular AD hypotheses!
Mitochondrial Dysfunction – A Destructive Chain Reaction
Given the impressive range of roles carried out by our mitochondria, it is not surprising that mitochondrial dysfunction has been associated with severe organ-wide health problems, including neurodegenerative disorders such as AD, Parkinson’s, and motor neuron disease (ALS).
The ATP produced through oxidative phosphorylation in the brain contributes to neuronal function in many ways, including: maintenance of ion gradients and generation of membrane potentials across neuronal cell membranes, mobilization of neurotransmitter vesicles from storage areas to release sites, supporting neurotransmitter release and recycling, and supporting synaptic assembly and plasticity.
Besides ATP production, mitochondria also sequester and buffer intracellular Ca2+ levels at synaptic terminals, activities that are believed to contribute to the maintenance and regulation of neurotransmission.
Reactive oxygen species (ROS) accumulate in mitochondria as a byproduct of respiration, and this leads to mitochondrial oxidative stress over time. Mitochondria that suffer oxidative damage may leak cytochrome c (and other components) from the inner mitochondrial membrane into the cytosol, leading to a destructive cascade of caspase activation, DNA damage, and apoptosis. This chain reaction, starting with dysfunctioning mitochondria, has been associated with neuronal death in AD, as well as several other neurodegenerative diseases.
The Mitochondrial Dysfunction Hypothesis
While the extracellular brain plaques and neurofibrillary tangles described in our last post represent the two defining pathological features of AD, the progressive accumulation of dysfunctional mitochondria in the axons and synapses throughout the lifetime of neurons could lead to the synaptic dysfunction and neuronal pathologies that occur during AD. The links between mitochondrial dysfunction and AD are at the heart of the mitochondrial dysfunction hypothesis, and several lines of evidence support this:
- Studies dating back to the 1980’s indicate that reduced glucose metabolism is an early occurrence during AD development, and abnormal accumulation of dysfunctional mitochondria is a prominent feature in both familial and sporadic cases of AD.
- The brains of AD patients show increased oxygen consumption rather than glucose. This, coupled with reduced activity of several glycolytic enzymes, backs up the notion that defects in ATP metabolism and the mitochondrial respiratory chain may be an aspect of AD neurodegeneration.
- Synaptic dysfunction and impaired neuronal communication occur very early on in AD, before the emergence of plaques and tangles.
- Extensive research shows that mitochondria from AD sufferers differ both structurally and functionally from those of healthy individuals.
Nowadays, most AD experts agree that the mitochondria play some role in AD, either by facilitating, driving, or simply contributing to the known AD pathologies. Research increasingly supports the significance of mitochondrial changes in AD, and many experts now see mitochondrial dysfunction as a promising therapeutic target. While a number of experimental therapies, predominantly aimed at either boosting mitochondrial function or removing damaged mitochondria, have shown encouraging results in preclinical studies, progress in the clinic is lagging far behind, and we have yet to see whether or not mitochondrial therapy is a worthwhile pursuit for AD patients.
Another Billion Dollar Question
Knowledge about the role of mitochondrial changes in AD is amassing, and the links between dysfunctional mitochondria and AD are generally accepted, but one major question remains: Where do the mitochondrial changes seen in AD originate? Some experts claim that they are a consequence of Aβ plaque formation. Others claim that mitochondrial dysfunction occurs independently and/or upstream of Aβ plaque formation, thus modifying the canonical amyloid cascade hypothesis to a primary mitochondrial cascade hypothesis, whereby mitochondrial changes occur upstream of Aβ plaque formation.
Tapping into Mitochondrial Health
Dysfunctioning mitochondria are not only lacking when it comes to ATP production and Ca2+ buffering, and the true extent of mitochondrial damage remains to be understood. Pinning down the factors that lead to mitochondrial dysfunction and their consequences is essential if we want to truly comprehend their contribution to AD pathology.
Fortunately, a number of robust tools exist, allowing researchers to dig into the known mitochondrial health parameters, and perhaps helping to reveal new contributing factors. For example, assays such as: TempoDual™-ATPMito-Rapid to measure calcium flux, TempoO2™-Rapid to measure oxygen metabolism, and TempoATP™-Rapid to measure ATP metabolism strengthen the researcher’s toolbox to decipher mitochondrial health, hopefully taking us one step closer to understanding the true etiology of AD.
September 2025 update:
Much has happened in the Alzheimer’s disease (AD) field since we published this article in 2017, so a brief update is in order! There are now two approved disease-modifying therapies for AD, which are designed to target underlying disease pathology rather than addressing symptoms alone. These include donanemab and lecanemab, both of which are anti-amyloid monoclonal antibodies indicated for early-stage AD.
Regarding the cause of AD, which was the main focus of our original article, the field has since shifted toward recognizing AD as a heterogenous and multifactorial disease rather than having a single cause and a single therapeutic target. Some progress has been made in understanding AD subtypes, including reproducible atrophy-based subtypes and molecular subtypes based on protein patterns. Additionally, AD diagnostics has advanced, with the FDA approval of the first blood-based diagnostic test for AD in May 2025 (Fujirebio’s P-tau-217/β-amyloid ratio test) and several other testing methods in development that focus on detection of phosphorylated forms of tau protein. Newer blood-based biomarkers, e.g., neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), are also emerging that may be useful in diagnosing and monitoring the progression of AD as well as other neurological diseases including ALS and MS.
As the neurodegeneration field continues to evolve, it is clear that there will not be a one-size-fits-all treatment for AD, but rather different therapies for different subtypes Since we summarized the prevailing hypotheses in 2017, the role of mitochondrial dysfunction in AD has attracted significant attention, with recent research identifying mitochondrial complex I as a potential therapeutic target. Blood-brain barrier (BBB) dysfunction has emerged in recent years as an early and critical player in AD, occurring before the onset of dementia and contributing to pathogenesis through impaired amyloid-β clearance and increased neuroinflammation. Newer targets include neuroinflammation of microglia and brain insulin resistance, with scientists exploring whether GLP-1 analogues, which are approved to treat type 2 diabetes, may also have utility in treating AD.
Stay tuned for more updates!
Further Reading: Review Article: Mitochondria and Mitochondrial Cascades in Alzheimer’s Disease.
Karen O’Hanlon Cohrt is an independent Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD, Karen relocated to Denmark where she held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Karen has been a full-time science writer since 2017, and has since then held numerous contract roles in science communication and editing spanning diverse topics including diagnostics, molecular biology, and gene therapy. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for learning helps her to keep abreast of exciting research developments as they unfold. Karen is currently based in Ireland, and you can follow her on Linkedin here.
