The Mitochondrial Hypothesis: Is Alzheimer’s a Metabolic Disease?

By Emilie Reas, PLOS Neuroscience Community Editor

Despite decades of research devoted to understanding its origins, Alzheimer’s disease remains a daunting and devastating neurological mystery, ranking as the sixth leading killer of Americans. Countless therapeutic attempts, each designed with fresh anticipation, have repeatedly failed. A common thread across many of these drugs is their targeting the defining marker of the disease, amyloid plaques – those nasty extracellular deposits of beta-amyloid protein that invariably present in the Alzheimer’s brain and are thought to be toxic to neurons. Given the frustrating loss of research money, time and effort, many scientists agree it’s time to stop running circles around the amyloid hypothesis and begin seriously considering alternative explanations. One such theory showing increasing promise is the “mitochondrial hypothesis”. Its proponents posit that mitochondrial dysfunction lies at the heart of neural degeneration, driven by metabolic abnormalities which lead to classic Alzheimer’s pathology.

Thank mom for your genetic risk

The first hints at this possibility arose from epidemiological observations about the genetic patterns of Alzheimer’s prevalence. These findings suggest that genetic influences may include more nuanced interactions than the better-known contributions from genes such as ApoE and TOMM40. Although both parents determine genetic risk, your likelihood of getting Alzheimer’s is much higher if the affected parent was your mother. This argues strongly that some maternal element underlies the association. Mitochondrial DNA is a logical target, as this subset of DNA is solely passed down from the mother. Many features of Alzheimer’s show this same maternal-dominant inheritance; those whose mother (but not father) had the disease also show reduced glucose metabolism and cognitive function, as well as elevated PIB uptake (a marker of amyloid) and brain atrophy.

Are metabolic enzymes the pathological trigger?

So if mitochondrial dysfunction initiates the Alzheimer’s cascade, what are the steps leading from metabolic disruption to neurodegeneration and ultimately, dementia? Studies point to cytochrome oxidase – a key enzyme for mitochondrial metabolism that’s encoded by both mitochondrial and nuclear DNA – as a likely trigger for early pathological events. Studies suggest that the enzyme is dysfunctional in the earliest disease stages; its activity is reduced not just in those with Alzheimer’s, but even in asymptomatic individuals who are at genetic risk for the disease or had a mother with Alzheimer’s. Furthermore, this stunted activity is linked directly to mitochondrial (or maternal) genetic contributions. By simply replacing the mitochondrial portion of the cytochrome oxidase DNA with DNA from Alzheimer’s patients, an otherwise normal cell will now have reduced cytochrome oxidase activity.

Bridging metabolism to Alzheimer’s pathology

For the mitochondrial theory to hold water, it must critically account for the classic pathological markers that define Alzheimer’s and have shaped traditional disease models – namely, amyloid plaques, tau tangles and brain atrophy. Indeed, growing evidence is elegantly bridging altered mitochondrial function to these key markers. For instance, disrupting mitochondrial electron transport chain activity (if you’ve forgotten your basic biochemistry, this is essential to cell metabolism) increases phosphorylated tau. What’s more, inhibiting cytochrome oxidase promotes a host of neurotoxic downstream effects including increased oxidative stress, apoptosis and amyloid production. Conversely, there’s also evidence that amyloid disrupts electron transport chain and cytochrome oxidase function, posing a chicken-or-egg conundrum. Amyloid has been found to buddy-up to mitochondria, but which comes first, the amyloid or the mitochondrial dysfunction, isn’t entirely clear. Both events occur early in the disease process, even before individuals show any symptoms of cognitive impairment. Whatever the mechanism, neurons from Alzheimer’s patients show signs of increased mitochondrial degradation. And when a neuron’s “powerhouse” begins to degrade, it cannot possibly support normal cognitive function.

A promising path for progress

It remains to be seen whether metabolic dysfunction is the key to unlocking the mechanisms of Alzheimer’s, and to ultimately developing effective therapeutics. While the current evidence is quite promising, many of the issues underlying the failure of other theories (poor translation of animal findings to humans, the challenge of identifying causal mechanistic pathways, etc.) similarly apply to the mitochondrial hypothesis. But at the very least, the proposal lays new ground for neuroscientists to continue progressing forward after a recent history of frustrating dead-ends. Even if mitochondria don’t hold the answer researchers have been seeking, understanding its contributions to Alzheimer’s pathology can only bring us closer to solving the mystery of this devastating disease.

Any views expressed are those of the author, and do not necessarily reflect those of PLOS.

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Emilie Reas received her PhD in Neuroscience from UC San Diego, where she used fMRI to study memory. As a postdoc at UCSD, she currently studies how the brain changes with aging and disease. In addition to her tweets for @PLOSNeuro she is @etreas.