Like many neurodegenerative conditions, Alzheimer's disease is associated with a general reduction in the function of mitochondria. Since these cellular components are responsible for generating energy store molecules to power cellular processes, and since brain cells require a lot of energy to function, it makes sense to find that declines in mitochondrial function are associated with disorders of the brain. Where does this fit into the chains of cause and consequence in aging, however? What causes global mitochondrial failure throughout cell populations?
Evidence suggests that these general mitochondrial declines are due to failing autophagy, the cellular processes responsible for removing damaged and dysfunctional mitochondria. Equally, it is the case that changes in mitochondrial dynamics, occurring for poorly understood reasons as reaction to other changes and damage in aging cells, appear to hinder autophagy. This is all quite distinct from the consensus on aggregation of damaged and misfolded proteins, amyloid-β and tau, as the primary cause of Alzheimer's disease. Until there are reliable methods to remove and repair one or more of these contributions to the condition, it is hard to do more than theorize on their relative importance.
For three decades, it has been thought that the accumulation of small toxic molecules in the brain, called amyloid beta, or in short, Aβ, is central to the development of Alzheimer's disease (AD). Strong evidence came from studying familial or early-onset forms of AD (EOAD) that affect about five percent of AD patients and have associations with mutations leading to abnormally high levels or abnormal processing of Aβ in the brain. However, the "Aβ hypothesis" has been insufficient to explain the pathological changes in the more common late-onset Alzheimer's disease (LOAD).
"Because late-onset Alzheimer's is a disease of age, many physiologic changes with age may contribute to risk for the disease, including changes in bioenergetics and metabolism. Bioenergetics is the production, usage, and exchange of energy within and between cells or organs, and the environment. It has long been known that bioenergetic changes occur with aging and affect the whole body, but more so the brain, with its high need for energy." It has been less clear what changes in bioenergetics are underlying and which are a consequence of aging and illness.
Researchers analyzed the bioenergetic profiles of skin fibroblasts from LOAD patients and healthy controls, as a function of age and disease. The scientists looked at the two main components that produce energy in cells: glycolysis, which is the mechanism to convert glucose into fuel molecules for consumption by mitochondria, and burning of these fuels in the mitochondria, which use oxygen in a process called oxidative phosphorylation or mitochondrial respiration. The investigators found that LOAD cells exhibited impaired mitochondrial metabolism, with a reduction in molecules that are important in energy production, including nicotinamide adenine dinucleotide (NAD). LOAD fibroblasts also demonstrated a shift in energy production to glycolysis, despite an inability to increase glucose uptake in response to the oxidative stress that impairs their mitochondrial energy production." Because the brain's nerve cells rely almost entirely on mitochondria-derived energy, failure of mitochondrial function, while seen throughout the body, might be particularly detrimental in the brain.