It is not particularly controversial to say that aging causes Alzheimer's disease, at least in the most common version of the condition in which there is no gene variant known to accelerate pathology. How exactly aging causes Alzheimer's disease is very much debated, however. This is not unusual; most age-related conditions have the same issue and the same debate.
The end stage pathology of age-related conditions is fairly well mapped, and we have a good idea as to what the root causes of aging are, the forms of damage and disarray that accumulate as a result of the operation of a normal metabolism. In between what is known of the cause and what is known of the end result, the map is poor at best, however. Drawing clear lines of cause and effect between those two areas of study remains very challenging. The operation of metabolism is ferociously complex, and deciphering cause and effect in a network of interacting processes is not as easy as one might think.
It is likely the case that even when the first body of rejuvenation therapies based on periodic repair of root cause damage exists and is widely used, there will still be debate and investigation over how exactly the processes of aging combine to cause the more complicated age-related conditions.
Aging increases the risk for developing Alzheimer's disease (AD). Pathological hallmarks of AD include abnormal deposits of extracellular beta amyloid (Aβ) plaques and intracellular neurofibrillary tangles, which are proposed to impair synaptic function to foster progressive cognitive impairment. Although aging and AD undeniably share a number of common features, such as oxidative stress, mitochondrial impairment, bioenergetic, and metabolic shifts, AD is not the inevitable co-morbidity of aging. This escape from AD arouses hope that anti-aging interventions could decelerate aging switches for AD dementia.
Our environment, lifestyle, stress, physical activity, and habits all modulate epigenetic control of gene expression for continuous environmental tracking. Age-related redox stress, often measured as oxidative stress in aging and AD, launches a global switch in the epigenetic landscape, widely affecting methylation, histone modification, and noncoding RNA regulation, to further drive downstream metabolic and energetic shifts.
According to a modified amyloid cascade hypothesis, amyloid-mediated oxidative stress triggers a cascade of downstream effects including mitochondrial dysfunction, excitotoxicity, synaptic loss, and neuroinflammation. However, the failure of anti-amyloid and anti-inflammatory therapy in clinical trials allows us to entertain other causal possibilities including an age-related oxidative redox shift as an upstream switch that changes amyloid processing, deposition, or clearance. Intriguingly, some resilient older individuals present with similar loads of Aβ and tangles compared to AD cases without experiencing dementia.
Further studies in resilient brains point out distinct upregulation of anti-inflammatory cytokines in entorhinal cortex, increased expression of neurotrophic factors and reduced expression of chemokines linked to microglial recruitment, which all suggest activated neuroglial inflammation in non-resilient AD. Since inflammation is switched on by an oxidative redox state, normal microglia that selectively remove excitotoxic synapses could be over-activated toward inflammatory neurodegeneration in AD. Suitable redox markers could enable measured redox therapies to decelerate inflammation and the neurodegenerative cascade.