Blog Post 8: Discuss the current theory driving Aging, Dementia, and Alzheimer Disease research.

Discuss the current theory driving Aging, Dementia, and Alzheimer Disease research.

Audience: Non-Scientific Family

At this point in time, is it believed that the most important distinctions between unhealthy aging and healthy again are altered memory function, personality changes, and compromised executive function in unhealthy aging  (Sontheimer, 2015). These changes appear to come about through both a  loss of short & long term memory, and an inability to form new memories  (Sontheimer, 2015). Within the brain’s structure itself, changes include reduced blood flow to the cortex; issues with the barrier that separates blood from the brain; deposits of a protein, amyloid outside of cells; an increase in the amount of another protein, tau, inside the cell; a decrease in number of neurons; and an increase in number of support cells  (Sontheimer, 2015). Loss of memory is a key hallmark of dementia  (Sontheimer, 2015). With regard to Alzheimer disease (AD), its theory includes genetics, changes in brain anatomy, changes in blood flow, and changes in the systems working within the brain. 

Regarding genetics, in addition to age, family history of dementia greatly increases one’s risk of developing AD (Sontheimer, 2015). For early-onset AD, mutations  in the genes APP, PSEN1, and PSEN2 appear to essentially guarantee disease onset  (Sontheimer, 2015). For late-onset AD, risk of development is significantly increased if a first-degree relative has dementia (Sontheimer, 2015). Disease risk of APOE is most strongly linked to the gene APOE, especially its form APOE4,  which increases risk by anywhere between 400% and 1500% (Sontheimer, 2015).

Regarding changes in brain anatomy, changes affect a range of regions, including the hippocampus and parts of the cortex  (Sontheimer, 2015). The damage eventually becomes widespread, as the part of the brain called “gray matter” begins to shrink  (Sontheimer, 2015). This gradual deterioration appears to explain how/why AD symptoms appear gradually and worsen over time (Sontheimer, 2015).  In fact, this pattern is what distinguishes AD from other forms of dementia  (Sontheimer, 2015). In addition, the characteristic abnormalities of AD are the accumulation of tau protein inside cells and amyloid protein outside of them; impaired clearance of amyloid also appears to contribute to AD (Sontheimer, 2015).

Regarding changes in blood flow, after age and family history, any health condition that affects the circulatory system, including hypertension, diabetes, or stroke, appears to also significantly increase one’s risk of AD  (Sontheimer, 2015). Conversely, AD leads to reduced blood flow in the cortex, in addition to issues with the barrier separating blood from the brain (Sontheimer, 2015).  

Regarding changes in the systems within the brain, many of the neurons of the cortex affected by AD utilize the neurotransmitter glutamate, especially those neurons involved in learning and memory (Sontheimer, 2015). However, cholinergic neurons (neurons that use the neurotransmitter acetylcholine) also affect memory formation, and the protein responsible for creating acetylcholine appears to decrease by 50%-90% in patients with AD, as well as be roughly proportional to loss in cognitive function (Sontheimer, 2015). In fact, autopsies of patients with AD have shown a decrease in neurons in an area of the brain that uses acetylcholine in its connection to the cerebral cortex (Sontheimer, 2015).  Furthermore, clinical trials indicate that protecting cholinergic neurons from death may in fact slow memory decline in patients  (Sontheimer, 2015).  Lastly, neurotransmitters for mood, behavior, and anxiety are all significantly reduced in patients with AD, potentially explaining the mood and behavior changes seen in late stages of AD  (Sontheimer, 2015).

Furthering the current theory, according to Bussian et al., an increase in the number of senescent cells (a type of cell that has been found to actively drive natural age-related tissue deterioration) appears to cause neuronal death in areas related to cognition (a type of cell death seen in neurodegenerative diseases) (2018). In the mouse model used, such cells were able to be cleared out using transgenes, which helped prevent both accumulation of the cells and decrease in the number of neurons in the cortex & hippocampus, as well as preserved cognitive function in the mice (Bussian et al., 2018). In addition, a first generation senolytic, ABT263 (or navitoclax), was able to control accumulation of tau (Bussian et al., 2018). According to the authors, this indicates that senescent cells play a role in the initiation and progression of diseases related to tau, and that targeting senescent cells in treatments may be another potential avenue for treating such diseases (Bussian et al., 2018). This new discovery greatly aids in furthering and expanding the theory of aging, dementia, and Alzheimer disease,  as well as opens up a new avenue for drug development and clinical trials in this area of research.