“”At first, the soliloquy was muted, almost a whisper. As 11:00 pm came and went, and the wall clock’s small hand pushed its cohort toward midnight with the determination of Sisyphus, the speaker picked up the pace . . .his larynx now pounding out the words like a finely-tuned Formula-One engine.
Soon he was shouting a litany of female names, peppered with the occasional “Bill” and “Serg.”
As time grinded forward with the speed of growing mushrooms, the timbre and urgency of the voice became demanding and cruel. “GINA!” he yelled, “Why did you run away?”
Last night, from 9:00 pm to 6:00 am, I experienced what I imagine a nine-hour rollercoaster ride in hell would be like, performed simultaneously with an exorcism.
In other words, I had my first, formal introduction to Alzheimer’s–no, not as a patient, not even as a caregiver, just as an observer/onlooker.
As some of you already know, I was recently admitted to a skilled nursing facility for an indeterminate period of rehabilitation. (A combination of Parkinson’s meds, sporadic bouts of depression, confinement to a wheel chair and myriad other factors, had created a long-standing battle with morbid obesity; and I was losing.)
I will freely admit the prospect of leaving the simple, private comfort of my 400 sq. feet of assisted living and trading down to the roommate mentality of skilled nursing, invoked sheer terror in this writer’s soul. Thus I was pleasantly surprised when I checked into my new digs three days ago: no roommate, air conditioning 24/7 and the worst food since Soylent Green.(Which was great for me! Even the thought of a complete meal was enough to induce nausea.)
AND THEN, LAST NIGHT, A PATIENT CHECKED INTO MY ROOM.
A mistake? An unfortunate Act of God? A practical joke? (No, none of these, but I can assure you this is where this fairy tale becomes Grimm).
You see, my new long-term care combatant is a 90+ retired auto body detailer with a broken hip and (lest I say the “A Word?”) Alzheimer’s.
Let’s start with what we know about Alzheimer’s — in a nutshell we know what we don’t know is infinitely greater than what we do know.
Look, I hate to be the bearer of bad news, but as an MIT scholar and former cell biologist, let me level with you, the news about Alzheimer’s ain’t good.
It is axiomatic of most human disease that “…within the cause lies the cure.” Thus, I’ve listed the latest causes of AD
The cause for most Alzheimer’s cases is still essentially unknown (except for 1% to 5% of cases where genetic differences have been identified). Several competing hypotheses exist trying to explain the cause of the disease:
The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitteracetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid, leading to generalised neuroinflammation.
In 1991, the amyloid hypothesis postulated that beta-amyloid (βA) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age. Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. Whilst apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain. Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer’s-like brain pathology with spatial learning deficits.
An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia. Researchers have been led to suspect non-plaque βA oligomers (aggregates of many monomers) as the primary pathogenic form of βA. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication. One receptor for βA oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt–Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer’s disease.
In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by ageing-related processes in later life to cause the neuronal withering of Alzheimer’s disease. N-APP, a fragment of APP from the peptide’s N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known asTNFRSF21). DR6 is highly expressed in the human brain regions most affected by Alzheimer’s, so it is possible that the N-APP/DR6 pathway might be hijacked in the ageing brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.
The tau hypothesis is the idea that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing the neuron’s transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.
Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE gene.
Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain. Iron released during myelin breakdown is hypothesised to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as beta-amyloid and tau.
Oxidative stress and dys-homeostasis of biometal (biology) metabolism may be significant in the formation of the pathology.
AD individuals show 70% loss of locus coeruleus cells that provide norepinephrine (in addition to its neurotransmitter role) that locally diffuses from “varicosities” as an endogenous anti-inflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus. It has been shown that norepinephrine stimulates mouse microglia to suppress βA-induced production of cytokines and their phagocytosis of βA. This suggests that degeneration of the locus ceruleus might be responsible for increased βA deposition in AD brains.
Well, I managed to complete this blog post on one hour of sleep. (Good for me!)
PS The title refers to a comment made by a personal care attendant to my new neighbor about a phlebotomist who wanted to draw a specimen.