Catching Alzheimer's

What do doctor's do? They restore the Ease, which we expect as our due, when dis-ease gets us down. If things are okay, don't go to the doctor - especially if it costs somewhere north of €50 to consult a GP and much, much more for 10 minutes with a consultant. If I was a doctor, I'd sort patients into four bins:

• Infectious disease
• plague, pox, pertussis, pediculus, pandas, polio, prions, pneumonia, puerperal fever, pinworms . . . and that's just the Ps . . . on The Blob
• Hereditary disease
• The Downs, Tay-Sachs, CF, PKU
• Homeostatic collapse
• diabetes, hypertension, Alzheimer's (all often associated with old age)
• cancers are uncontrolled cell division; normally cells divide until feedback signals say "stop dividing". Feedback = homeostasis. There is no such thing as a fish cancer: it is a very wide range of diseases, with a wider range of causes, affecting pretty much all tissues but not all at once.
• Accidental damage
• child with lego head up its nose; carpenter who missed with his hammer; fell down stairs in the dark; shot himself in foot; caught his own ear while fishing

I think it is becoming clearer that these divisions / categories are quite leaky. It's the interaction terms! Some people have a genetic pre-disposition which makes them more likely to have an adverse reaction to an environmental challenge. Some people can hold their liquor; some die of cirrhosis. Heart disease runs in families but more in families that start each day with an Ulster fry [Right ready to eat]. Multiple sclerosis used to be as an Act of [a petulant 6 y.o.] God, a bad roll of the dice. But when MS clusters appear in Orkney or Nova Scotia, you have to suspect that the disease might be triggered by an infectious virus - like Guillain-Barré syndrome [another disease of peripheral neuro-degeneration] triggered by Campylobacter chickennuggeti.

What about Alzheimer's? I suspect that, for readers and thinkers (like yourself, dear reader), dementia-with-forgetting has a special place among the horrors of getting old. And it is increasingly likely that is how we are going to go out. Alzheimer's is now the 6th cause of death in the USA, with 6 million (2%) USAlzheimeristas and costing $600 billion every year worldwide. You may bet that Megapharm Inc would like to get its fingers in that pie but so far effective treatments have eluded licencing despite million$ and m€llions being spend on development. It's not a field I know, but I suspect that a lot of these new drug development projects have been based on a faulty understanding of cause and effect. Another problem is that Alzheimer's is like cancer - many diseases with similar symptoms, like Terry Pratchett's PCA which is less about loss of memory as loss of underpants.
Indicators; signs; symptoms:

• Memory loss
• Dementia - as in rage and inappropriate speech
• Depression
• Can't start crosswords let alone finish them
• Asking what day it is
• and who are you?
• Losing the car keys
• good thing because can't drive car safely
• Suspicion and paranoia
• except w.r.t. folks who offer to tarmac your drive, for cash.
• Post-mortem
• Tissue loss in the brain (R,R it rattles in the skull like a pea in a drum)
• Beta amyloid plaques
• Tau tangles

Thus many of the drugs that have been under development by Megapharm Inc. have targetted the Beta Amyloid plaques. But so far these drugs have all failed in Phase I or Phase III trials.

I was up in TCD on Mayday and caught an interesting event about language as well as a film about contemplating its absence. All good; but good things come in threes and in the evening Marina Lynch, a researcher in the Trinity College Institute of Neuroscience TCIN, was awarded the Annual ISI Medal of Freedom. Luckily for us she had to sing for her supper - about her research into the inflammatory triggers to Alzheimer's.

Twenty+ years ago, Dr Lynch noted that in addition to the other symptoms enumerated above, there was significant neuroinflammation in mice and humans who went on to develop dementia. That was quite left-field at the time and so ignored by the Alzheimer's community. How could there possibly be inflammation in the brain if there was a blood brain barrier BBB to keep the brain clear of circulating causes of inflammation? It was an article of faith that the brain was immune privileged. What no meningitis? That's what faith does: it allows you to ignore uncomfortable truths if they disagree with your certainties.

One of her observations was that NSAID anti-inflammatories like aspirin provide some prophylaxis against Alzheimer's. When folks did a meta-analysis of all the NSAID/Alz studies and then a genome-wide association study GWAS they found that all the genes that lit up were associated with immunity, inflammation or microglia - the specialist cells that the brain uses to sniff out and deal with damage. That must be the immune insults, the occurence of which neurological dogma refused to accept. But insults clearly do happen [meningitis], and these specialised cells have evolved to cope. It looks like beta amyloid plaques, those obvious predictors of Alzheimer's, may be a useful response to infection. So targetting amyloid with drugs is about as sensible knocking down all the fire-fighters with a bus-load of rubber-neckers.

What it looks like is that amyloid is deposited to deal with a transitory infection, then the microglia mobilise to clean up the mess. When you're young and your immune system is hair-trigger precise with managing alien invasions by bacteria and viruses, then you never even notice that your brain has been insulted. Maybe that's what many of those transitory head-aches are about? With age, all the homeostatic checks-and-balances get less precise: responses are blundering too little, too late or far too much. The microglia seemingly get tired and can no longer cope with the deluge of amyloid, other inflammatory molecules move in the 'help' but they cause more tissue damage with their enthusiastic pokes and jabs.

We have no idea what virus triggers multiple sclerosis (perhaps because the condition is much rarer than dementia?) but the finger is pointing at a number of microbes as precursors to Alzheimer's.

• Porphyromonas gingivalis is the cause of periodontal gum inflammation, which you may barely notice. If you've had such an infection, you are 10x more likely to develop Alzheimer's. It is known to cross the blood-brain barrier and has been isolated from the hippocampus - the seat of memory.
• Chlamydophila pneumoniae is related the STI Chlamydia trachomatis. It appears to invade the brain from the mouth via the trigeminal nerve where it also lodges in the hippocampus - making Alzheimer's 5x more likely.
• Bordatella pertussis [the boyo for whooping cough] is hard to clear [been there, tried that with The Boy aged 12] and also predisposes to Alzheimer's. 
• Even the humble cold-sore herpes simplex virus strains HSV1-6A and HSV1-7 seem to be associated with the later development of Alzheimer's. A bit like HPV sitting latent for decades before starting cervical cancer.

During the questions afterwards, I asked if there might be utility in vaccinating everyone against one or other of these infections so they never big enough and bold enough to trigger the inflammation that is a prelude to Alzheimer's. Nope, Dr Lynch replied, but we could all engage to brush our teeth more carefully as a hedge against P. gingivalis. For her, the way forward is to do something to boost the poor overwhelmed microglia so that they can make a better fist of cleaning up the damage before it clogs the brain entirely. Sounds sensible to me.

More women in science.