Here are a couple of new developments in Alzheimer’s and dementia – nothing encouraging, unfortunately. A new paper in JAMA Internal Medicine, from a team that’s looked at multiyear patient records, suggests that there’s a dose-response relationship between use of strong anticholinergic drugs and later development of dementia and Alzheimer’s. These compounds include tricyclic antidepressants, first-generation antihistamines (chlorpheniramine, etc.) , and muscarinic antagonists given for bladder control, and you also have pure muscarinic compounds like hyoscine/scopolamine that are given in a number of indications. The results here look pretty solid, as far as I can tell – increased use of cholinergic antagonists seems to be a risk factor, and the risk goes up with dose. That’s not very welcome news, given the number of older patients who are taking one or more drugs in these classes. This is another one to add to the “environmental insult” part of the ledger on slow-developing CNS problems, which is getting to be a thicker stack of evidence than I would have once thought.
Now, just why such exposure should lead to a higher rate of dementia is a good question. It’s certainly true that cholinergic neurons take a beating in Alzheimer’s pathology. There are five types of muscarinic receptors, though, and they can’t all be the same here, mechanistically (that said, many compounds are rather unselective among them). For a while in the 1990s, companies were actually working on m2 antagonists as a possible mechanism for potentiating cholinergic signaling in Alzheimer’s (I was involved in some of that), but they were trying to be as selective as possible, just for the normal gamut of side effects.
In another area, there’s been another report on the “transmissible Alzheimer’s” front. Swiss pathologists have examined brain tissue from several people who died of Creuzfeld-Jacob disease, as in the earlier report in this area. These patients had contracted C-J from surgical grafts of dura mater (the previous report was from people who’d been exposed from human-derived growth hormone treatment). But these patients, in addition to the prion damage from the disease itself, also (as in the previous work) showed amyloid plaques in the brain and in vascular tissue, and they were quite young to have developed them. Control samples from people who’d died of sporadic Creuzfeld-Jacob (not associated with transfer of tissue) showed no such findings.
This paper is completely consistent, then, with the earlier paper’s hypothesis that surgery might transfer “seeds” of pathological amyloid protein, that over the years spread into plaques. That still doesn’t mean that Alzheimer’s is transmissible under ordinary circumstances – you could hardly duplicate the experience of having someone else’s amyloid protein inserted directly into your central nervous system, I’d think. But it does mean that surgical procedures (and surgical instruments) used in brain operations are worth considering closely. And it adds another piece to the amyloid puzzle.