What’s holding back Alzheimer Disease therapy?

My dad died a few years ago with dementia. The diagnosis was Frontotemporal Lobe Dementia (FTD), based on a psychiatric evaluation and brain imaging. After he died, we had a brain autopsy done, which returned a diagnosis of Alzheimer’s Disease. So which was it? As far as I know, it could be both. But what this little anecdote illustrates is the tension between diagnosis of dementia in a living patient and the use of histopathological diagnostic criteria postmortem.

The New York Review of Books has a review of “How not to study a disease: The story of Alzheimer’s” by Karl Herrup. The review itself is paywalled, but I’ve attached a link to a summary of the book’s premise by the author.

Alzheimer’s disease was first described in 1906, based on a single patient. She was 51 years old. Postmortem histopathology revealed extensive plaques and tangles that Alzheimer and his collaborator concluded likely explained the dementia in this patient. There are two obvious problems with this logic. One is the “post hoc ergo propter hoc” conclusion that the histopathology explained the clinical symptoms, rather than that the histopathology was an epiphenomenon. The other is that the plural of anecdote isn’t data.

Where Herrup says things really ran off the rails was when plaques and tangles were found in the brains of geriatric dementia patients, and the mechanistic extrapolation from a rare form of pre-senile dementia and the much more common dementia seen in individuals of advanced age. What concerns Herrup, and should give all of us pause, is that amyloid plaques are also found in ca. 30% of geriatric brains from people without dementia symptoms.

Disappointingly, drugs that have been show to reduce plaques have had little or no mitigating effect on dementia progression so far. In most cases, these drugs are tested on patients with pre-senile dementia, which may not be representative of most patients. And since there is a paucity of reliable pre-symptomatic markers for dementia, it may be that the drugs need to be administered earlier.

What Herrup argues, however, is that Alzheimer’s research and drug development has been stampeded by orthodoxy into a misplaced focus on amyloid mitigation, when there may be overlooked mechanisms that represent better drug targets. In her New York Review of Books review, Natalie de Souza explains why she thinks Herrup is overstating his criticism, but she does acknowledge the soundness of some of his critique. She notes that genetic research does point strongly to alleles of beta-amlyloid and Tau protein genes in association with Alzheimers. They are clearly important, if not the whole story.

For my part, I’ve mined my genome for the known variants associated with increased risk of Alzheimers, FTD and Parkinson’s Disease, and I don’t have those. But there may well be other alleles of other genes that haven’t yet been flagged. As a geneticist, I think that’s certainly one way to study a disease.

Redefining Alzheimer’s Disease