In Context
Book
How Not to Study a Disease:
The Story of Alzheimer’s
Karl Herrup
MIT Press, 2023
Pp 272, $19·95
ISBN 9780262546010
For the amyloid cascade
hypothesis see Science 1992;
256: 184–85
For more on Robert Katzman’s
contributions see Obituary
Lancet 2008; 372: 1804
For the NIA-AA criteria see
Alzheimers Dement 2011;
7: 257–62
970
Alzheimer’s disease: a history revisited
The tortured story of Alzheimer’s disease, in neurobiologist
Karl Herrup’s book How Not to Study a Disease, swerves
between bewilderment about and appeasement with
the idea of amyloid toxicity. Amyloid plaques had to be
the cause of Alzheimer’s disease. That was the obvious
conclusion when families with an aggressive early-onset
form of dementia and brain amyloidosis were discovered to
carry APP mutations on chromosome 21. People with Down
syndrome, who develop a dementia neuropathologically
indistinguishable from Alzheimer’s disease, also over­
express the amyloid precursor protein (APP). The field
went on to produce genetically engineered mice with brain
amyloid and a vaccine that cleared it. Curing Alzheimer’s
disease in mice has not led to curing the human version
yet; nevertheless, amyloid became the central problem, and
a “bully.” Herrup recalls that, after the publication of the
influential article by John Hardy and Gerald Higgins on the
amyloid cascade hypothesis in 1992, the orthodox view was
that researchers not studying amyloid were not studying
Alzheimer’s disease.
About a third of the individuals with amyloid plaques in
the brain never develop cognitive impairment within their
life spans. However, the amyloid hypothesis has withstood
the test of time. “A hypothesis can never be proven to be
100 percent true”, writes Herrup, “it can only be tested and
tested and tested until we find the limits of its applicability”.
Left implicit, the amyloid hypothesis can never be disproven
with certainty—even if, in Herrup’s account, it has already
failed the “three basic tests”. Test 1: in animal models,
injecting human amyloid into healthy brains does not start
a cascade leading to neurodegeneration; test 2: removing
amyloid from the brains of people with Alzheimer’s disease
does not seem to stop their disease; test 3: blocking amyloid
formation by inhibiting the APP does not seem to stop the
disease either, and actually can make patients sicker.
This negative trifecta notwithstanding, Alzheimer’s
disease is subjected to three artificial “inflations” in
Herrup’s storyline. In the first, Alois Alzheimer’s study of
Auguste Deter, who died in her fifties with a brain filled
with amyloid plaques and tau tangles, explained all pre-
senile dementias. In the second “inflation”, in 1976,
Robert Katzman proposed that senile dementia was
the same as Alzheimer’s disease, mischaracterising data
actually showing that only about 50% of cases of senile
dementia had plaques and tangles. And in the third, in
2011, diagnostic criteria (also known as the National
Institute on Ageing-Alzheimer’s Association criteria)
elevated neuropathology as the gold standard of diagnosis,
regardless of symptoms. In Herrup’s translation, people
with plaques but also normal brain function are not just
healthy people with plaques—but sick people without
symptoms. Yet Herrup vacillates in condemning the anti-
amyloid therapeutic approach. He longs for a world not
incompatible with the amyloid hypothesis. By page 161 he
still finds “not enough data to accept it or reject it”.
Herrup sensibly argues for research efforts centred on
studying the biology of ageing, but advocates for defining
Alzheimer’s disease on clinical grounds. Let’s imagine what
other fields of medicine, such as oncology or diabetology,
might look like today if their diagnostic criteria would
have remained constrained to the bedside observations
of physicians rather than the results of molecular and
biological testing. Also, as Herrup admits, clinical criteria
require the exclusion of “a better alternative explanation”.
A disease cannot be defined any better by its clinical
presentation than by its pathological features, nor by the
extent to which nothing else could explain it. But neither
clinical presentation nor pathology can confirm the
singular biology of every patient. Herrup favours reframing
Alzheimer’s disease as a multi-layered, network-based
brain disorder that requires increased attention to different
targets (myelin, mitochondria, nutrition, oxidation, senes­
cence, etc) in acknowledgement of its heterogeneity. As
each individual affected is a single puzzle, treatments can
succeed only when targeting every patient’s specific biology.
But here is the greatest omission in the book. Herrup
acknowledges the ubiquity of APP in every cell in the brain,
yet nowhere does he consider its product, amyloid β, as a
crucial protein for a healthy brain. The relevance of the loss
of the normal function of amyloid β is invisible in his story.
For all his courageous stance against the amyloid “bully”,
Herrup does not abandon the amyloid-is-toxic narrative.
Even by page 217, he continues to view amyloid as a
part, not as a consequence, of the problem. For instance,
basic research shows that amyloid stimulates microglia
to mount an inflammatory response; therefore, “getting
rid of the amyloid irritant” remains a goal. His parting
mollification is: “…the alternative views of Alzheimer’s
disease are compatible with most, if not all, of the ideas
behind the amyloid cascade hypothesis”. In conclusion,
the toxic amyloid hypothesis is not (cannot be) false, just
incomplete.
Altogether, Herrup brings a welcome re-examination of
the history of Alzheimer’s disease as a path resisting every
challenge to its amyloid roots. Because amyloid continues
to be the central villain of neurodegeneration, this book is
a must-read and a thoughtful cautionary tale for everyone
interested in ageing disorders of the brain.
Alberto J Espay
www.thelancet.com/neurology Vol 21 November 2022