Donald
Weaver is Professor of Chemistry and Director of Krembil
Research Institute, University Health Network, University
of Toronto. Disclosure statement: He receives funding from
Canadian Institutes of Health Research, Krembil Foundation,
Weston Brain Institute and the Harrington Discovery Institute.
This article was originally published in The Conversation
(https://theconversation.com)
As a researcher
who studies Alzheimer’s disease and a neurologist
who cares for people with Alzheimer’s, I share in
the frustration, indeed anger, of people and families when
I tell them that I have no cure to offer.
Over the past
year, scientists have tackled COVID-19, a previously unknown
disease and within months developed effective new vaccines.
Over that same time frame, the list of Alzheimer’s
treatment failures got longer. Currently, the only approved
drugs for Alzheimer’s merely alleviate some of the
symptoms — partially and temporarily — but do
not stop the disease from progressing.
Although it
was first officially described 115 years ago, and of course
existed long before that, we still do not have a cure for
this devastating disease. Why?
Let’s
start by following the money. For years, patient advocates
have pointed to the escalating toll and ballooning costs
of Alzheimer’s as the world’s population ages.
Alzheimer’s is severely underfunded in comparison
to cancer, heart disease, HIV/AIDS and even COVID-19.
Sadly, the mistaken
belief that Alzheimer’s only affects older people
is a contributing factor to this underfunding. However,
five to 10 per cent of people with Alzheimer’s are
under 65 years of age; some are even in their 40s. Alzheimer’s
is also a disease of the entire family, causing anxiety,
depression and exhaustion in caregivers and loved ones,
exacting a disproportionately high socio-economic cost.
CONFLICTING
THEORIES
Funding is not
the only issue here. The human brain is extremely complex,
and Alzheimer’s disease is the most complex disease
of the brain. The challenges that arise from this collision
of complexities are reflected by the many competing theories
of Alzheimer’s.
The most time-honoured
theory is that Alzheimer’s is caused by misfolded
proteins that aggregate or clump, killing brain cells and
giving rise to the symptoms of memory loss and reduced cognition.
Initially, the culprit in this misfolding story was a protein
called beta-amyloid. More recently, another protein, tau,
has emerged as a possible contributor.
Although a wealth
of research data have supported this protein misfolding
theory, referred to as the amyloid hypothesis, multiple
drugs designed to block the brain’s toxic protein
misfolding processes have failed in human trials, repeatedly.
In fact, in the past two years, several major clinical trials
based on the field’s leading hypothesis — that
reducing the level of aggregated beta-amyloid that riddles
the brains of Alzheimer’s patients would halt disease
progression — have dramatically failed.
And so there
are many other theories. A new heavyweight contender is
the neuroinflammation theory of Alzheimer’s which
suggests that the disease arises from an excessive release
of toxic inflammatory chemicals from immune cells in the
brain called microglia. Drugs designed to address this theory
are fundamentally different from those addressing the amyloid
hypothesis, and are still early in the developmental process.
A different
theory claims that Alzheimer’s is a disease of synapses,
which are the junctions between brain cells, and yet another
suggests that Alzheimer’s is a disease of mitochondria,
a structure central to energy production in every brain
cell.
CHALLENGES TO
FINDING A CURE
The path towards
a cure is not going to be easy, and even if these theories
do lead to the development of drugs, these drugs may fail
for a host of other reasons.
Alzheimer’s
is a very long, chronic disease, probably present 20 to
30 years before the first symptoms become obvious. Giving
the drug when a person becomes symptomatic may be too late
for it to make any difference. But we do not have the ability
to diagnose it 30 years before the first symptoms, and even
if we could, we would need to consider the ethics of giving
a potentially toxic drug long-term to someone who may or
may not get a disease in three decades.
Also, unlike
developing antibiotics in which the researchers know within
days if the drug works, the chronic nature of Alzheimer’s
requires long, expensive trials — years in duration
— before an answer can be attained. Such time and
expense is a further impediment to drug development.
One final problem
is that Alzheimer’s may not simply be one disease.
It may in fact be a collection of similar diseases. A 52-year-old
with early onset Alzheimer’s certainly has a clinical
course distinct and different from an 82-year-old with late
onset Alzheimer’s. Will a drug that works in an 82-year-old
also work in a 52-year-old person’s disease? Maybe,
or maybe not.
Thankfully,
despite these many hurdles, a wealth of fascinating and
encouraging research is taking place in laboratories around
the world. The successes of science and the pharmaceutical
industry against many other diseases over the past century
have often arisen from picking low-hanging fruit. Alzheimer’s
disease is not a low-hanging fruit, but the apple at the
very top of the tree, and scientists are going to have to
climb a lot of branches — many of which have never
been trodden upon — on the way to a cure. But we’ll
get there.
