Amyloid-β potency peaks in the earliest
stages of pathology:
Implications for Alzheimer’s disease therapeutics
Written by Jay Rasmussen
With the advancement of medicine and health practices in the modern era, the average age of the
population has increased. The healthcare system has continually been pushed to adapt in order to
properly care for these elderly individuals and the health problems that arise with age. Advanced
age in itself is one of the main risk factors for dementia, a perplexing class of neurological diseases.
These devastating disorders place a large burden on families and the healthcare system in general.
It is estimated that 47 million people are living with dementia worldwide, which carries an economic
burden of almost $800 billion USD [1]. These numbers are expected to grow along with the global
population emphasizing the need to more deeply understand this pathology of memory loss.
Alzheimer’s disease (AD) is the most
common form of dementia in the
world and contributes substantially to
the above-mentioned statistics. Cur-
rently, AD remains an incurable condi-
tion despite a number of attempts at
developing a therapy. The progressive
loss of memory describes the general
patient symptoms in AD while, at a
cellular level, there is neuronal death
and the deposition of two proteins,
amyloid- β ( A β ) in extracellular plaques
and tau in intracellular tangles, in the
brain. There has been a great focus on
these disease-associated protein hall-
marks of AD in order to better under-
stand their contributions to disease. A
popular explanation for the progres-
sion of AD is the amyloid cascade hy-
pothesis, where the misfolding of A β
peptide initiates changes in the brain,
leading to inflammation, intracellular
tau tangles and neuronal death [2].
This framework for disease progres-
sion is supported by studies showing
that the earliest noticeable changes in
early-stage AD involve perturbations
in A β homeostasis, such as a decrease
in a 42 amino acid species of A β in
the cerebrospinal fluid [3]. Based on
these prevailing ideas within the field,
A β has been targeted for therapeutics
with the aim of preventing the initial
changes that ultimately lead to mem-
ory loss.
Investigations into A β biology have
been extensive since its discovery
as the main component of amyloid
plaques [4;5]. The A β peptide is a
cleavage product of the amyloid pre-
cursor protein (APP) with a length of
37-42 amino acids depending on the
cut site [6]. The trigger for the amy-
loid cascade hypothesis is an increase
in the amount of A β present in the
brain either through mutations lead-
ing to the generation of pathogenic
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