Recently, the search for a treatment for Alzheimer's
disease (AD) has reached a turning point.
New clinical tools to identify subjects that have Alzheimer’s disease,
and methods to more accurately follow the progression of the disease, have
significantly enabled clinical development of new therapies. Biogen has presented clinical data showing
for the first time therapeutic intervention changing the natural course of the
disease (1). In addition, reported studies in JAMA of 9500
subjects support the critical role of amyloid-beta (Aβ) early in the disease
process (2). These
studies provide further and substantial evidence for Aβ’s central role in the pathobiology
of Alzheimer’s disease and support therapeutic intervention limiting
undesirable Aβ-driven effects as a cornerstone of the management of AD, and
perhaps the prevention of dementia.
The Alzheimer's disease process may begin as early as
two decades before clinical symptoms.
Therefore, early therapeutic intervention targeting the biological
dysregulations, such as apolipoprotein E (ApoE) dysfunction and Aβ and tau accumulation that set the stage for the
complex late-stage disease process, is required. A polypharmacological approach, tailored to an
individual’s unique disease state, may be optimal.
molecule clinical agents, designed to limit undesirable Aβ in the brain, have thus far focused on
the inhibition of Aβ production. This approach was based on the hypothesis that AD patients have
increased production of Aβ. However, a recent study has shown that Aβ
accumulation in AD patient’s brains is due to a decreased ability of the
patients to clear pathogenic Aβ peptide from their brains and not from an
overproduction of Aβ (3).
Approaches for early therapeutic intervention in the
Alzheimer’s disease process - to prevent the progression to dementia - in many
ways mirrors the successful strategies employed to prevent myocardial infarction
and stroke by reducing lipid accumulation in blood vessels and by controlling
hypertension. However, in AD, the therapeutic
intervention with biologics to remove Aβ rather than
with small molecule therapeutics, over a long period of time and involving such
a large patient population, will lead to significant pharmacoeconomic challenges. An alternative to biologics for AD is Merck’s
small molecule BACE inhibitor, MK-8931, currently under evaluation in a Phase 3
trial evaluating its effects on subjects with prodromal Alzheimer’s disease (4). This may provide a cost-effective therapeutic. However, safety concerns have stopped the
progress of other experimental Alzheimer’s therapeutics that limit the
production of Aβ, and ideally a Alzheimer’s drug given to patients over many
years would have a similar safety profile as mainstream cardiovascular agents.
Development of an Beta Amyloid-Mediated Chronic Inflammatory State
Neuroinflammation plays a central role in Alzheimer’s
disease pathology. The interrelationship
between Aβ and the inflammatory response in the brain continues to be
elucidated. Recent genetic studies have
shown genes for immune receptors TREM2
and CD33 are associated with
Alzheimer’s disease. Furthermore, a rare
mutation in TREM2 increases the risk of Alzheimer’s disease to a similar extent
as ApoE4 (5). TREM2 is highly expressed in microglia and mediates phagocytic
clearance of Aβ and neuronal debris. A feedback-back loop may develop for Aβ
whereby the immune system’s response to Aβ, damaged cells, pathogens, and
proinflammatory cytokines impairs microglial clearance of Aβ and increases APP
processing (6). As shown above, Aβ and proinflammatory mediators favor an activation
state for microglia that leads to the expression of proinflammatory cytokines
and an impaired phagocytic capacity, hence a diminution of Aβ clearance. In addition to the modulation of inflammation
though the changes in Aβ, ApoE has been shown to suppress both LPS and
oligomerized Aβ-induced TNFalpha secretion (7).