Stuart R. Gallant, MD, PhD
One of the most useful words in medicine is “multifactorial.” Commonly, in science and medicine, we struggle to find a single root cause or principle of each problem we study. However, humans are complex and frequently resist attempts to find simple explanations for their afflictions.
Some diseases (for example, lysosomal storage diseases and sickle cell anemia) result from a single malfunctioning gene. In the case of Alzheimer’s disease, there are several intertwined causes contributing to pathological cognitive decline:
- Molecular: Accumulation amyloid plaque, followed by tau neurofibullary tangles
- Inflammatory: Reaction of microglia (macrophages) and astrocytes driving oxidative damage to the cells of the brain
- Metabolic: Excess weight and poor diet leading to elevated blood pressure, poor glucose control, and cholesterol mediated vascular disease
One commonly available Alzheimer’s disease gene assay from Thermo (TaqMan® Array 96-well Mouse Alzheimer’s Disease Plate) contains 92 mouse genes which are thought to play a role in the Alzheimer’s disease mouse model. Of course, that list is grossly truncated by virtue of the rapid rate of advance in Alzheimer research and the delay bringing an assay to the commercial market, as well as the limited number of wells in a 96-well plate. The point is that Alzheimer’s disease involves a lot of genes.
Because of the multifactorial nature of Alzheimer’s disease, development of new treatments contains several hazards:
- Target identification: Presumably, some genes are more important than others. Development of a treatment strategy always involves selecting one or a small number of genes as targets for intervention. There is the risk that the wrong target(s) will be selected.
- Genetic diversity of patients: The risk of individual patients for molecular, metabolic, and inflammatory causes of Alzheimer’s disease varies substantially through the population. What is known is that only 5-10% of Alzheimer’s disease patients have familial risk [1]; the remaining 90-95% of patients occur sporadically throughout society. With a diverse genetic risk of disease, there is risk that a medication may be useful (alone or in combination with other drugs) but that the beneficial effect can be difficult to observe if only a subset of the population is improved by the treatment.
- Slow development of disease: Alzheimer’s takes years to develop—clinical trials are slow and expensive as a result.
This post will address drugs currently in clinical trials to treat Alzheimer’s disease. In the first part of this post, normal aging and pathological aging are addressed. In the second part, treatments are summarized, and some attempts are made to draw lessons from drugs which have been evaluated.
Normal Aging
The brain changes throughout human life, from infancy through the senior years. One measure of the size and function of the brain is “white matter,” the long, myelinated projections which integrate and coordinate the brain’s activities. In terms of brain structure and function, 50 years of age is a pivotal moment. On the good side, human white matter peaks at age 50 [2], so processing power of the brain is quite high at that age. However, after that age, normal aging reduces white matter mass in a linear fashion. After reaching peaks size, most areas of the brain decline in volume at a rate of 0.5% to 1.0% per year [2].
So, our brains get smaller as we age, what does that mean functionally? In normal aging, remote memory (child-hood memories, things we experienced years ago), procedural memory (routines and tasks we have learned), and semantic recall (facts we learned in school and through work) all remain intact. However, learning and recalling new information can become more difficult.
Another area that can be distressing for seniors is difficulty with word finding, the feeling that a word or name which used to be part of their common vocabulary has become difficult to recall. However, this phenomena is within the normal range of aging and does not, by itself indicated underlying pathology.
Alzheimer’s Disease
The introduction of this post lists the three causes of Alzheimer’s disease. What makes Alzheimer’s disease unique is the molecular cause. The inflammatory and metabolic causes follow and pile onto the initial molecular insult. The current thinking about this disease is that it begins with and requires the presence of beta amyloid deposition [1]. Amyloid precursor protein (APP) is a cell surface protein with single transmembrane domain:
As seen in the figure, APP maybe processed in one of two ways. If alpha-secretase cleaves the protein, followed by gamma-secretase, soluble fragments result, leading to normal, non-amyloidogenic degradation. On the other hand, if beta-secretase cleaves the protein, followed by gamma-secretase, in soluble amyloidogenic fragments result. These insoluble fragments (beta amyloid) form beta amyloid oligomers which are toxic to neuronal cells. Following death of the neurons, larger aggregates (amyloid fibrils form) which are visible to microscopic examination.
A separate dysfunctional protein (tau) is also present in Alzheimer’s disease; however, it is generally viewed as a secondary cause following the primary event of beta amyloid oligomer formation. Tau is normally a protein associated with microtubules. In Alzheimer’s disease, tau is hyperphosphorylated and unable to associate with microtubules. Neurofibullary tangles composed of dysfunctional tau are a second microscopic finding in Alzheimer’s disease.
As the normal mechanisms responsible for regulation and degradation of APP and tau are overwhelmed, an avalanche of further damage accumulates. Microglia (macrophages) and astrocytes are mobilized to remove the pathologic beta amyloid deposits, resulting in an inflammatory cascade, leading to oxidative damage and further cell death.
It was discussed above that white matter contains long, myelinated projections which integrate and coordinate the brain’s activities. The kind of damage wrought by the immune attack on the brain is analogous to the effect of cutting down the long-distance lines in a telephone network. The system left in the wake of this attack coordinates and communicates to only a fraction of the degree that it did before the attack.
And finally, there is metabolic disease. Many of the themes present in metabolic illness are also important in Alzheimer’s disease, such as: advance glycation end products (encountered in diabetes), trafficking of cholesterol by proteins like apolipoprotein E (encountered in hyperlipidemia), and the effects of poor control of blood pressure (encountered in hypertension). Metabolic disease greatly enhances the impact of Alzheimer’s disease and speeds its progress.
Predictably, these combined toxic insults (molecular, immune, and metabolic) lead to significant loss of brain mass—in-excess of what would be expected in normal aging. Characteristic findings of imaging studies include shrinkage of the hippocampus and cerebral cortex, as well enlargement of the ventricles. The impact of this damage to the patient’s ability to go about activities of daily living, maintain personal relationships, and even regulate their emotions can be devastating. Thus, development of new treatments has high priority. In the second part of this post, the status of treatments under clinical investigation is reviewed and some thoughts are provided on the prospects of the different approaches.
[1] Kumar, V., et al. Pathologic Basis of Disease, 10th Edition (2020).
[2] Fjell, A.M. and Walhovd, K.B. “Structural Brain Changes in Aging: Courses, Causes and Cognitive Consequences,” Reviews in the Neurosciences 21, 187-221 (2010).
Disclaimer: PharmaTopoTM provides commentary on topics related to drugs. The content on this website does not constitute technical, medical, legal, or financial advice. Consult an appropriately skilled professional, such as an engineer, doctor, lawyer, or investment counselor, prior to undertaking any action related to the topics discussed on PharmaTopo.com.