Why anti-amyloid drugs have failed to treat Alzheimer's disease

Lane Simonian

Eli Lilly is the latest company to acknowledge that its drug candidate only helps a segment of the Alzheimer's population: APOE4 carrier (although Biogen never did acknowledge this for Aduhelm/aducanumab; an FDA statistician did).

Donanemab Analyses Suggest Benefits for Select Alzheimer's Patients

A disease-progression model showed a significant association between the percentage of amyloid reduction and changes on the integrated Alzheimer Disease Rating Scale (iARDS) in people who carried an APOE4 risk allele, but not in others.

https://www.medpagetoday.com/neurology/alzheimersdisease/100667

Anti-amyloid drugs do not help non-carriers.  They slow down the progression of Alzheimer's disease to a limited extent, but with the risk of brain bleeds and brain swelling.  

Individuals with the APOE4 gene or genes have more amyloid in their brain to begin with and generally progress more rapidly in Alzheimer's disease.  Removal of amyloid may bring their progression closer to non-carriers during the early stages of the disease.

The "success" of anti-amyloid drugs then does not depend on how early they are given, but the amount of amyloid a person has.  And even if you remove all amyloid in APOE4 carriers it still does little more than modestly slow down the progression of the disease.

Why is this?  First of all a person can have a considerable amount of amyloid in their brain, but if they also have relatively high antioxidant levels in their brain amyloid cannot damage their brain.

Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active. [Protein Kinase C alpha is an enzyme that early on leads to oxidative stress in Alzheimer's disease].

https://today.ucsd.edu/story/genetic_variations_that_boost_pkc_enzyme_contribute_to_alzheimers_disease

Bolstered Neuronal Antioxidant Response May Confer Resistance to Development of Dementia in Individuals with Alzheimer's Neuropathology by Ameliorating Amyloid-β-Induced Oxidative Stress

Arguing against the amyloid hypothesis, some individuals maintain intact cognitive ability throughout their lives, yet display widespread AD neuropathology on postmortem analysis of brain tissue (Price et al., 2009; Maarouf et al., 2011; Zolochevska and Taglialatela, 2016). These individuals, termed as being nondemented with Alzheimer's neuropathology (NDAN), exhibit extensive Aβ plaques and NFTs [Neurofibrillary Tangles/tau tangles] that are comparable to those of individuals with advanced AD, yet they score normally on cognitive assessments and show no clinical signs of dementia...Considering the above, a recent study by Fracassi et al. (2021) in The Journal of Neuroscience sought to determine whether the oxidative state of neurons and glia is related to the resistance to cognitive decline in NDAN patients. The authors hypothesized that NDAN individuals, though having elevated production of reactive oxygen species as a result of Aβ accumulation, also have a more efficacious antioxidant response, which increases their ability to cope with oxidative stress relative to AD patients.

https://www.jneurosci.org/content/41/29/6187

Protection against Amyloid-β Oligomer Neurotoxicity by Small Molecules with Antioxidative Properties: Potential for the Prevention of Alzheimer’s Disease Dementia

AβOs exert neurotoxicity and synaptotoxicity and play a critical role in the pathological progression of AD by aggravating oxidative and synaptic disturbances and tau abnormalities. As such, they are important therapeutic targets. From a therapeutic standpoint, it is not only important to clear AβOs or prevent their formation, it is also beneficial to reduce their neurotoxicity. In this regard, recent studies have reported that small molecules, most with antioxidative properties, show promise as therapeutic agents for reducing the neurotoxicity of AβOs. In this mini-review, we briefly review the significance of AβOs and oxidative stress in AD and summarize studies on small molecules with AβO-neurotoxicity-reducing effects. We also discuss mechanisms underlying the effects of these compounds against AβO neurotoxicity as well as their potential as drug candidates for the prevention and treatment of AD.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773221/

And here is the crux of it: amyloid can contribute to oxidative stress but it is also largely the product of oxidative stress.  Without the primary triggers for oxidative stress such as environmental toxins, an unhealthy diet, stress, sleep deprivation, unresolved infections, and genetic mutations there would be little amyloid to begin with.  Those other factors will continue to produce oxidative stress during the early stages of Alzheimer's disease even if you remove all the amyloid.  The key then to the prevention and treatment of Alzheimer's disease is not to remove amyloid but to employ the most effective antioxidants.