The Amyloid Hypothesis of Alzheimer’s: Are we on the right track?

The Amyloid Hypothesis Of Alzheimer’s

According to estimates, the global dementia population will grow from roughly 57 million in 2019 to 153 million by 2050 [1]. About 60–70% of these cases are due to Alzheimer’s. After age 65, its prevalence doubles every five years, increasing the burden on aging communities in terms of both human distress and healthcare expenses [2].

Nearly all current Alzheimer’s treatments only deal with the cognitive and behavioral symptoms of the disease, not their underlying causes. There is still no known means to stop the illness, let alone cure it.

The Amyloid Hypothesis

The amyloid hypothesis was the primary origin story for the disease for over 30 years [3]. It argues that this sticky protein causes a series of changes in the brain which disturb synapses, produce inflammation, kill nerve cells, and cause gradually increasing dementia.

However, contradicting evidence from brain-imaging studies over the last decade, with a lengthy string of disappointing failures in anti-amyloid medication and vaccination trials, has led to a gradual issue for the amyloid theory.

Beta-amyloid with another protein, tau, are primarily responsible for brain changes associated with Alzheimer’s. According to the amyloid hypothesis, beta-amyloid starts the cascade of degenerative alterations decades before symptoms appear. The two proteins may cooperate to create dementia.

An enzyme breaks down the larger molecule, the amyloid precursor protein (APP), which is essential for the central nervous system’s development and the survival of nerves following injury, to produce soluble units of beta-amyloid.

According to the theory, problems arise when beta-amyloid generates more quickly than its removal from the brain. Insoluble plaques can form when many units group together to produce poisonous, free-floating “oligomers,” which spread.

What evidence supports the theory

However, there hasn’t been any firm evidence to support the amyloid theory. The best evidence for Alzheimer’s disease up until recently came from genetics, which connected genes to the production and processing of amyloid [4].

For instance, people with Down syndrome frequently experience Alzheimer’s in their 40s or earlier. The gene for APP is present on chromosome 21, which has an extra copy that causes Down syndrome. It means that those with Down syndrome make a lot of beta-amyloid.

The gene variations that provide this additional risk either increase overall beta-amyloid synthesis or enhance the production of a particularly sticky type of beta-amyloid that is more likely to clump together. Early-onset Alzheimer’s disease can also run in families.

What evidence contradicts the theory

The amyloid theory faces significant obstacles despite these genetic smoke signals [5]. The discovery that some older individuals without dementia have massive plaque buildup in their brains while others with clinical Alzheimer’s symptoms have little or no plaque was one of them. In fact, a far stronger correlation exists between symptoms getting worse and tau fibril distribution across the brain.

This data has led some neuroscientists to assert that Alzheimer’s doesn’t have a single original cause but develops as the result of two or more loosely connected causal chains of events [6].

A slew of disappointing failures of beta amyloid-targeting medicines — both monoclonal antibodies and vaccinations — appeared to support this viewpoint [7][8]. Several medications were successful in removing amyloid plaques from the brain. However, they did not slow cognitive deterioration.

The conclusion was that beta-amyloid was a result of the disease rather than its cause. Some others argued that stress and declining immunity caused infectious organisms like the herpes simplex virus, which had remained dormant for years, to reactivate in aged brains [9]. According to this view, beta-amyloid—which has antimicrobial properties—was only a defense mechanism, whereas pathogens, directly or indirectly through inflammation, damaged nerves.

Some blamed the gum disease-causing Porphyromonas gingivalis bacteria, which has also been discovered in Alzheimer’s patient’s brains. The bacterium produces destructive enzymes known as gingipains that may encourage the development of tau tangles [10].

The trials targeting beta-amyloid

The previously approved medications for beta-amyloid

In June 2021, the FDA authorized aducanumab, an anti-amyloid treatment, despite problems with the amyloid hypothesis and against the advice of its own advisory council. The medication, a monoclonal antibody, removes amyloid. However, experts found contradictory results from two identical clinical trials.

In January 2023, the FDA’s clearance of another anti-amyloid antibody, lecanemab, marked the emergence of real hope. It was the first clinical experiment to demonstrate that focusing on amyloid oligomers that float freely can halt cognitive deterioration in people with early Alzheimer’s.

Although the medicine slowed the decline by 27% over 18 months, the therapeutic effect was small.

The Lilly Trial: A new hope?

Last month, the manufacturer of another monoclonal, donanemab, issued a press release with better news [11]. According to its clinical trial, the medication resulted in a 35% slower rate of cognitive decline over 18 months in individuals with early-stage dementia than the placebo, as well as a 40% slower rate of decrease in their ability to do daily tasks like handling money.

How do scientists explain the failure of numerous earlier experiments using such comparable drugs? They assert that either the treatment term was too brief, the doses were too low, or the studies did not begin early enough during the disease. Monoclonals can result in brain swelling or minor bleeding as a side consequence of removing plaque, which completely justifies the warning. However, the more recent monoclonals work to reduce these side effects. Additionally, they may be more effective at halting the production and spread of hazardous oligomers by focusing on a sweet spot in the beta-amyloid molecule.

The most recent studies support the need to halt plaque spread before it leads to the development of tau tangles inside neurons, the next stage of the illness. Neuroscientists had no idea that cells like microglia, which are the brain’s own immune cells, would be a hidden factor in the illness process that could explain the apparent irregularities in brain imaging studies when the amyloid theory was originally put forth. Numerous genetic factors influence how well they work to prevent the production and spread of amyloid oligomers.

Challenges remain

Numerous obstacles still exist. In the most recent trials, patients’ symptoms did not actually get better or even stop getting worse; monoclonals only slowed down the disease. Furthermore, screening for illness indicators – a difficult task in and of itself — will be critical to reaping the benefits of these medications because the treatments must begin before the toxic effects of tau take effect.

Other difficulties include exorbitant prices and the requirement to set up specialized treatment facilities for routine infusions. Vaccines focused on beta-amyloid oligomer removal would be less expensive and probably safer if they could successfully activate our own immune system. A few are still under development. The condition, it turns out, includes a variety of controllable risk factors, such as social isolation, cardiovascular disease, gut bacteria, and sleep apnea.

Although the causes of Alzheimer’s may be straightforward, the course of the disease’s development is far from it.


  1. Nichols, E., Steinmetz, J.D., Vollset, S.E., Fukutaki, K., Chalek, J., Abd-Allah, F., Abdoli, A., Abualhasan, A., Abu-Gharbieh, E., Akram, T.T. and Al Hamad, H., 2022. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. The Lancet Public Health, 7(2), pp.e105-e125.
  2. Lane, C.A., Hardy, J. and Schott, J.M., 2018. Alzheimer’s disease. European journal of neurology, 25(1), pp.59-70.
  3. Selkoe, D.J. and Hardy, J., 2016. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO molecular medicine, 8(6), pp.595-608.
  4. Haass, C. and Selkoe, D., 2022. If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline?. PLoS biology, 20(7), p.e3001694.
  5. Kametani, F. and Hasegawa, M., 2018. Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’s disease. Frontiers in neuroscience, 12, p.25.
  6. Chételat, G., 2013. Aβ-independent processes—rethinking preclinical AD. Nature Reviews Neurology, 9(3), pp.123-124
  7. Van Dyck, C.H., 2018. Anti-amyloid-β monoclonal antibodies for Alzheimer’s disease: pitfalls and promise. Biological psychiatry, 83(4), pp.311-319.
  8. Nicoll, J.A., Buckland, G.R., Harrison, C.H., Page, A., Harris, S., Love, S., Neal, J.W., Holmes, C. and Boche, D., 2019. Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer’s disease. Brain, 142(7), pp.2113-2126.
  9. Itzhaki, R.F., Lathe, R., Balin, B.J., Ball, M.J., Bearer, E.L., Braak, H., Bullido, M.J., Carter, C., Clerici, M., Cosby, S.L. and Del Tredici, K., 2016. Microbes and Alzheimer’s disease. Journal of Alzheimer’s disease : JAD, 51(4), p.979.
  10. Dominy, S.S., Lynch, C., Ermini, F., Benedyk, M., Marczyk, A., Konradi, A., Nguyen, M., Haditsch, U., Raha, D., Griffin, C. and Holsinger, L.J., 2019. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science advances, 5(1), p.eaau3333.
  11. Lilly’s Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer’s Disease. Lilly. Published Online: 3rd May, 2023. Accessed: 4th August, 2023.
  12. Kingsland. J. Do we finally know what causes Alzheimer’s? Freethink. Published Online: 27th May, 2023. Accessed: 4th August, 2023.
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