On the Path to Preventing Alzheimer’s Disease




Antibodies in blood

Nearly 30 million people worldwide are affected by the Alzheimer’s disease (AD) and the most recent estimates indicate that this number will quadruple within the next 40 years. The concern increases as AD is the leading cause of dementia, and, so far, there is no effective treatment to slow the progression or delay the onset of this malady.

It is known that AD is a disease of protein aggregation mainly involving accumulation of beta-amyloid (Abeta) in the brain, a peptide of 36-43 amino acids, mostly in the form of tau fibrils and amyloid plaques.

Currently, 10 genes have been identified as influencers of the AD’s risk. The autosomal dominant mutations in the precursor protein (APP) and presenilin (PSEN) genes encoding amyloid precursor protein and the presenilin proteins are accepted as the causes of the hereditary forms of AD.

Most of these mutations increase total Abeta or Abeta42 production, leading to an increased amyloid plaque formation — a pathological hallmark of AD. Thus, Abeta lowering has become a vital therapeutic goal, with various paths within antibodies against Abeta (anti-Abeta) being tested. Over the past few years, the research has been mostly developed after the detection of disease, pursuing a means of lowering the production of the Abeta by inhibiting the enzymes responsible for the generation of this peptide, preventing the formation of Abeta aggregates, and increasing the rate of Abeta clearance from the brain. Presently, several different anti-Abeta therapies are in clinical trials worldwide. Although some modest reductions in plaque burden have been achieved, no obvious clinical benefit or arrest in the progression of cognitive decline was further confirmed.

Given this lack of success, the Alzheimer’s research community has moved toward a consensus that diagnosing and treating the disease before overt symptoms may be more advantageous to slow the disease’s pathogenic process. Among this novel approach, has been particularly suggested that pre-symptomatic individuals with deterministic mutations in APP, PSEN1, or PSEN2 could undergo treatment with an anti-Abeta agent before the expected age of onset of frank symptoms. Individuals with brain amyloid deposits (detected by positron emission tomography) exceeding normal thresholds, as well as low cerebrospinal fluid Abeta 42 levels, may respond to an anti-Abeta treatment.

The Dominantly Inherited Alzheimer Network (DIAN) investigators showed that the changes in cerebrospinal fluid levels of Abeta42 that accompany Abeta deposition are possible to be detected nearly 25 years before the symptom’s onset. This suggests that, in persons with mutations for dominantly inherited AD, the primary prevention with anti-Abeta agents might need to begin, at least, 25 years before the earliest signs.

Following this lead, a prevention trial with an anti-Abeta in around 300 presymptomatic individuals with presenilin mutations has been approved to be carried out by an academic consortium sponsored in part by the United States National Institutes of Health (NIH) and a biotechnology company. Still in the domain of the autosomal dominant AD, another secondary prevention trial has been proposed to the NIH by the Dominantly Inherited Alzheimer Network, the Alzheimer’s Association and some pharmaceutical companies.

Nevertheless, beyond these prevention trials in presymptomatic participants with rare, dominantly inherited AD, there is an intention to initiate similar studies in presymptomatic persons with common, late-onset (so-called sporadic) AD. Hereupon, another secondary prevention trial of an anti-Abeta in sporadic AD subjects (the A4 trial) will be carried out by a consortium led by the Alzheimer’s Disease Cooperative Study group funded by NIH. They recently announced the selection of Eli Lilly’s monoclonal antibody solanezumab as the first therapeutic drug to be evaluated.

Will this novel approach help overcoming this terrible disease? We shall see.

References

Bateman RJ, Aisen PS, De Strooper B, Fox NC, Lemere CA, Ringman JM, Salloway S, Sperling RA, Windisch M, & Xiong C (2011). Autosomal-dominant Alzheimer’s disease: a review and proposal for the prevention of Alzheimer’s disease. Alzheimer’s research & therapy, 3 (1) PMID: 21211070

Gandy S (2012). Lifelong management of amyloid-beta metabolism to prevent Alzheimer’s disease. The New England journal of medicine, 367 (9), 864-6 PMID: 22931321

Golde TE, Schneider LS, & Koo EH (2011). Anti-a? therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron, 69 (2), 203-13 PMID: 21262461

Holtzman DM, Morris JC, & Goate AM (2011). Alzheimer’s disease: the challenge of the second century. Science translational medicine, 3 (77) PMID: 21471435

Holtzman DM, Goate A, Kelly J, & Sperling R (2011). Mapping the road forward in Alzheimer’s disease. Science translational medicine, 3 (114) PMID: 22190237

NIH Fogarty International Center. First-ever Alzheimer’s prevention trial to take place in Colombia. 2012.

Selkoe DJ (2012). Preventing Alzheimer’s disease. Science (New York, N.Y.), 337 (6101), 1488-92 PMID: 22997326

Image via Sebastian Kaulitzki / Shutterstock.

  • Carla

    Early diagnosis and treatment at the soonest most possible point is the best we can hope for near term. Much like Multiple Sclerosis, the ability to slow disease progression is the first step.

  • This is an unbelievably sad, sad disease. I’ve seen first hand what it can do to an individual and hope we can find a cure, or at least really effective treatments soon. I’m not sure of the statistics, but it seems that it is becoming more and more common though, and I wonder if there aren’t some environmental factors that are contributing to the disease.

  • Ola

    Hello there! This post could not be written any better! Reading this post reminds me of my old room mate!
    He always kept talking about this. I will forward this write-up to him.
    Fairly certain he will have a good read. Thank you for sharing!

  • I am regular visitor, how are you everybody?
    This piece of writing posted at this website is genuinely nice.

  • This blog was… how do you say it? Relevant!! Finally I’ve found something that helped me. Cheers!

  • Alzheimer Clinic

    I think that earlier detection of Alzheimer’s Disease will be of great benefit to the aging population.Not only will early treatment help slow down the illness, but a lot can be learned about prevention.The elderly is a large group of people who have a lot to offer. I am very pleased to hear about any kind of research being done in this needed area.

Cristiano Batista, PhD

Cristiano Batista, PhD, is a Portuguese lecturer and researcher with more than 10 years of experience. He hold s a PhD in Public Health from the University of Porto, Portugal. Additionally, he is the author and reviewer of several peer-reviewed publications within health issues. He is an expert in the epidemiology field, particularly focused on its relationship with physical activity or inactivity. When he is not lecturing or researching, he enjoys writing about distinct health related findings. He has written both in English and Portuguese. He is now developing an investigation on the association between exercise and psychological and neurological disorders.
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