Alzheimer's disease clinical update

Show Notes

By Jacqueline Posada, MD, 4th-year resident in the department of psychiatry & behavioral sciences at George Washington University, Washington.

Guest

George T. Grossberg, MD: Samuel W. Fordyce Professor; director, geriatric psychiatry at Saint Louis University.

Dr. Grossberg spoke at the American Academy of Clinical Psychiatrists 2019 annual meeting in Chicago, sponsored by Global Academy for Medical Education (GAME). GAME and the MDedge Psychcast are owned by the same company.

New developments in Alzheimer's research

• The Systolic Blood Pressure Intervention Trial, also known as the SPRINT MIND Study, showed that tightly controlled systolic blood pressure (SBP) of 120 mm Hg, compared with an SBP of 140 mm Hg, resulted in a 20% reduced risk of developing mild cognitive impairment.
  • The SPRINT study was terminated early at the median follow-up of 3.26 years as its results showed that tightly controlled SBP significantly reduces the risk of stroke and heart disease.
  • The Alzheimer's Association has agreed to fund an additional 2 years of the SPRINT MIND Study to evaluate whether tightly controlled BP is effective in reducing the risk of Alzheimer's disease.
• In the brain, the glymphatic system was discovered in 2012 and is similar to the lymphatic system in its role as a drainage system for removing toxins.
  • Glial cells mediate toxin removal, and the glymphatic system removes toxins that eventually can cause cell death in the brain.
  • Because the glymphatic system is involved in removing the beta-amyloid plaques that contribute to cell death in AD, the glymphatic system is another area of investigation in the pathogenesis of AD.
• Novel treatment of moderate to advanced AD involves using plasma infusion.
  • Infusion of plasma products from healthy, nonimmunocompromised 18-year-old individuals into older patients with AD is a potential treatment for AD.
  • Precedent for this intervention comes from animal studies investigating parabiosis, a procedure in which two animals are connected so that they share each other's blood stream.
    • When such a circulatory exchange occurs between a younger mouse and an older mouse with AD, the older AD model mouse regains cognitive abilities and is able to complete mazes that it was unable to complete before.
• How can this model be adapted to humans? One possibility might involve infusing plasma from young healthy individuals into older adults with advanced AD.
• • A safety proof-of-concept study, published recently, found that plasma products can be safely infused. The next step is an efficacy study.
• A relationship has been found between AD and periodontal disease.
  • The primary bacteria related to periodontal disease, Porphyromonas gingivalis, is found in close proximity in the brain to the plaques and tangles of AD.
  • One theory posits that the presence of this bacteria is related to inflammation that may contribute to the causality of AD.
  • Could AD be treated with the antibiotics used to treat periodontal disease? The answers remain unclear.
• Aducanumab, a monoclonal antibody targeting the beta-amyloid plaques of AD, initially showed favorable changes in imaging studies of the brains of people with AD.
  • In March 2019, the study was halted because of futility.
  • An independent data-monitoring committee determined that the early results seen on imaging did not result in clinically meaningful changes, compared with placebo.
  • Some AD researchers consider this drug failure the "final nail in the coffin" of the amyloid hypothesis, and the pathogenesis of AD is most likely related to tau neurofibrillary tangles and other mediators, such as the immune system and inflammation.

References

SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 26 Nov 2015;373:2103-16.

Jessen NA et al. The glymphatic system: A beginner's guide. Neurochem Res. 2015 Dec;40(12):2583-99.

Dominy SS et al. Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science Advances. 23 Jan 2019;5(1): doi: 10.1126//sciadv.aau3333.

Conese M et al. The fountain of youth: A tale of parabiosis, stem cells, and rejuvenation.

Open Med (Wars). 2017;12:376-83.

Phase 3 study of aducanumab in early Alzheimer's disease. ClinicalTrials.gov Identifier: NCT02477800.

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