Historically, Alzheimer disease (AD) research and drug development has disproportionately emphasized amyloid pathology. This component of the neurodegenerative disease process, though crucial to AD pathogenesis, has fallen short as the primary target for disease-modifying interventions. After decades of failed anti-amyloid therapies, AD research efforts have been redirected toward alternative pathologies that emerge as the disease progresses.

In November 2019, the New York Academy of Sciences hosted experts in the field of AD research at a 1-day symposium to discuss advances in AD therapy research alternative to amyloid-targeting interventions.

Panelists described the progress made toward deciphering AD’s complex pathologies and proposed corresponding intervention strategies, including novel therapies currently under investigation.

As AD research evolves beyond targeting a single pathology, interventions should coordinate disease stage with pathology and the patient’s presenting characteristics.

This contemporary approach suggests that previous anti-amyloid therapy failures may be attributed to poor timing. Studies are now considering this approach for asymptomatic and early stage AD.

Progression of AD is associated with neuroinflammation caused by an innate immune response within the brain. TREM2, a receptor normally responsible for stimulating microglia within the CNS, becomes dysfunctional as AD progresses. Pharmacologically activating TREM2 is a method proposed to ameliorate neuroinflammation and control amyloid plaque deposition.

Another possible way to target neuroinflammation is through TNF inhibition. TNF inhibitors have been proven useful as a treatment option for patients with rheumatoid arthritis (RA), but an unanticipated benefit of TNF inhibitors may give them a place in AD therapy. Patients with RA receiving anti-TNF therapy less frequently develop AD compared to those with RA not using a TNF inhibitor and with the general public.

As AD pathologies become better understood and new therapies are introduced to the clinical stage, AD treatment must be directed against the appropriate pathology during the course of disease. This management model demands an assortment of distinct therapy options, including combination therapies, that may be adapted to address disease characteristics on a patient level.
Katherine E. MacDonald, is a 2021 PharmD candidate at the University of Connecticut in Storrs.


Cable J, Holtzman DM, Hyman BT, et al. Alternatives to amyloid for Alzheimer's disease therapies-a symposium report [published online ahead of print, 2020 May 29]. Ann N Y Acad Sci. 2020;10.1111/nyas.14371. doi:10.1111/nyas.14371