The currently dominant hypothesis for the pathogenesis of Alzheimer disease (AD) is that either amyloid itself or oligomers derived from the amyloid precursor peptide (APP) are causal. Strong data support their roles. Nevertheless, there are reasons to doubt their unique importance. Not only are there exceptions to their having sole participation, but there is also much evidence for contributions to pathogenesis by several subcellular reactions in neurons, astrocytes and endothelial cells. Moreover, for almost no disease is there only one pathogenetic factor; it is usually a + b + c .etc. The model for AD proposed in this lecture is that both amyloid and APP oligomers are important yet alone, without co-factors, are inadequate to reach the threshold for causing dementia; that threshold is reached with the addition of one or more subcellular reactions. Those subcellular reactions involve tau protein, mitochondria, the unfolded protein response, the ubiquitin/proteasome system, the Wnt/catenin and notch signaling systems, and calcium homeostasis. Thus, the pathogenesis of AD is multifactorial. Eight available drugs might benefit the involved subcellular systems; they should be used in combinations of three or four of them because in any particular case of AD it is not possible to know which system or systems are at fault. Finally, no scientific hypothesis has worth unless testable; the structure of a clinical trial to test the proposed model will be described.
Prof. W Jeffrey Fessel born in London 1932. University College HospitalMedical School, London. Fellowship in Rheumatology, University of California, San Francisco. Chief, Dept of Medicine, Kaiser Permanente Medical Care Program, 1979-1989. Director, Clinical Trials Unit, Kaiser Permanente Medical Care Program, 1991-present. Professor of Clinical Medicine, University of California, San Francisco, 1983-present. Listed in "Whos Who in America", 2005-present (Marquis).Listed in "Whos Who in the World", 2005-present (Marquis). Research in schizophrenia, Dept Psychiatry, University of California 1959-65. Since 1991, conducted clinical trials in gout, osteoarthritis, rheumatoid arthritis, HIV/AIDS, hepatitis C, hepatitis B. >140 publications concerning schizophrenia, autoimmune diseases, HIV/AIDS, hepatitis C, hepatitis B, and Alzheimers disease. Fessel WJ, Concordance of several subcellular interactions initiates Alzheimers Dementia: their reversal requires combination treatment,Amer J Alzheimer's Dis Other Dementias, 2017;32:166-181.Fessel J, Amyloid is essential but insufficient for Alzheimer causation: addition of subcellular cofactors is required for dementia, Internat J Geriatr Psychiatry, 2018;33:e14-e21.Fessel WJ, Alzheimer's disease may require combination treatment, Neurobiology of Aging, 2017;Nov 8.Fessel WJ, Imbalance between multiple factors, none having sole importance, instigates Alzheimers disease. (Presented at the Alzheimer Association International Conference, Toronto, Canada, July 24-29, 2016).Fessel WJ, Alzheimers Disease. Combination treatment for the mitochondriopathy. (Presented at the Alzheimer Association International Conference, Toronto, Canada, July 24-29, 2016).