Alzheimer’s Disease: Overview

Alzheimer’s disease is now the third leading cause of death in the United States [1-6], and the development of effective treatment and prevention is a major healthcare goal. However, clinical trials of drug candidates for Alzheimer’s disease treatment have been almost uniformly unsuccessful.

There may be several reasons for such repeated failure:

(1) given the long pre-symptomatic period, treatment is typically initiated late in the pathophysiological process; (2) what is referred to as Alzheimer’s disease is not a single disease, but rather exhibits several different subtypes [3,4]; (3) just as for other complex chronic illnesses such as cardiovascular disease, there may be many potential contributors to Alzheimer’s disease, such as inflammation, various chronic pathogens, trophic withdrawal, insulin resistance, vascular compromise, trauma, and exposure to specific toxins. Therefore, a monotherapeutic, monophasic approach is likely to be suboptimal, and personalized, multiphasic programs based on each individual’s genetics and biochemistry may be preferable.’

Bredesen, Dale E, Kenneth Sharlin, David Jenkins, Miki Okuno, Wes Youngberg, Sharon Hausman Cohen, Anne Stefani, et al. “Reversal of Cognitive Decline: 100 Patients.” Journal of Alzheimer’s Disease & Parkinsonism 08, no. 05 (2018). https://doi.org/10.4172/2161-0460.1000450.

Despite great scientific efforts to find treatments for Alzheimer disease (AD), only 5 medications are marketed, with limited beneficial effects on symptoms, on a limited proportion of patients, without modification of the disease course. The prevalence of AD doubles every 5 years, reaching the alarming rate of 50% in those aged 85 years and older. In the context of the demographic trends of modern society, where the elderly are the fastest growing segment of the population, identification of new therapeutic targets that may prevent, delay, or cure AD is critically needed.

Beeri, Michal Schnaider, and Joshua Sonnen. “Brain BDNF Expression as a Biomarker for Cognitive Reserve against Alzheimer Disease Progression.” Neurology 86, no. 8 (February 23, 2016): 702–3. https://doi.org/10.1212/WNL.0000000000002389.

Jack, Clifford R., David A. Bennett, Kaj Blennow, Maria C. Carrillo, Billy Dunn, Samantha Budd Haeberlein, David M. Holtzman, et al. “NIA-AA Research Framework: Toward a Biological Definition of Alzheimer’s Disease.” Alzheimer’s & Dementia 14, no. 4 (April 2018): 535–62. https://doi.org/10.1016/j.jalz.2018.02.018.

Early Lifestyle Treatment

Research into dementia prevention is of paramount importance if the dementia epidemic is to be halted. Observational studies have identified several potentially modifiable risk factors for dementia, including hypertension, dyslipidaemia and obesity at midlife, diabetes mellitus, smoking, physical inactivity, depression and low levels of education. Given the multifactorial etiology of dementia and late-onset Alzheimer disease, multidomain interventions that target several risk factors and mechanisms simultaneously might be necessary for an optimal preventive effect.

Kivipelto, Miia, Francesca Mangialasche, and Tiia Ngandu. “Lifestyle Interventions to Prevent Cognitive Impairment, Dementia and Alzheimer Disease.” Nature Reviews Neurology 14, no. 11 (November 2018): 653–66. https://doi.org/10.1038/s41582-018-0070-3.

A brain energy deficit may be an important pre-symptomatic feature of Alzheimer’s disease (AD). This deficit appears to be specific to glucose, precedes cognitive decline associated with AD, and becomes more severe as MCI progresses toward AD. Since glucose is the brain’s main fuel, gradual brain glucose exhaustion may be contributing significantly to the onset or progression of AD. Interventions that raise ketone availability to the brain improve cognitive outcomes in both MCI and AD as well as in acute experimental hypoglycemia.

Cunnane, Stephen C., Alexandre Courchesne-Loyer, Camille Vandenberghe, Valérie St-Pierre, Mélanie Fortier, Marie Hennebelle, Etienne Croteau, Christian Bocti, Tamas Fulop, and Christian-Alexandre Castellano. “Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease.” Frontiers in Molecular Neuroscience 9 (July 8, 2016). https://doi.org/10.3389/fnmol.2016.00053.

A targeted, personalized, precision medicine approach that addresses the multiple potential contributors to cognitive decline for each patient shows promise for the treatment of Alzheimer’s disease and its harbingers, MCI and SCI. The improvements documented in the 100 patients reported here provide support for the performance of a prospective, randomized, controlled clinical trial, especially given the current lack of effective treatment for this common and otherwise terminal illness.