Review of Advanced Drug Trials Focusing on the Reduction of Brain Beta-Amyloid to Prevent and Treat Dementia

Abstract

Alzheimer disease (AD) is the most common neurodegenerative disease and typically affects patients older than age 65. Around this age, the number of neurons begins to gradually decrease in healthy brains, but brains of patients with AD show a marked increase in neuron death, often resulting in a significant loss of cognitive abilities. Cognitive skills affected include information retention, recognition capabilities, and language skills. At present, AD can be definitively diagnosed only through postmortem brain biopsies via the detection of extracellular amyloid beta (Aβ) plaques and intracellular hyperphosphorylated tau neurofibrillary tangles. Because the levels of both Aβ plaques and tau tangles are increased, these 2 proteins are thought to be related to disease progression. Although relatively little is known about the cause of AD and its exact pathobiological development, many forms of treatment have been investigated to determine an effective method for managing AD symptoms by targeting Aβ. These treatments include but are not limited to using small molecules to alter the interactions of Aβ monomers, reducing hyperactivation of neuronal circuits altering Aβ’s molecular pathway of synthesis, improving degradation of Aβ, employing passive immunity approaches, and stimulating patients’ active immunity to target Aβ. This review summarizes the current therapeutic interventions in Phase II/III of clinical development or higher that are capable of reducing abnormal brain Aβ levels to determine which treatments show the greatest likelihood of clinical efficacy. We conclude that, in the near future, the most promising therapeutic interventions for brain Aβ pathology will likely be passive immunotherapies, with aducanumab and donanemab leading the way, and that these drugs may be combined with antidepressants and acetylcholine esterase inhibitors, which can modulate Aβ synthesis.

Association of sugar intake from different sources with incident dementia in the prospective cohort of UK Biobank participants

“…Even though age is one of the most important risks factors for dementia [ 1 ], there is evidence that being overweight [ 2 ] and obese [ 3 ] in midlife is similarly associated with a higher disease risk. Despite a large amount of research that has been conducted over the past decades, no effective pharmacological treatment for the main dementia types has been developed to date [ 4 ]. Therefore, dietary changes and lifestyle interventions remain important approaches, not only to delay the progress of a decline in cognitive function [ 5 ], but also to combat overweight and obesity [ 6 ].…”

Efficacy assessment of an active tau immunotherapy in Alzheimer’s disease patients with amyloid and tau pathology: a post hoc analysis of the “ADAMANT” randomised, placebo-controlled, double-blind, multi-centre, phase 2 clinical trial

“…AADvac1 did not show a statistically significant slowing down of brain atrophy as assessed via MRI volumetry–most importantly though, the vaccine did not contribute to a decrease in brain volume, which has been observed in several anti-amyloid therapies. 14 , 15 …”

Alzheimer’s Disease—Biochemical and Psychological Background for Diagnosis and Treatment

“…Another psychological aspect is the instigation of various therapies offering improvements to the patient’s quality of life. Researchers have noted that the pathological process of AD offers a significant amount of freedom and variety in terms of intervention options, with emphasis on the contribution of non-pharmacological methods of treatment [ 33 ]. This results in the need to deal with behavioral problems and for psychoanalytic understanding of personality changes occurring in patients [ 34 , 35 ].…”