Rationale for a Multi-Factorial Approach for the Reversal of Cognitive Decline in Alzheimer’s Disease and MCI: A Review

Abstract

Alzheimer’s disease (AD) is a multifactorial, progressive, neurodegenerative disease typically characterized by memory loss, personality changes, and a decline in overall cognitive function. Usually manifesting in individuals over the age of 60, this is the most prevalent type of dementia and remains the fifth leading cause of death among Americans aged 65 and older. While the development of effective treatment and prevention for AD is a major healthcare goal, unfortunately, therapeutic approaches to date have yet to find a treatment plan that produces long-term cognitive improvement. Drugs that may be able to slow down the progression rate of AD are being introduced to the market; however, there has been no previous solution for preventing or reversing the disease-associated cognitive decline. Recent studies have identified several factors that contribute to the progression and severity of the disease: diet, lifestyle, stress, sleep, nutrient deficiencies, mental health, socialization, and toxins. Thus, increasing evidence supports dietary and other lifestyle changes as potentially effective ways to prevent, slow, or reverse AD progression. Studies also have demonstrated that a personalized, multi-therapeutic approach is needed to improve metabolic abnormalities and AD-associated cognitive decline. These studies suggest the effects of abnormalities, such as insulin resistance, chronic inflammation, hypovitaminosis D, hormonal deficiencies, and hyperhomocysteinemia, in the AD process. Therefore a personalized, multi-therapeutic program based on an individual’s genetics and biochemistry may be preferable over a single-drug/mono-therapeutic approach. This article reviews these multi-therapeutic strategies that identify and attenuate all the risk factors specific to each affected individual. This article systematically reviews studies that have incorporated multiple strategies that target numerous factors simultaneously to reverse or treat cognitive decline. We included high-quality clinical trials and observational studies that focused on the cognitive effects of programs comprising lifestyle, physical, and mental activity, as well as nutritional aspects. Articles from PubMed Central, Scopus, and Google Scholar databases were collected, and abstracts were reviewed for relevance to the subject matter. Epidemiological, pathological, toxicological, genetic, and biochemical studies have all concluded that AD represents a complex network insufficiency. The research studies explored in this manuscript confirm the need for a multifactorial approach to target the various risk factors of AD. A single-drug approach may delay the progression of memory loss but, to date, has not prevented or reversed it. Diet, physical activity, sleep, stress, and environment all contribute to the progression of the disease, and, therefore, a multi-factorial optimization of network support and function offers a rational therapeutic strategy. Thus, a multi-therapeutic program that simultaneously targets multiple factors underlying the AD network may be more effective than a mono-therapeutic approach.

Estradiol improves behavior in FAD transgenic mice that express APOE3 but not APOE4 after ovariectomy

“…Cognitive decline is one of main symptoms of AD ( 49 ). In FAD transgenic mouse models, including EFAD mice, learning and memory deficits are often assessed using the Morris water maze test ( 31 , 32 , 50 , 51 ).…”

Aerobic exercise combined with chlorogenic acid exerts neuroprotective effects and reverses cognitive decline in Alzheimer’s disease model mice (APP/PS1) via the SIRT1/ /PGC-1α/PPARγ signaling pathway

“…In addition, according to the results of human studies, the intestinal absorption of chlorogenic acid is not excellent; only about 1/3 will be absorbed by the intestinal tract, so all things considered, the dose of 80 mg/kg/day of chlorogenic acid can better simulate the absorption effect of the human body and has the highest potency ratio ( Wang Z. et al, 2018 ; Caruso et al, 2022 ). While single polyphenols have been observed to be effective in animal experiments or cohort studies, these results cannot be replicated in human trials, so we should focus on a variety of foods with high polyphenol content when advancing our research to the clinical stage rather than discussing the effects of a single polyphenol alone, and it is true that we consume foods that are rich in polyphenol species when they are abundant, rather than a single one ( Rao et al, 2012 , 2023 ).…”

A cingulate-hippocampal circuit mediates early depressive-like behavior in the mouse model of Alzheimer disease

“…Alzheimer disease (AD) is an irreversible neurodegenerative disease characterized by cognitive dysfunction. 1 , 2 Before cognitive decline, 80% of AD patients exhibit neuropsychiatric symptoms (NPS), which tend to have a more rapid decline in cognition compared with those without NPS. 3 Among the NPS, depression, in particular, is a symptom with a high prevalence in AD and severely worsens the progress of AD.…”