APOE ε4 allele (ApoE4) is the primary genetic risk factor for sporadic Alzheimer’s disease (AD), expressed in 40–65% of all AD patients. ApoE4 has been associated to many pathological processes possibly linked to cognitive impairment, such as amyloid-β (Aβ) and tau pathologies. However, the exact mechanism underlying ApoE4 impact on AD progression is unclear, while no effective therapies are available for this highly debilitating neurodegenerative disorder. This review describes the current knowledge of ApoE4 interaction with mitochondria, causing mitochondrial dysfunction and neurotoxicity, associated with increased mitochondrial Ca2+ and reactive oxygen species (ROS) levels, and it effects on mitochondrial dynamics, namely fusion and fission, and mitophagy. Moreover, ApoE4 translocates to the nucleus, regulating the expression of genes involved in aging, Aβ production, inflammation and apoptosis, potentially linked to AD pathogenesis. Thus, novel therapeutical targets can be envisaged to counteract the effects induced by ApoE4 in AD brain.

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Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies

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.

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

The complex genetic architecture of Alzheimer's disease: novel insights and future directions

Study in cells and mice suggests that the variant APOE4 affects the all-important insulation around nerve cells. Study in cells and mice suggests that the variant APOE4 affects the all-important insulation around nerve cells. 

https://www.nature.com/articles/d41586-022-03724-2.pdf

This is how an Alzheimer’s gene ravages the brain

Multiple genetic, metabolic, and environmental abnormalities are known to contribute to the pathogenesis of Alzheimer’s dementia (AD). If all of those abnormalities were addressed it should be possible to reverse the dementia; however, that would require a suffocating volume of drugs. Nevertheless, the problem may be simplified by using available data to address, instead, the brain cells whose functions become changed as a result of the abnormalities, because at least eleven drugs are available from which to formulate a rational therapy to correct those changes. The affected brain cell types are astrocytes, oligodendrocytes, neurons, endothelial cells/pericytes, and microglia. The available drugs include clemastine, dantrolene, erythropoietin, fingolimod, fluoxetine, lithium, memantine, minocycline, pioglitazone, piracetam, and riluzole. This article describes the ways by which the individual cell types contribute to AD’s pathogenesis and how each of the drugs corrects the changes in the cell types. All five of the cell types may be involved in the pathogenesis of AD; of the 11 drugs, fingolimod, fluoxetine, lithium, memantine, and pioglitazone, each address all five of the cell types. Fingolimod only slightly addresses endothelial cells, and memantine is the weakest of the remaining four. Low doses of either two or three drugs are suggested in order to minimize the likelihood of toxicity and drug–drug interactions (including drugs used for co-morbidities). Suggested two-drug combinations are pioglitazone plus lithium and pioglitazone plus fluoxetine; a three-drug combination could add either clemastine or memantine. Clinical trials are required to validate that the suggest combinations may reverse AD.

https://www.mdpi.com/2077-0383/12/5/2049/pdf?version=1678087489

Cure of Alzheimer’s Dementia Requires Addressing All of the Affected Brain Cell Types

APOE4 is the strongest genetic risk factor for Alzheimer’s disease1–3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer’s disease4–8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2–6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes—myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer’s disease. APOE4 is associated with widespread gene expression changes across all cell types of the human brain, altered cholesterol homeostasis and transport signalling pathways, and decreased myelination in the brain. 

Liwang Liu

Papers

APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes