Alzheimer\'s disease (AD) is a neurodegenerative condition that displays a high prevalence in Lebanon causing a local burden in healthcare and socio-economic sectors. Unfortunately, the lack of prevalence studies and clinical trials in Lebanon minimizes the improvement of AD patient health status. In this review, we include over 155 articles to cover the different aspects of AD ranging from mechanisms to possible treatment and management tools. We highlight some important modifiable and non-modifiable risk factors of the disease including genetics, age, cardiovascular diseases, smoking, etc. Finally, we propose a hypothetical genetic synergy model between APOE4 and TREM2 genes which constitutes a potential early diagnostic tool that helps in reducing the risk of AD based on preventative measures decades before cognitive decline. The studies on AD in Lebanon and the Middle East are scarce. This review points out the importance of genetic mapping in the understanding of disease pathology which is crucial for the emergence of novel diagnostic tools. Hence, we establish a rigid basis for further research to identify the most influential genetic and environmental risk factors for the purpose of using more specific diagnostic tools and possibly adopting a local management protocol.

The clinical features and pathophysiology of neuropsychiatric symptoms (NPSs) in dementia have been extensively studied. However, the genetic architecture and underlying neurobiological mechanisms of NPSs at preclinical stages of cognitive decline and Alzheimer\'s disease (AD) remain largely unknown. Mild behavioral impairment (MBI) represents an at-risk state for incident cognitive impairment and is defined by the emergence of persistent NPSs among non-demented individuals in later life. These NPSs include affective dysregulation, decreased motivation, impulse dyscontrol, abnormal perception and thought content, and social inappropriateness. Accumulating evidence has recently begun to shed more light on the genetic background of MBI, focusing on its potential association with genetic factors related to AD. The Apolipoprotein E (APOE) genotype and the MS4A locus have been associated with affective dysregulation, ZCWPW1 with social inappropriateness and psychosis, BIN1 and EPHA1 with psychosis, and NME8 with apathy. The association between MBI and polygenic risk scores (PRSs) in terms of AD dementia has been also explored. Potential implicated mechanisms include neuroinflammation, synaptic dysfunction, epigenetic modifications, oxidative stress responses, proteosomal impairment, and abnormal immune responses. In this review, we summarize and critically discuss the available evidence on the genetic background of MBI with an emphasis on AD, aiming to gain insights into the potential underlying neurobiological mechanisms, which till now remain largely unexplored. In addition, we propose future areas of research in this emerging field, with the aim to better understand the molecular pathophysiology of MBI and its genetic links with cognitive decline.

Alzheimer\'s disease (AD) is a prevalent neurodegenerative disorder without a cure. Innovative disease models, such as induced neurons (iNs), could enhance our understanding of AD mechanisms and accelerate treatment development. However, a review of AD human iN studies is necessary to consolidate knowledge.
The objective of this review is to examine the current body of literature on AD human iN cells and provide an overview of the findings to date.
We searched two databases for relevant studies published between 2010 and 2023, identifying nine studies meeting our criteria.
Reviewed studies indicate the feasibility of generating iNs directly from AD patients\' fibroblasts using chemical induction or viral vectors. These cells express mature neuronal markers, including MAP-2, NeuN, synapsin, and tau. However, most studies were limited in sample size and primarily focused on autosomal dominant familial AD (FAD) rather than the more common sporadic forms of AD. Several studies indicated that iNs derived from FAD fibroblasts exhibited abnormal amyloid-β metabolism, a characteristic feature of AD in humans. Additionally, elevated levels of hyperphosphorylated tau, another hallmark of AD, were reported in some studies.
Although only a limited number of small-scale studies are currently available, AD patient-derived iNs hold promise as a valuable model for investigating AD pathogenesis. Future research should aim to conduct larger studies, particularly focusing on sporadic AD cases, to enhance the clinical relevance of the findings for the broader AD patient population. Moreover, these cells can be utilized in screening potential novel treatments for AD.

UNASSIGNED: Alzheimer\'s disease (AD) has several risk factors. APOE4 is the main one, and it has been suggested that there may be a synergy between it and BCHE-K as a risk factor.
UNASSIGNED: To investigate the association between APOE4 and BCHE-K as a risk factor for AD.
UNASSIGNED: We searched PubMed, Web of Science, Embase, and Scopus on August 8, 2021 for studies that analyzed the association of APOE4 and BCHE-K with AD. The random effect model was performed in meta-analysis according to age group. A chi-square was performed with the meta-analysis data to verify if the effect found is not associated only with the E4 allele.
UNASSIGNED: Twenty-one studies with 6,853 subjects (3,528 AD and 3,325 Controls) were included in the meta-analysis. The quality of the evidence is moderate. There is a positive E4-K association for subjects with AD as shown by the odds ratio of 3.43. The chi-square meta test, which measures the probability that the E4-K association is due to chance, has an odds ratio of 6.155, indicating that the E4-K association is not a random event. The odds ratio of an E4-K association in subjects with AD increases to OR 4.46 for the 65- to 75-year-old group and OR 4.15 for subjects older than 75 years. The probability that the E4-K association is due to chance is ruled out by chi-square meta test values of OR 8.638 and OR 9.558.
UNASSIGNED: The synergy between APOE4 and BCHE-K is a risk factor for late-onset AD.

Many lines of evidence suggest that mitochondria have a central role in aging-related neurodegenerative diseases, such as Alzheimer\'s disease (AD). Mitochondrial dysfunction, cerebral energy dysmetabolism and oxidative damage increase with age, and are early event in AD pathophysiology and may precede amyloid beta (Aβ) plaques. In vivo probes of mitochondrial function and energy metabolism are therefore crucial to characterize the bioenergetic abnormalities underlying AD risk, and their relationship to pathophysiology and cognition. A majority of the research conducted in humans have used 18F-fluoro-deoxygluose (FDG) PET to image cerebral glucose metabolism (CMRglc), but key information regarding oxidative phosphorylation (OXPHOS), the process which generates 90% of the energy for the brain, cannot be assessed with this method. Thus, there is a crucial need for imaging tools to measure mitochondrial processes and OXPHOS in vivo in the human brain. 31Phosphorus-magnetic resonance spectroscopy (31P-MRS) is a non-invasive method which allows for the measurement of OXPHOS-related high-energy phosphates (HEP), including phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi), in addition to potential of hydrogen (pH), as well as components of phospholipid metabolism, such as phosphomonoesters (PMEs) and phosphodiesters (PDEs). Herein, we provide a systematic review of the existing literature utilizing the 31P-MRS methodology during the normal aging process and in patients with mild cognitive impairment (MCI) and AD, with an additional focus on individuals at risk for AD. We discuss the strengths and limitations of the technique, in addition to considering future directions toward validating the use of 31P-MRS measures as biomarkers for the early detection of AD.

We postulate that myelin injury contributes to cholesterol release from myelin and cholesterol dysmetabolism which contributes to Abeta dysmetabolism, and combined with genetic and AD risk factors, leads to increased Abeta and amyloid plaques. Increased Abeta damages myelin to form a vicious injury cycle. Thus, white matter injury, cholesterol dysmetabolism and Abeta dysmetabolism interact to produce or worsen AD neuropathology. The amyloid cascade is the leading hypothesis for the cause of Alzheimer\'s disease (AD). The failure of clinical trials based on this hypothesis has raised other possibilities. Even with a possible new success (Lecanemab), it is not clear whether this is a cause or a result of the disease. With the discovery in 1993 that the apolipoprotein E type 4 allele (APOE4) was the major risk factor for sporadic, late-onset AD (LOAD), there has been increasing interest in cholesterol in AD since APOE is a major cholesterol transporter. Recent studies show that cholesterol metabolism is intricately involved with Abeta (Aβ)/amyloid transport and metabolism, with cholesterol down-regulating the Aβ LRP1 transporter and upregulating the Aβ RAGE receptor, both of which would increase brain Aβ. Moreover, manipulating cholesterol transport and metabolism in rodent AD models can ameliorate pathology and cognitive deficits, or worsen them depending upon the manipulation. Though white matter (WM) injury has been noted in AD brain since Alzheimer\'s initial observations, recent studies have shown abnormal white matter in every AD brain. Moreover, there is age-related WM injury in normal individuals that occurs earlier and is worse with the APOE4 genotype. Moreover, WM injury precedes formation of plaques and tangles in human Familial Alzheimer\'s disease (FAD) and precedes plaque formation in rodent AD models. Restoring WM in rodent AD models improves cognition without affecting AD pathology. Thus, we postulate that the amyloid cascade, cholesterol dysmetabolism and white matter injury interact to produce and/or worsen AD pathology. We further postulate that the primary initiating event could be related to any of the three, with age a major factor for WM injury, diet and APOE4 and other genes a factor for cholesterol dysmetabolism, and FAD and other genes for Abeta dysmetabolism.

Alzheimer\'s disease (AD) is a degenerative disease of the central nervous system with insidious onset and chronic progression. The pathogenesis of AD is complex, which is currently considered to be the result of the interaction between genetic and environmental factors. The APOE ɛ4 is the strongest genetic risk factor for sporadic AD and a risk factor for progression from mild cognitive impairment (MCI) to AD. So far, no effective drugs have been found for the progression of MCI. However, the effects of nonpharmacological interventions such as nutrition, cognitive, and physical exercises on early AD have received increasing attention. We followed up cognitive assessment scales, Aβ-PET and MRI examination of a patient with MCI for 4 years, who carried APOE ɛ4 homozygous with a clear family history. After 4 years of multi-domain lifestyle interventions including nutrition, socialization, and physical exercises, the patient\'s cognitive function, especially memory function, improved significantly. Intracerebral amyloid deposition was decreased, and hippocampal atrophy improved. Based on this case, this study reviewed and discussed the interaction of APOE ɛ4 with the environment in AD research in recent years, as well as the impact and mechanisms of non-pharmaceutical multi-domain lifestyle interventions on MCI or early AD. Both the literature review and this case showed that multi-domain lifestyle interventions may reduce the risk of disease progression by reducing Aβ deposition in the brain and other different pathologic mechanisms, which offers promise in brain amyloid-positivity or APOE ɛ4 carriers.

Parkinson\'s disease (PD)-a neurodegenerative disorder (NDD) characterized by progressive destruction of dopaminergic neurons within the substantia nigra of the brain-is associated with the formation of Lewy bodies containing mainly α-synuclein. HDL-related proteins such as paraoxonase 1 and apolipoproteins A1, E, D, and J are implicated in NDDs, including PD. Apolipoprotein J (ApoJ, clusterin) is a ubiquitous, multifunctional protein; besides its engagement in lipid transport, it modulates a variety of other processes such as immune system functionality and cellular death signaling. Furthermore, being an extracellular chaperone, ApoJ interacts with proteins associated with NDD pathogenesis (amyloid β, tau, and α-synuclein), thus modulating their properties. In this review, the association of clusterin with PD is delineated, with respect to its putative involvement in the pathological mechanism and its application in PD prognosis/diagnosis.

Introduction: The apolipoprotein E ɛ4-allele (APOE-ɛ4) increases the risk not only for Alzheimer\'s disease (AD) but also for Parkinson\'s disease dementia and dementia with Lewy bodies (collectively, Lewy body dementia [LBD]). Hippocampal volume is an important neuroimaging biomarker for AD and LBD, although its association with APOE-ɛ4 is inconsistently reported. We investigated the association of APOE-ε4 with hippocampal atrophy quantified using magnetic resonance imaging in AD and LBD.Areas covered: Databases were searched for volumetric and voxel-based morphometric studies published up until December 31st, 2020. Thirty-nine studies (25 cross-sectional, 14 longitudinal) were included. We observed that (1) APOE-ε4 was associated with greater rate of hippocampal atrophy in longitudinal studies in AD and in those who progressed from mild cognitive impairment to AD, (2) association of APOE-ε4 with hippocampal atrophy in cross-sectional studies was inconsistent, (3) APOE-ɛ4 may influence hippocampal atrophy in dementia with Lewy bodies, although longitudinal investigations are needed. We comprehensively discussed methodological aspects, APOE-based therapeutic approaches, and the association of APOE-ε4 with hippocampal sub-regions and cognitive performance.Expert opinion: The role of APOE-ɛ4 in modulating hippocampal phenotypes may be further clarified through more homogenous, well-powered, and pathology-proven, longitudinal investigations. Understanding the underlying mechanisms will facilitate the development of prevention strategies targeting APOE-ɛ4.

Possession of the ε4 allele of apolipoprotein E (APOE) is the primary genetic risk factor for the sporadic form of Alzheimer\'s disease (AD). While researchers have extensively characterized the impact that APOE ε4 (APOE4) has on the susceptibility of AD, far fewer studies have investigated the phenotypic differences of patients with AD who are APOE4 carriers vs. those who are non-carriers. In order to understand these differences, we performed a qualitative systematic literature review of the reported cognitive and pathological differences between APOE4-positive (APOE4+) vs. APOE4-negative (APOE4-) AD patients. The studies performed on this topic to date suggest that APOE4 is not only an important mediator of AD susceptibility, but that it likely confers specific phenotypic heterogeneity in AD presentation, as well. Specifically, APOE4+ AD patients appear to possess more tau accumulation and brain atrophy in the medial temporal lobe, resulting in greater memory impairment, compared to APOE4- AD patients. On the other hand, APOE4- AD patients appear to possess more tau accumulation and brain atrophy in the frontal and parietal lobes, resulting in greater impairment in executive function, visuospatial abilities, and language, compared to APOE4+ AD patients. Although more work is necessary to validate and interrogate these findings, these initial observations of pathological and cognitive heterogeneity between APOE4+ vs. APOE4- AD patients suggest that there is a fundamental divergence in AD manifestation related to APOE genotype, which may have important implications in regard to the therapeutic treatment of these two patient populations.