Abstract: Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E (APOE) genotypes and their corresponding protein (ApoE) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes (APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer’s disease, synucleinopathies such as Parkinson’s disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among ApoE, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of ApoE’s role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides ApoE-specific isoforms’ link to increased neuropsychiatric symptoms in Alzheimer’s disease (depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer’s disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson’s disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer’s disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due to its role in compromising endothelial integrity and promoting blood–brain barrier dysfunction.

Key words: Alzheimer’s disease, ApoE isoforms, apolipoprotein E gene, depression, Lewy body disease, mild cognitive impairment, neuroinflammation, neuropsychiatric symptoms, Parkinson’s disease, stroke, traumatic brain injury