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Neuropsychiatric symptoms and apolipoprotein E
genotypes in neurocognitive disorders
Madia Lozupone, Ivana Leccisotti , Anita Mollica , Giuseppe Berardino , Maria Claudia Moretti , Mario Altamura , Antonello Bellomo, Antonio Daniele , Vittorio Dibello , Vincenzo Solfrizzi , Emanuela Resta, Francesco Panza
2026, 21 (4):
1528-1541.
doi: 10.4103/NRR.NRR-D-24-01274
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.
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