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ApolipoproteinE ε4 allelic variant, cognitive decline and psychosis in Alzheimer disease: a review of the literature and suggestions for upcoming studies

Apolipoprotein E (ApoE) e4 allele represents a well known vascular risk factor for developing Alzheimer disease (AD) and differences in ApoE genotypes may explain a part of the variability in AD phenotypes. In fact, ApoE e4 allele possession seems to be associated with a more precocious age of onset, greater episodic memory impairment, and psychotic symptoms. The first question we discuss regards the role of ApoE e4 on cognitive progression of AD. In fact, while a general agreement exists about the role played by ApoE e4 on the precocious onset of AD, cognitive decline has been differently associated with ApoE e4 allele possession in AD patients in a continuum of faster decline, no effect, and slower decline. An attemptable interpretation is that the biological processes leading to the onset of AD are different from those involved in determining its clinical course. The second question regards the possible relationship between the presence of the degenerative pathological hallmarks of the disease in specific cerebral areas and different cognitive or behavioural symptoms. In fact, there is evidence that degenerative pathology in hippocampal formation and frontal cortex reflects the progression of cognitive deficits in brain aging and AD and that hypometabolism in right frontal lobe and greater frontal neuropsychological deficits occur in AD patients with psychosis in comparison to those without. The third question regards, specifically, the relationship between ApoE e4 variant and behavioural symptoms. In fact, there is evidence supporting the link between being carriers of ApoE e4 allele and severity of delusions, mostly at the early stage of the illness. In an interpretative challenge, we suggest that the link between being carriers of ApoE e4 allele and suffering from delusions in AD may be explained by frontal lobe dysfunctions. Finally, we hypothesize that the most precocious onset of AD illness, described in carriers of ApoE e4 allelic variant, may also be related to the precocious onset of psychotic symptoms, which produces caregiver and patient distress and requires immediate assessment and treatment.