The apolipoprotein E gene, attention, and brain function.

Abstract

The ɛ4 allele of the apolipoprotein E (ApoE) gene is associated with alterations in brain function and is a risk factor for Alzheimer's disease (AD). Changes in components of visuospatial attention with ApoE-ɛ4, aging, and AD are described. Healthy middle-aged adults without dementia who have the ApoE-ɛ4 gene show deficits in spatial attention and working memory that are qualitatively similar to those seen in clinically diagnosed AD patients. The findings support an association between ApoE polymorphism and specific components of visuospatial attention. Molecular mechanisms that may mediate the ApoE-attention link by modulating cholinergic neurotransmission to the posterior parietal cortex are discussed. Studies of attention and brain function in ApoE-ɛ4 carriers without dementia can advance knowledge of the genetics of visual attention, may enhance understanding of the preclinical phase of AD, and may lead to better methods for early AD detection.Apolipoprotein E (ApoE) is an amino acid glycoprotein that is important in lipid storage, transport, and metabolism (Mahley, 1988). Although synthesized mainly in the liver, ApoE is also found in the peripheral and central nervous systems, including the brain. ApoE has long been of interest in medicine, but its importance in neuroscience increased dramatically with the identification of the ɛ4 allele of the ApoE gene on chromosome 19 as a major risk factor for the development of late-onset Alzheimer's disease (AD) in older adults Strittmatter et al., 1993). This discovery led to a growing number of studies examining the role of the ApoE gene in normal brain function and cognition, as well as in disorders such as AD, brain injury, and stroke (Higgins, Large, Rupniak, & Barnes, 1997;Horsburgh, McCarron, White, & Nicol, 2000; J. D. Smith, 2000).Polymorphisms of the ApoE gene are associated with significant alterations in brain morphology (Plassman et al., 1997) and cognitive functioning, including attention (Greenwood, Sunderland, Friz, & Parasuraman, 2000) and memory (Bondi et al., 1995). Studies of ApoE may thus reveal information relevant to the genetics of attention and memory in normal individuals. At the same time, such studies may identify cognitive and neural changes that may be characteristic of preclinical stages of AD. In this article, we review the role of the ApoE gene in normal cognition and in the development of deficits indicative of early AD.Currently, no reliable methods exist for the early detection and treatment of AD. New techniques for preventing, slowing the progression of, and treating AD are being urgently sought. Such efforts would be aided considerably if AD could be detected prior to the clinical diagnosis of AD and before irreversible brain changes occur (Daffner & Scinto, 2000). Postmortem studies show that neuropathological changes occur decades before the onset of NIH Public Access Author ManuscriptNeuropsychology. Author manuscript; available in PMC 2006 January 25. Published in final edited form as:Neuropsychology. 2002 April ; ...

Apolipoprotein ɛ4 and neuropsychological performance in Alzheimer's disease and vascular dementia

“…As AD usually appears later in life and progresses slowly, the APOE 4 allele may exert its effect prior to the clinical diagnosis of AD. Studies using information-processing approaches to dissect cognition into component operations found impairments in attention and working memory in individual carriers of the APOE 4 gene [13,24]. These changes were found in healthy middleaged adults in their 50s who were clinically without dementia.…”

“…Several studies have shown a relatively selective effect of the 4 allele on episodic memory [32,35] and attention [24], especially in the early stages of the disease. A cognitive phenotype characterized by memory and verbal comprehension deficits has been claimed for APOE 4 homozygotes with AD as well as those with mild cognitive impairment [32].…”

Regional atrophy of transcallosal prefrontal connections in cognitively normal APOE ϵ4 carriers

“…Subsequently, evidence supporting the role of APOE ε4 allele as a risk factor for development of AD has accumulated (2). Furthermore, it has been reported that the ε4 allele contributes in age-related cognitive decline (3,4) and functional (5) and structural (6) brain changes of middle-age healthy ε4 carriers. In particular, functional studies using positron emission tomography (PET) have provided evidence of reduced glucose metabolism rate in prefrontal, posterior cingulated, and parietotemporal regions of young (7) and late middle aged (8) cognitively normal APOE ε4 carriers.…”

Asymmetry in Auditory and Spatial Attention Span in Normal Elderly Genetically At Risk for Alzheimer’s Disease

“…One area of cognition that has shown promise as a preclinical marker of AD in elderly individuals with the ApoE-e4 allele is attention and working memory. Specifically, some studies have found that nondemented elderly with the e4 genotype show subtle deficits on neuropsychological tests that have strong attentional demands, such as the Digit Span subtest (Albert, Moss, Tanzi, & Jones, 2001;Caselli et al, 1999;Caselli et al, 2001;Linn et al, 1995;Wilson et al, 2002); WMS-R Mental Control subtest (Tierney et al, 1996), Operation Span Test (Rosen, Bergeson, Putnam, Harwell, & Sunderland, 2002), Digit Symbol subtest (Masur, Sliwinski, Lipton, Blau, et al, 1994;Yaffe, Cauley, Sands, & Browner, 1997), attentional switching and disengagement (Greenwood, Sunderland, Friz, & Parasuraman, 2000;Parasuraman, Greenwood, & Sunderland, 2002), and supra-span ability and divided attention (Rosen et al, 2002). However, several other studies have failed to replicate findings of attentional deficits in nondemented e4 elderly groups (Baeckman, Small, & Fratiglioni, 2001;Elias et al, 2000;Flory, Manuck, Ferrell, Ryan, & Muldoon, 2000;Smith et al, 1998).…”