The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.

Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neuroflbrillary tangles of Alzheimer diwase. In

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Background-The ε4 allele of the apolipoprotein E gene (APOE) is the chief known genetic risk factor for Alzheimer's disease, the most common cause of dementia late in life. To determine the relation between brain responses to tasks requiring memory and the genetic risk of Alzheimer's disease, we performed APOE genotyping and functional magnetic resonance imaging (MRI) of the brain in older persons with intact cognition.

Apolipoprotein E (apoE), a plasma apolipoprotein that plays a central role in lipoprotein metabolism, is localized in the senile plaques, congophilic angiopathy, and neurofibrillary tangles of Alzheimer disease. Late-onset familial and sporadic Alzheimer disease patients have an increased frequency of one of the three common apoE alleles, e4, suggesting apoE4 is associated with increased susceptibility to disease. To follow up on this suggestion, we compared the binding of synthetic amyloid .8 (.3/A4) peptide to purified apoE4 and apoE3, the most common isoform. Both isoforms bound synthetic P/A4 peptide, the primary constituent of the plaque and angiopathy, forming a complex that resisted dissociation by boiling in SDS. Oxygen-mediated complex formation was implicated because binding was increased in oxygenated buffer, reduced in nitrogen-purged buffer, and prevented by reduction with dithiothreitol or 2-mercaptoethanol. Binding of fI/A4 peptide was saturable at 10-4 M peptide and required residues 12-28. Examination of apoE fragments revealed that residues 244-272 are critical for complex formation. Both oxidized apoE4 and apoE3 bound fi/A4 peptide; however, binding to apoE4 was observed in minutes, whereas binding to apoE3 required hours. In addition, apoE4 did not bind (8/A4 peptide at pH < 6.6, whereas apoE3 bound P/A4 peptide from pH 7.6 to 4.6. Together these results indicate differences in the two isoforms in complexing with the f/A4 peptide. Binding of P/A4 peptide by oxidized apoE may determine the sequestration or targeting of either apoE or ./A4 peptide, and isoformspecific differences in apoE binding or oxidation may be involved in the pathogenesis of the intra-and extracellular lesions of Alzheimer disease.

Amyloid -peptide (AP) deposition in senile plaques and cerebral vessels is a neuropathological feature of Alzheimer disease (AD). We examined the possibility that commonly observed variability in Af8 deposition in late-onset AD might be related to apolipoprotein E genotype (APOE gene; the two most common alleles are 3 and 4), since APOE4 is a susceptibility gene for late-onset AD and apolipoprotein E interacts strongly with A.8 in vitro. In an autopsy series of brains of late-onset AD patients, we found a strong association of APOE4 allele with increased vascular and plaque Af3 deposits. Late-onset AD patients with one or two APOE4 alleles have a distinct neuropathological phenotype compared with patients homozygous for APOE3.

Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with Alzheimer's dementia (AD) have abnormally low rates of cerebral glucose metabolism in posterior cingulate, parietal, temporal, and prefrontal cortex. We previously found that cognitively normal, late-middle-aged carriers of the apolipoprotein E 4 allele, a common susceptibility gene for late-onset Alzheimer's dementia, have abnormally low rates of glucose metabolism in the same brain regions as patients with probable AD. We now consider whether 4 carriers have these regional brain abnormalities as relatively young adults. Apolipoprotein E genotypes were established in normal volunteers 20 -39 years of age. Clinical ratings, neuropsychological tests, magnetic resonance imaging, and PET were performed in 12 4 heterozygotes, all with the 3͞ 4 genotype, and 15 noncarriers of the 4 allele, 12 of whom were individually matched for sex, age, and educational level. An automated algorithm was used to generate an aggregate surface-projection map that compared regional PET measurements in the two groups. The young adult 4 carriers and noncarriers did not differ significantly in their sex, age, educational level, clinical ratings, or neuropsychological test scores. Like previously studied patients with probable AD and late-middleaged 4 carriers, the young 4 carriers had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Carriers of a common Alzheimer's susceptibility gene have functional brain abnormalities in young adulthood, several decades before the possible onset of dementia.apolipoprotein E ͉ positron emission tomography ͉ glucose metabolism ͉ brain mapping ͉ surrogate markers A lzheimer's dementia (AD) afflicts Ϸ10% of those over the age of 65 and almost half of those over the age of 85 (1). To develop and test effective primary prevention therapies, it would be helpful to characterize brain changes associated with the susceptibility to AD as early as possible before the onset of cognitive impairment (2).Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with AD have abnormally low cerebral metabolic rates for glucose (CMRgl) in posterior cingulate, parietal, temporal, and prefrontal cortex and a progressive decline in these rates over time (3-8). We (2, 9, 10) and others (11, 12) have been using PET to detect and track these functional brain abnormalities before the onset of dementia in carriers of the apolipoprotein E (APOE) 4 allele, a common Alzheimer's susceptibility gene associated with up to half of cases of late-onset AD (13-15). Previously, we found that cognitively normal 50-to 65-year-old 4 carriers have abnormally low CMRgl in each of the same regions as patients with probable AD and abnormal rates of regional CMRgl decline over time (2, 9, 10). We now consider whether 4 carriers have these regional brain abnormalities as relatively young adults, several decades before the possible onset of dementia. Our a...

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