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Preclinical Evidence of Alzheimer's Disease in Persons Homozygous for the ε4 Allele for Apolipoprotein E
Open accessAbstract
BACKGROUND: Variants of the apolipoprotein E allele appear to account for most cases of late-onset Alzheimer's disease, and persons with two copies of the epsilon 4 allele appear to have an especially high risk of dementia. Positron-emission tomography (PET) has identified specific regions of the brain in which the rate of glucose metabolism declines progressively in patients with probable Alzheimer's disease. We used PET to investigate whether these same regions of the brain are affected in subjects homozygous for the epsilon 4 allele before the onset of cognitive impairment. METHODS: Apolipoprotein E genotypes were established in 235 volunteers 50 to 65 years of age who reported a family history of probable Alzheimer's disease. Neurologic and psychiatric evaluations, a battery of neuropsychological tests, magnetic resonance imaging, and PET were performed in 11 epsilon 4 homozygotes and 22 controls without the epsilon 4 allele who were matched for sex, age, and level of education. An automated method was used to generate an aggregate surface-projection map that compared regional rates of glucose metabolism in the two groups. RESULTS: The epsilon 4 homozygotes were cognitively normal. They had significantly reduced rates of glucose metabolism in the same posterior cingulate, parietal, temporal, and prefrontal regions as in previously studied patients with probable Alzheimer's disease. They also had reduced rates of glucose metabolism in additional prefrontal regions, which may be preferentially affected during normal aging. CONCLUSIONS: In late middle age, cognitively normal subjects who are homozygous for the epsilon 4 allele for apolipoprotein E have reduced glucose metabolism in the same regions of the brain as in patients with probable Alzheimer's disease. These findings provide preclinical evidence that the presence of the epsilon 4 allele is a risk factor for Alzheimer's disease. PET may offer a relatively rapid way of testing future treatments to prevent Alzheimer's disease.
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TL;DR
In cognitively normal late-middle-aged ε4 homozygotes with a family history of probable Alzheimer's disease, PET showed reduced glucose metabolism in the same posterior cingulate, parietal, temporal, and prefrontal regions as in probable Alzheimer's disease, plus additional prefrontal reductions. These findings provide preclinical evidence that the ε4 allele is a risk factor for Alzheimer's disease and suggest PET may help test prevention therapies.
Key findings
- Among 11 ε4 homozygotes and 22 non-ε4 controls matched for sex, age, and education, neuropsychological tests showed no significant differences in verbal memory, visual memory, naming, or visuospatial/constructional skills; MMSE scores were 29.4±0.8 vs. 29.8±0.6.
- PET showed no significant whole-brain glucose metabolism difference (5.1±1.0 vs. 5.2±0.8 mg/min/100 g, P=0.62) or pontine difference (5.0±1.0 vs. 5.0±0.7, P=0.90), but ε4 homozygotes had significant bilateral reductions in the same posterior cingulate, parietal, temporal, and prefrontal regions as probable Alzheimer's disease; the text reports a maximal posterior cingulate z score of 8.26 (P<0.001), while Table 4 lists z=6.58 for posterior cingulate.
- ε4 homozygotes also had significant reductions in additional prefrontal regions (maximal z=4.76, P<0.001 without correction for multiple comparisons), which the authors suggest may reflect accelerated aging.
- One ε4 homozygote had neuropsychological evidence of mild cognitive impairment and the greatest metabolic reductions; excluding his data only minimally affected group means, and reductions remained.
Methods
- Apolipoprotein E genotypes were established in 235 volunteers aged 50 to 65 who reported a family history of probable Alzheimer's disease in at least one first-degree relative; 12 ε4 homozygotes were identified, and 11 underwent imaging.
- For each ε4 homozygote, 2 controls without the ε4 allele (6 ε2/ε3 and 16 ε3/ε3) were matched for sex, age within 3 years, and education within 2 years; subjects had neurologic and psychiatric evaluations, a neuropsychological battery, MRI, and FDG PET.
- An automated three-dimensional stereotactic surface-projection algorithm compared regional glucose metabolism in ε4 homozygotes vs. controls and superimposed results on a prior probable-Alzheimer's disease map (37 patients vs. 22 normal controls); a critical z score of 4.32 identified voxels significant after correction for 278 resolution elements (P<0.05), with post hoc unpaired two-tailed t-tests.
Limitations
- The paper states the findings should be considered preliminary; no attempt was made to address the combined effect of atrophy and partial-volume averaging on whole-brain or regional measurements.
- The paper states that apolipoprotein E genotypes cannot predict whether or when Alzheimer's disease will develop, and that prospective longitudinal studies have not yet specified genotype-specific risks, onset ages, or attributable fractions; genotype-specific preventive therapies have not been identified.
- Evident from the text: the imaging sample was small (11 ε4 homozygotes vs. 22 controls), the design was cross-sectional without longitudinal follow-up, and one ε4 homozygote had mild cognitive impairment and was excluded in a sensitivity analysis.
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29 Not checked yet · 16 Own result · 10 Own interpretation · 3 Own method · 1 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“They had significantly reduced rates of glucose metabolism in the same posterior cingulate, parietal, temporal, and prefrontal regions as in previously studied patients with probable Alzheimer's disease.”
- Also stated in: § PET · plain
“The group of e 4 homozygotes had significant bilateral reductions in glucose metabolism in the same posterior cingulate, parietal, temporal, and prefrontal regions as the group with probable Alzheimer's disease (Fig. 2 and Table 4)”
- Also stated in: § DISCUSSION · plain
“we found that the presymptomatic e4 homozygotes had significantly reduced rates of glucose metabolism in the same parietal, temporal, prefrontal, and posterior cingulate regions as patients with probable Alzheimer's disease.”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > Abstract
plaincorrelationaln = 22- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Cognitively normal e4 homozygotes in late middle age are in a presymptomatic stage of Alzheimer's disease.
- Also stated in: § PET · plain
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In the paper
“They also had reduced rates of glucose metabolism in additional prefrontal regions”
- Also stated in: § PET · plain
“The e4 homozygotes also had significant reductions in glucose metabolism in additional prefrontal regions (Fig. 2) (maximal z score, 4.76; PϽ0.001 without correction for multiple comparisons)”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § PET · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The e 4 homozygotes were cognitively normal.”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > Abstract
plainn = 22- Asserted: passes — The authors put it forward as true.
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In the paper
“The exclusion of his data in a subsequent analysis only minimally affected the mean scores in the group of e 4 homozygotes.”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > Neuropsychological Tests
plainSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“the maximal reduction in glucose metabolism in the posterior cingulate cortex was significantly greater than those in the other regions (z score, 8.26; PϽ0.001).”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > PET
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“There were no significant differences between the e 4 homozygotes and control subjects in the rates of wholebrain glucose metabolism (mean [ Ϯ SD], 5.1 Ϯ 1.0 vs. 5.2 Ϯ 0.8 mg per minute per 100 g; P ϭ 0.62 by twotailed, unpaired t-test)”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > PET
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The percentage of e 4 homozygotes in this sample was higher than that in the general population (5.1 percent vs. 2 to 3 percent), 8”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > R ESULTS
What the sources say
- Not checked yetcites [8] source
plaincorrelationaln = 235- Asserted: passes — The authors put it forward as true.
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In the paper
“When his data were excluded in a subsequent analysis, glucose metabolism remained reduced”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > PET
plainSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“As compared with the control subjects, the e 4 homozygotes had slightly lower scores on the Mental Arithmetic test, Similarities test, and Freedom from Distractibility factor (measures of concentration and abstract reasoning)”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > Neuropsychological Tests
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The e4 homozygote with neuropsychological evidence of mild cognitive impairment had the greatest reductions in glucose metabolism in each of the locations listed in Table 4.”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > PET
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 8
- Probably not a substantial claim. 15
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no significant differences between groups in verbal memory (as measured by the Auditory Verbal Learning Test), visual memory (as measured by the recall portion of the Complex Figure Test), naming (as assessed by the Boston Naming Test), or visuospatial and constructional skills (as assessed by the copy portion of the Complex Figure Test and the Block Design subtest of the Wechsler Adult”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > Neuropsychological Tests
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“There were no significant differences in language skills or psychomotor speed (as measured by the Controlled Oral Word Association Test), estimates of premorbid intellectual function (as assessed by the Information subtest of the Wechsler Adult Intelligence Scale-Revised), or directed attention span (as assessed by the Digit Span subtest).”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > Neuropsychological Tests
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The metabolic reductions were greatest in an e4 homozygote with neuropsychological evidence of mild cognitive impairment, but were also apparent in the remaining, cognitively intact e4 homozygotes.”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“If, as case-control studies suggest, persons with two copies of the e 4 allele (the e 4/ e 4 genotype) have an especially high risk of Alzheimer's disease”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > V ARIANTS of the apolipoprotein E gene appear to
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
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In the paper
“abnormally low prefrontal and whole-brain levels in more severely affected patients”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > V ARIANTS of the apolipoprotein E gene appear to
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“In contrast, the e 4 allele appears to be harmful, increasing the risk of Alzheimer's disease and hastening the onset of dementia.2,5”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > V ARIANTS of the apolipoprotein E gene appear to
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“When used to measure cerebral glucose metabolism, PET reveals characteristic abnormalities in patients with probable and definite Alzheimer's disease, including abnormally low parietal, temporal, and posterior cingulate levels”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > V ARIANTS of the apolipoprotein E gene appear to
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
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In the paper
“and a progressive decline in these levels over time.”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > V ARIANTS of the apolipoprotein E gene appear to
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In a recent study, subjects with the apolipoprotein E e 3/ e 4 genotype, age-associated memory impairment, and a family history of Alzheimer's disease had abnormally low and asymmetric rates of glucose metabolism in a preselected parietal region before the onset of dementia.15”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > V ARIANTS of the apolipoprotein E gene appear to
What the sources say
- Not checked yetcites [15] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“which PET, [29][30][31]32 and neuropathological studies 33 suggest are preferentially affected during normal aging.”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > PET
What the sources say
- Not checked yetcites [29] source
- Not checked yetcites [30] Salmon E, 1991, Acta Neurol Belg
- Not checked yetcites [31] Loessner A, 1995, J Nucl Med
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Measurements in each voxel were normalized to that in the pons, which appears to be the region least affected in patients with Alzheimer's disease.27”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > Image Analysis
What the sources say
- Not checked yetcites [27] source
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“which is affected in Alzheimer's disease, 34,35”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no significant differences in age, sex, handedness, years of education, age of the affected family member at the onset of dementia, scores on the Hamilton Depression Rating Scale, or scores on the Mini-Mental State Examination (range, 28 to 30 in both groups).”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > R ESULTS
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“A critical z score of 4.32 was used to identify voxels in which the homozygous group had significant reductions in glucose metabolism in the same regions as the patients with probable Alzheimer's disease (P Ͻ 0.05 after correction for the number of comparisons [i.e., the 278 resolution elements] in the searched volume 28 ) as well as in additional regions.”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > Image Analysis
What the sources say
- Not checked yetcites [28] source
plain- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Investigators who were unaware of the subjects' apolipoprotein E genotypes obtained data from medical and family histories, a neurologic examination, a structured psychiatric interview, 20 the Folstein modified Mini-Mental State Examination (MMSE), 21 the Hamilton Depression Rating Scale, 22 a battery of neuropsychological tests, and brain-imaging studies.”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > Subjects
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Although the reductions in regional glucose metabolism could reflect decreased activity of terminal neuronal fields, 36 decreased density of terminal neuronal fields, atrophy, or some combination of these factors”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > DISCUSSION
What the sources say
- Not checked yetcites [36] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For each of the 11 e 4 homozygotes who agreed to participate in the imaging studies, 2 control subjects without this allele (6 with the e 2/ e 3 genotype and 16 with the e 3/ e 3 genotype) were matched for sex, age (within three years), and level of education (within two years).”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > Subjects
plainn = 2- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PET may offer a relatively rapid way of testing future treatments to prevent Alzheimer's disease.”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“an increased risk of coronary artery disease and fatal myocardial infarctions, [41][42][43]”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > DISCUSSION
What the sources say
- Not checked yetcites [41][42][43]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“a decreased risk of coronary artery disease (unless it is associated with type III hyperlipoproteinemia), 42,43”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“the e2 allele has been associated with a decreased risk of Alzheimer's disease, 4”
§ PRECLINICAL EVIDENCE OF ALZHEIMER'S DISEASE IN PERSONS HOMOZYGOUS FOR THE e 4 ALLELE FOR APOLIPOPROTEIN E > DISCUSSION
What the sources say
- Not checked yetcites [4] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Cognitively normal e4 homozygotes in late middle age are in a presymptomatic stage of Alzheimer's disease.
“we found that the presymptomatic e4 homozygotes had significantly reduced rates of glucose metabolism in the same parietal, temporal, prefrontal, and posterior cingulate regions as patients with probable Alzheimer's disease.”
The paper relies on this without support.
Prospective, longitudinal studies of the general population have not yet specified the risk of Alzheimer's disease associated with each apolipoprotein E genotype, the mean age and variety of ages at the onset of dementia for each genotype, or the percentage of cases of Alzheimer's disease that are attributable to variants of the apolipoprotein E allele.
“Prospective, longitudinal studies of the general population have not yet specified the risk of Alzheimer's disease associated with each apolipoprotein E genotype, the mean age and variety of ages at the onset of dementia for each genotype, or the percentage of cases of Alzheimer's disease that are attributable to variants of the apolipoprotein E allele.”
The paper relies on this without support.
Genotype-specific preventive therapies have not yet been identified that might outweigh the psychological and social risks involved in making predictions about such a catastrophic illness.
“Genotype-specific preventive therapies have not yet been identified that might outweigh the psychological and social risks involved in making predictions about such a catastrophic illness.”
The paper relies on this without support.
The association between the e4 allele and Alzheimer's disease has been observed internationally in about 100 clinics.
“an association that has now been observed internationally in about 100 clinics.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Our hypothesis, therefore, can accommodate a growing realization that for many subjects with suspected AD, or who have an increased risk of developing AD, what are currently considered downstream biomarker changes potentially precede upstream biomarker changes [206-213].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [209]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As shown in previous studies, the brains of APOE4 carriers display decreased glucose utilization in numerous AD-relevant brain regions, as observed by FDG-PET16–18.”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“early reports by Reiman and colleagues demonstrated that both young and old APOE4 carriers display decreased glucose utilization, as measured by fluorodeoxyglucose positron emission tomography (FDG-PET), in brain regions similar to those seen with AD patients16–18.”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Young, cognitively normal apoE4 carriers have glucose hypometabolism in brain regions affected by AD [29–31]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [29]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“[18F] fluorodeoxyglucose (FDG)-PET imaging showed hypometabolism in AD brains, mainly in the temporoparietal cortex including the precuneus and posterior cingulate cortex (Reiman et al., 1996; Foster et al., 2007).”
From APOE genotype-dependent differences in human astrocytic energy metabolism (2025) · cites this paper as Reiman et al., 1996
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As such, APOE4 is associated with increased Aβ deposition but accumulating evidence suggests that its influence on metabolic pathways may contribute to disease risk independently of Aβ [3][4][5][6][7] .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This suggests the possibility that an apoE-related decrease in brain metabolism may contribute to development of AD (Reiman et al., 1996; Reiman et al., 2004, 2005; Small et al., 2000).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Reiman et al., 1996
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Furthermore, studies looking at both young and old non-demented carriers of the apoE4 isoform observed a similar regional pattern of hypometabolism prior to the onset of disease that correlates with the changes seen in the AD brain.”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Reiman et al., 1996
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“It has been suggested that this association may account for the earlier onset of symptoms in E4 carriers (21–23).”
From Prediction of cognitive decline in normal elderly subjects with 2-[ 18 F]fluoro-2-deoxy- d -glucose/positron-emission tomography (FDG/PET) (2001) · cites this paper as [22]
In the citing paper
“Moreover, both cross-sectional (21, 22) and longitudinal PET studies (23) show that nondemented E4 carriers have more hypometabolic regions than controls, but a relationship to longitudinally observed decline has not been reported.”
From Prediction of cognitive decline in normal elderly subjects with 2-[ 18 F]fluoro-2-deoxy- d -glucose/positron-emission tomography (FDG/PET) (2001) · cites this paper as [22]
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Metadata
- Authors
- Reiman, E. M., Caselli, R. J., Yun, L. S., Chen, K., Bandy, D., Minoshima, S., Thibodeau, S. N., & Osborne, D.
- Affiliations
- University of Arizona (US)
- Mayo Clinic in Arizona (US)
- University of Michigan (US)
- Mayo Clinic (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 1996-03-21
- Volume
- 334
- Issue
- 12
- Pages
- 752-758
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2023121717
- Semantic Scholar
- a04d6dd3638573927f661225155d8ef1ee0fff4d
- Cited by
- 1,366
- References
- 44
- Citations by year
- 2026: 15 · 2025: 10 · 2024: 20 · 2023: 28 · 2022: 28 · 2021: 27 · 2020: 30 · 2019: 30 · 2018: 40 · 2017: 41 · 2016: 42 · 2015: 37 · 2014: 53 · 2013: 56 · 2012: 64
- FWCI
- 42.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Academy of Neurology
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › Cancer-related cognitive impairment studies
- Keywords
- Alzheimer's disease, apolipoprotein E, ε4 allele, homozygosity, preclinical Alzheimer's disease, glucose metabolism, positron emission tomography, brain glucose hypometabolism, family history of Alzheimer's disease, prefrontal cortex, posterior cingulate cortex, parietal cortex, temporal cortex, normal aging, genetic risk factors
- MeSH terms
- Aged, Alleles, Alzheimer Disease, Apolipoproteins E, Brain, Female, Genotype, Glucose, Homozygote, Humans, Image Processing, Computer-Assisted, Male, Middle Aged, Neuropsychological Tests, Tomography, Emission-Computed, Case-Control Studies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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