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. Author manuscript; available in PMC: 2012 Mar 1.
Published in final edited form as: Lancet Neurol. 2011 Mar;10(3):241–252. doi: 10.1016/S1474-4422(10)70325-2

Table 1.

Levels of evidence for an association of APOE with occurrence and progression for neurological disorders. Levels of evidence are adapted from the Categories of Association established and used by the Institute of Medicine for association between a factor and a specific health outcome (Committee on Health Effects Associated with Exposures During the Gulf War. Institute of Medicine, 2000) [also see Tarawneh et al., 2010].172

Disease Disease Occurrence and Levels of Evidence Disease Progression and Levels of Evidence Possible Mechanisms of ApoE In Disease References
AD ε4>ε3>ε2
Sufficient evidence of a direct relationship (A) 		Inadequate/insufficient evidence to determine whether an association exists (C)

  • Aβ aggregation and clearance

  • Tau phosphorylation and aggregation

  • ApoE protein stability, lipid metabolism, inflammation, altered neuronal repair and synaptic plasticity

 1–5,13–24,35–40, 41, 45, 47–57,160–162, 164–170
CAA ε4>ε3
Sufficient evidence of a direct relationship (A)
ε2 and ε4 risk for hemorrnage Suggestive evidence of an association (B) 		ε4>ε3
sufficient evidence of a direct relationship (A) 		Aβ metabolism 25–34, 38–40, 43, 46, 160–162, 164–170
TBI Not Applicable ε4>ε3
Sufficient evidence of a direct relationship (A) 		Aβ and Tau accumulation 82–101,160–162, 164–170
DAD ε4> Non-carriers
Suggestive evidence of an association (B) 		ε4> Non-carriers
Suggestive evidence of an association (B) 		Aβ metabolism 102–105, 160–162, 164–170
Stroke (IS, SAH, ICH) Inadequate/insufficient evidence to determine whether an association exists (C) IS: Inadequate/insufficient evidence to determine whether an association exists (C)
SAH: ε4 > Non-carriers
ICH: ε >Non-carriers
suggestive evidence of an association (B) 		Unclear 106–111, 160–170
VaD ε4> Non-carriers
Suggestive evidence of an association (B) 		Inadequate/sufficient evidence to determine whether an association exists (C) Unclear 112–120, 160–162, 164–170
CJD Suggestive evidence of no association (D) Suggestive evidence of no association (D) Not applicable 2, 121–124, 160–162, 164–170
MS Suggestive evidence of no association (D) ε4> Non-carriers
Suggestive evidence of an association (B) 		Unclear 125–128, 160–162, 164–170
ALS Suggestive evidence of no association (D) ε4>ε2
Suggestive evidence of an association (B) 		Unclear 129–132, 160–162, 162–170
IBM Inadequate/insufficient evidence to determine whether an association exists (C) Inadequate/insufficient evidence to determine whether an association exists (C) Not applicable 133–139, 160–164–170
PD ε2> Non-carriers
Suggestive evidence of an association (B) 		ε2> Non-carriers
Suggestive evidence of an association (B) 		Unclear 140–145, 160–162, 164–170
DLB ε4>
Non-carriers Suggestive evidence of an association (B) 		Inadequate/insufficient evidence to determine whether an association exists (C) Aβ metabolism 146–152, 160–162, 164–170
CP, HD, FTD, TL-E Inadequate/insufficient evidence to determine whether an association exists (C) Inadequate/insufficient evidence to determine whether an association exists (C) None proposed 153–159, 162–164, 164–170
(A)

Sufficient evidence of a direct relationship: Evidence fulfills the guidelines for sufficient evidence of an association, is supported by experimental data in humans and animals, and satisfies several of the guidelines used to assess causality: strength of association, dose response relationship, and consistency of association.

(B)

Suggestive evidence of an association: Evidence is suggestive of an association between APOE and the neurological disorder in humans, but the body of evidence is limited by the inability to exclude chance and bias, and confounding factors with confidence.

(C)

Inadequate/insufficient evidence to determine whether an association exists: Evidence is of insufficient quantity, quality, or consistency to permit a conclusion regarding the existence of an association between APOE and the neurological disorder in humans.

(D)

Suggestive evidence of no association. There are several adequate studies that are consistent in not showing a positive association between APOE and the neurological disorder in humans.

Table Abbreviations: AD: Alzheimer’s disease; CAA: cerebral amyloid angiopathy; TBI: traumatic brain injury; IS: ischemic stroke, ICH: intracerebral hemorrhage; SAH: subarachnoid hemorrhage; DAD: Down’s syndrome-associated dementia; CJD: Creutzfeldt-Jakob disease; MS: multiple sclerosis; ALS: amyotrophic lateral sclerosis; IBM: Inclusion-body myositis; PD: Parkinson’s disease; VaD: Vascular dementia; DLB: Dementia with Lewy bodies; CP: cerebral palsy; HD: Huntington’s disease; TL-E: temporal lobe-epilepsy; FTD: Frontotemporal dementia