Letters
although they exhibit enhanced responses to CNS injury.2 However, there is evidence to suggest a dramatic upregulation of apolipoprotein D in apoE-deficient animals.3 Similarly, a clinical study of patients with Alzheimer disease with the APOE4 polymorphism and low levels of CNS apoE protein demonstrated increased levels of apolipoprotein J (clusterin), which might also play a compensatory role.4 Although the lack of evident CNS abnormalities in an individual with congenital absence of apoE is interesting, it likely does not reflect the biological importance of apoE in the CNS of individuals in which this protein is present throughout development. Additionally, these results do not address how the absence of functional apoE will affect an individual’s response to CNS injury or aging. Thus, it is premature to conclude that apoE does not play a critical role in the CNS in patients with normal synthesis of apoE, nor do the observations in this individual patient necessarily suggest that depleting overall apoE levels in the CNS would represent an optimal therapeutic strategy.
increases the synaptic location of β-amyloid oligomers.3 The lack of apparent deleterious neurocognitive effects of the absence of apoE in our patient tends to minimize the likelihood of neuroprotective effects that have been postulated for the apoE proteins.2 Thus, therapeutic strategies directed at knockdown of apoE4 in the brain may offer a new venue for treatment of a variety of neurodegenerative disorders. If this is accomplished within the central nervous system, it would not be expected to have a significant impact on lipoprotein transport in the blood and peripheral tissues. Mary J. Malloy, MD John P. Kane, MD, PhD Author Affiliations: University of California–San Francisco, Cardiovascular Research Institute. Corresponding Author: Mary J. Malloy, MD, University of California– San Francisco Cardiovascular Research Institute, 555 Mission Bay Blvd S, San Francisco, CA 94158 ([email protected]). Conflict of Interest Disclosures: None reported.
Daniel T. Laskowitz, MD, MHS Dawn N. Kernagis, PhD
1. Mak AC, Pullinger CR, Tang LF, et al. Effects of the absence of apolipoprotein E on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014;71(10):1228-1236.
Author Affiliations: Department of Neurobiology, Duke University Medical Center, Durham, North Carolina (Laskowitz); Department of Neurology, Duke University Medical Center, Durham, North Carolina (Laskowitz, Kernagis).
2. Potter H, Wisniewski T. Apolipoprotein E: essential catalyst of the Alzheimer amyloid cascade [published online July 15, 2012]. Int J Alzheimers Dis. doi:10 .1155/2012/48942.
Corresponding Author: Daniel T. Laskowitz, MD, MHS, Departments of Neurology and Neurobiology, Duke Box 2900, Duke University Medical Center, Durham, NC 27710 ([email protected]).
3. Jones PB, Adams KW, Rozkalne A, et al. Apolipoprotein E: isoform specific differences in tertiary structure and interaction with amyloid-β in human Alzheimer brain. PLoS One. 2011;6(1):e14586.
Conflict of Interest Disclosures: Dr Laskowitz is a founding officer of and Dr Kernagis serves as a consultant for Cerenova LLC. 1. Mak AC, Pullinger CR, Tang LF, et al. Effects of the absence of apolipoprotein E on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014;71(10):1228-1236. 2. Laskowitz DT, Sheng H, Bart RD, Joyner KA, Roses AD, Warner DS. Apolipoprotein E-deficient mice have increased susceptibility to focal cerebral ischemia. J Cereb Blood Flow Metab. 1997;17(7):753-758. 3. Terrisse L, Séguin D, Bertrand P, Poirier J, Milne R, Rassart E. Modulation of apolipoprotein D and apolipoprotein E expression in rat hippocampus after entorhinal cortex lesion. Brain Res Mol Brain Res. 1999;70(1):26-35. 4. Bertrand P, Poirier J, Oda T, Finch CE, Pasinetti GM. Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer disease. Brain Res Mol Brain Res. 1995;33(1):174-178.
In Reply We believe that our findings1 do not negate the evidence that apolipoprotein E (apoE) 4 plays an active role in the development of neurocognitive disorders because abundant evidence supports deleterious activity of the E4 isoform. The observation that there is essentially no neurocognitive deficit in our middle-aged patient who was unable to produce any apoE supports the belief that this protein does not have an essential role in the development or later function of the brain, while suggesting that there may be a surrogate protein subserving its roles, including the cerebral transport of cholesterol. Discovery of 1 or more surrogates would enhance knowledge of lipid transport in the brain. Two foci of investigation suggest that apoE and, in particular, apoE4 contribute to processes central to Alzheimer disease. Apolipoprotein E4 supports the polymerization of amyloid precursor protein in a dose-dependent fashion 2 and jamaneurology.com
Heritability of Amyotrophic Lateral Sclerosis To the Editor We read with interest the article by Keller et al1 titled “Genome-Wide Analysis of the Heritability of Amyotrophic Lateral Sclerosis,” in which the contribution of common variation to the heritability (h2) of amyotrophic lateral sclerosis (ALS) was estimated to be 21%. The authors used the popular GCTA software, which uses a linear mixed model accounting for all single-nucleotide polymorphisms simultaneously, with imputed genotype data for 1223 cases and 1591 control individuals. They estimated heritability under the assumption of a disease prevalence of 10 of 100 000 personyears. We previously reported the heritability of sporadic ALS using identical methods and a larger sample of 6100 cases and 7125 control individuals.2 The prevalence of a rare disease, such as ALS, is difficult to estimate and ALS prevalence could be underestimated in populations where life expectancy is progressively increasing. Thus, we estimated heritability over a range of prevalences (see the Results section of our article2) and presented the results in Supplementary Figure S5 of our publication.2 We showed that, for a prevalence of ALS of 5 of 100 000 person-years, the heritability estimate was about 12%, but using a prevalence of 10 of 100 000 person-years, heritability estimates ranged from 20% to 25% across the 8 independent cohorts we analyzed. Summary h2 calculated by meta-analysis (random effects) was 21.5% (95% CI, 19.9-23.0; SE, 0.8%),2 a value strikingly similar to that of Keller et al.1 One cohort3 analyzed by Keller et al1 was included in our study; therefore, we JAMA Neurology December 2014 Volume 71, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Florida International University Medical Library User on 05/30/2015
1579
Letters
estimated the summary heritability excluding the overlapping data set. We still achieve a similar result (h2, 21.4%; 95% CI, 19.9-23.0; SE, 0.8%). In conclusion, we are pleased that the study of Keller et al1 has validated our previous results when using the same assumptions. This demonstrates that the methods used to estimate the additive genetic variance due to common variation are reliable. However, contrary to the assertion of Keller et al,1 the heritability of ALS is highly dependent on the estimated prevalence; therefore, heritability should be presented for a range of plausible values for prevalence. This approach has been applied to estimates for the heritability of ALS from family data obtained from a research register.4 For the same range of prevalences, heritability estimated from family data is consistently greater than values for heritability that we have estimated using common variation, indicating that there are potentially rarer variants not captured by commercial genotyping arrays that contribute to the risk for ALS. Isabella Fogh, PhD Ammar Al-Chalabi, PhD John Powell, PhD Author Affiliations: King’s College London, Institute of Psychiatry, Department of Basic and Clinical Neuroscience, London, England. Corresponding Author: Isabella Fogh, PhD, King’s College London, Institute of Psychiatry, Department of Basic and Clinical Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, England ([email protected]).
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Conflict of Interest Disclosures: None reported. 1. Keller MF, Ferrucci L, Singleton AB, et al. Genome-wide analysis of the heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2014;71(9):1123-1134. 2. Fogh I, Ratti A, Gellera C, et al; SLAGEN Consortium and Collaborators. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2014;23 (8):2220-2231. 3. Chiò A, Schymick JC, Restagno G, et al. A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2009;18(8):1524-1532. 4. Wingo TS, Cutler DJ, Yarab N, Kelly CM, Glass JD. The heritability of amyotrophic lateral sclerosis in a clinically ascertained United States research registry. PLoS One. 2011;6(11):e27985.
CORRECTION Incorrect Information in Reply Letter: In the Reply Letter titled “The Central Clock in Patients With Parkinson Disease—Reply,” published in the November issue of JAMA Neurology (2014;71[11]:1456-1457), there was incorrect information in the last 2 sentences of the second paragraph. The end of the paragraph should have read as follows: “In contrast to these findings, Bolitho and colleagues3 found increased melatonin secretion and prolonged phase angle of entrainment in medicated patients with PD (n = 16) but not in unmedicated patients (n = 13) or matched control individuals (n = 28).” This article was corrected online. Error in Funding/Support: In the Original Investigation entitled “Effect of Leukocyte Telomere Length on Total and Regional Brain Volumes in a Large PopulationBased Cohort,” published in the October 2014 issue of JAMA Neurology (2014; 71[10]:1247-1254. doi:10.1001/jamaneurol.2014.1926), one of the funding sources was inadvertently omitted from the Funding/Support section. This article was corrected online.
JAMA Neurology December 2014 Volume 71, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Florida International University Medical Library User on 05/30/2015
jamaneurology.com
although they exhibit enhanced responses to CNS injury.2 However, there is evidence to suggest a dramatic upregulation of apolipoprotein D in apoE-deficient animals.3 Similarly, a clinical study of patients with Alzheimer disease with the APOE4 polymorphism and low levels of CNS apoE protein demonstrated increased levels of apolipoprotein J (clusterin), which might also play a compensatory role.4 Although the lack of evident CNS abnormalities in an individual with congenital absence of apoE is interesting, it likely does not reflect the biological importance of apoE in the CNS of individuals in which this protein is present throughout development. Additionally, these results do not address how the absence of functional apoE will affect an individual’s response to CNS injury or aging. Thus, it is premature to conclude that apoE does not play a critical role in the CNS in patients with normal synthesis of apoE, nor do the observations in this individual patient necessarily suggest that depleting overall apoE levels in the CNS would represent an optimal therapeutic strategy.
increases the synaptic location of β-amyloid oligomers.3 The lack of apparent deleterious neurocognitive effects of the absence of apoE in our patient tends to minimize the likelihood of neuroprotective effects that have been postulated for the apoE proteins.2 Thus, therapeutic strategies directed at knockdown of apoE4 in the brain may offer a new venue for treatment of a variety of neurodegenerative disorders. If this is accomplished within the central nervous system, it would not be expected to have a significant impact on lipoprotein transport in the blood and peripheral tissues. Mary J. Malloy, MD John P. Kane, MD, PhD Author Affiliations: University of California–San Francisco, Cardiovascular Research Institute. Corresponding Author: Mary J. Malloy, MD, University of California– San Francisco Cardiovascular Research Institute, 555 Mission Bay Blvd S, San Francisco, CA 94158 ([email protected]). Conflict of Interest Disclosures: None reported.
Daniel T. Laskowitz, MD, MHS Dawn N. Kernagis, PhD
1. Mak AC, Pullinger CR, Tang LF, et al. Effects of the absence of apolipoprotein E on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014;71(10):1228-1236.
Author Affiliations: Department of Neurobiology, Duke University Medical Center, Durham, North Carolina (Laskowitz); Department of Neurology, Duke University Medical Center, Durham, North Carolina (Laskowitz, Kernagis).
2. Potter H, Wisniewski T. Apolipoprotein E: essential catalyst of the Alzheimer amyloid cascade [published online July 15, 2012]. Int J Alzheimers Dis. doi:10 .1155/2012/48942.
Corresponding Author: Daniel T. Laskowitz, MD, MHS, Departments of Neurology and Neurobiology, Duke Box 2900, Duke University Medical Center, Durham, NC 27710 ([email protected]).
3. Jones PB, Adams KW, Rozkalne A, et al. Apolipoprotein E: isoform specific differences in tertiary structure and interaction with amyloid-β in human Alzheimer brain. PLoS One. 2011;6(1):e14586.
Conflict of Interest Disclosures: Dr Laskowitz is a founding officer of and Dr Kernagis serves as a consultant for Cerenova LLC. 1. Mak AC, Pullinger CR, Tang LF, et al. Effects of the absence of apolipoprotein E on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014;71(10):1228-1236. 2. Laskowitz DT, Sheng H, Bart RD, Joyner KA, Roses AD, Warner DS. Apolipoprotein E-deficient mice have increased susceptibility to focal cerebral ischemia. J Cereb Blood Flow Metab. 1997;17(7):753-758. 3. Terrisse L, Séguin D, Bertrand P, Poirier J, Milne R, Rassart E. Modulation of apolipoprotein D and apolipoprotein E expression in rat hippocampus after entorhinal cortex lesion. Brain Res Mol Brain Res. 1999;70(1):26-35. 4. Bertrand P, Poirier J, Oda T, Finch CE, Pasinetti GM. Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer disease. Brain Res Mol Brain Res. 1995;33(1):174-178.
In Reply We believe that our findings1 do not negate the evidence that apolipoprotein E (apoE) 4 plays an active role in the development of neurocognitive disorders because abundant evidence supports deleterious activity of the E4 isoform. The observation that there is essentially no neurocognitive deficit in our middle-aged patient who was unable to produce any apoE supports the belief that this protein does not have an essential role in the development or later function of the brain, while suggesting that there may be a surrogate protein subserving its roles, including the cerebral transport of cholesterol. Discovery of 1 or more surrogates would enhance knowledge of lipid transport in the brain. Two foci of investigation suggest that apoE and, in particular, apoE4 contribute to processes central to Alzheimer disease. Apolipoprotein E4 supports the polymerization of amyloid precursor protein in a dose-dependent fashion 2 and jamaneurology.com
Heritability of Amyotrophic Lateral Sclerosis To the Editor We read with interest the article by Keller et al1 titled “Genome-Wide Analysis of the Heritability of Amyotrophic Lateral Sclerosis,” in which the contribution of common variation to the heritability (h2) of amyotrophic lateral sclerosis (ALS) was estimated to be 21%. The authors used the popular GCTA software, which uses a linear mixed model accounting for all single-nucleotide polymorphisms simultaneously, with imputed genotype data for 1223 cases and 1591 control individuals. They estimated heritability under the assumption of a disease prevalence of 10 of 100 000 personyears. We previously reported the heritability of sporadic ALS using identical methods and a larger sample of 6100 cases and 7125 control individuals.2 The prevalence of a rare disease, such as ALS, is difficult to estimate and ALS prevalence could be underestimated in populations where life expectancy is progressively increasing. Thus, we estimated heritability over a range of prevalences (see the Results section of our article2) and presented the results in Supplementary Figure S5 of our publication.2 We showed that, for a prevalence of ALS of 5 of 100 000 person-years, the heritability estimate was about 12%, but using a prevalence of 10 of 100 000 person-years, heritability estimates ranged from 20% to 25% across the 8 independent cohorts we analyzed. Summary h2 calculated by meta-analysis (random effects) was 21.5% (95% CI, 19.9-23.0; SE, 0.8%),2 a value strikingly similar to that of Keller et al.1 One cohort3 analyzed by Keller et al1 was included in our study; therefore, we JAMA Neurology December 2014 Volume 71, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Florida International University Medical Library User on 05/30/2015
1579
Letters
estimated the summary heritability excluding the overlapping data set. We still achieve a similar result (h2, 21.4%; 95% CI, 19.9-23.0; SE, 0.8%). In conclusion, we are pleased that the study of Keller et al1 has validated our previous results when using the same assumptions. This demonstrates that the methods used to estimate the additive genetic variance due to common variation are reliable. However, contrary to the assertion of Keller et al,1 the heritability of ALS is highly dependent on the estimated prevalence; therefore, heritability should be presented for a range of plausible values for prevalence. This approach has been applied to estimates for the heritability of ALS from family data obtained from a research register.4 For the same range of prevalences, heritability estimated from family data is consistently greater than values for heritability that we have estimated using common variation, indicating that there are potentially rarer variants not captured by commercial genotyping arrays that contribute to the risk for ALS. Isabella Fogh, PhD Ammar Al-Chalabi, PhD John Powell, PhD Author Affiliations: King’s College London, Institute of Psychiatry, Department of Basic and Clinical Neuroscience, London, England. Corresponding Author: Isabella Fogh, PhD, King’s College London, Institute of Psychiatry, Department of Basic and Clinical Neuroscience, De Crespigny Park, Denmark Hill, London SE5 8AF, England ([email protected]).
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Conflict of Interest Disclosures: None reported. 1. Keller MF, Ferrucci L, Singleton AB, et al. Genome-wide analysis of the heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2014;71(9):1123-1134. 2. Fogh I, Ratti A, Gellera C, et al; SLAGEN Consortium and Collaborators. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2014;23 (8):2220-2231. 3. Chiò A, Schymick JC, Restagno G, et al. A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2009;18(8):1524-1532. 4. Wingo TS, Cutler DJ, Yarab N, Kelly CM, Glass JD. The heritability of amyotrophic lateral sclerosis in a clinically ascertained United States research registry. PLoS One. 2011;6(11):e27985.
CORRECTION Incorrect Information in Reply Letter: In the Reply Letter titled “The Central Clock in Patients With Parkinson Disease—Reply,” published in the November issue of JAMA Neurology (2014;71[11]:1456-1457), there was incorrect information in the last 2 sentences of the second paragraph. The end of the paragraph should have read as follows: “In contrast to these findings, Bolitho and colleagues3 found increased melatonin secretion and prolonged phase angle of entrainment in medicated patients with PD (n = 16) but not in unmedicated patients (n = 13) or matched control individuals (n = 28).” This article was corrected online. Error in Funding/Support: In the Original Investigation entitled “Effect of Leukocyte Telomere Length on Total and Regional Brain Volumes in a Large PopulationBased Cohort,” published in the October 2014 issue of JAMA Neurology (2014; 71[10]:1247-1254. doi:10.1001/jamaneurol.2014.1926), one of the funding sources was inadvertently omitted from the Funding/Support section. This article was corrected online.
JAMA Neurology December 2014 Volume 71, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Florida International University Medical Library User on 05/30/2015
jamaneurology.com
