Clinical Review & Education
From The JAMA Network
Serum Brain-Derived Neurotrophic Factor and the Risk for Dementia Paul S. Aisen, MD
JAMA NEUROLOGY Serum Brain-Derived Neurotrophic Factor and the Risk for Dementia: The Framingham Heart Study
related BDNF genetic variants to AD risk. This communitybased, prospective cohort study involved 2131 dementia-free participants aged 60 years and older (mean [SD] age, 72 [7] years; 56% women).
Galit Weinstein, PhD; Alexa S. Beiser, PhD; Seung Hoan Choi, MS; Sarah R. Preis, ScD, MPH; Tai C. Chen, PhD; Demetrios Vorgas, MSc; Rhoda
MAIN OUTCOMES AND MEASURES Ten-year incidence of
Au, PhD; Aleksandra Pikula, MD; Philip A. Wolf, MD; Anita L.
dementia and AD.
DeStefano, PhD; Ramachandran S. Vasan, MD; Sudha Seshadri, MD IMPORTANCE In animal studies, brain-derived neurotrophic
factor (BDNF) has been shown to impact neuronal survival and function and improve synaptic plasticity and long-term memory. Circulating BDNF levels increase with physical activity and caloric restriction, thus BDNF may mediate some of the observed associations between lifestyle and the risk for dementia. Some prior studies showed lower circulating BDNF in persons with Alzheimer disease (AD) compared with control participants; however, it remains uncertain whether reduced levels precede dementia onset. OBJECTIVE To examine whether higher serum BDNF levels in
cognitively healthy adults protect against the future risk for dementia and AD and to identify potential modifiers of this association.
RESULTS During follow-up, 140 participants developed dementia, 117 of whom had AD. Controlling for age and sex, each standard-deviation increment in BDNF was associated with a 33% lower risk for dementia and AD (P = .006 and P = .01, respectively) and these associations persisted after additional adjustments. Compared with the bottom quintile, BDNF levels in the top quintile were associated with less than half the risk for dementia and AD (hazard ratio, 0.49; 95% CI, 0.28-0.85; P = .01; and hazard ratio, 0.46; 95% CI, 0.24-0.86; P = .02, respectively). These associations were apparent only among women, persons aged 80 years and older, and those with college degrees (hazard ratios for AD: 0.65, [95% CI, 0.50-0.85], P = .001; 0.63 [95% CI, 0.47-0.85], P = .002; and 0.27 [95% CI, 0.11-0.65], P = .003, respectively). Brain-derived neurotrophic factor genetic variants were not associated with AD risk.
CONCLUSIONS AND RELEVANCE Higher serum BDNF levels may DESIGN, SETTING, AND PARTICIPANTS Framingham Study original
and offspring participants were followed up from 1992 and 1998, respectively, for up to 10 years. We used Cox models to relate BDNF levels to the risk for dementia and AD and adjusted for potential confounders. We also ran sensitivity analyses stratified by sex, age, and education, as well as
In view of the substantially increasing epidemic of Alzheimer disease (AD), efforts to find and explain genetic, biological, and environmental influences on the risk of AD are essential. The Framingham Heart Study (FHS) is the exemplar of long-term community-based studies and, despite some limitations involving generalizability, provides a rich opportunity for investigation of AD risk factors,1 including peripheral blood biomarkers of risk. The findings of such research can guide therapeutic trials, improving the likelihood of success in finding preventive and disease-slowing interventions. Biomarkers are critical to the accurate diagnosis and monitoring of AD because the clinical manifestations of the disease are not directly observable by clinicians and cognitive performance tests are variable and noisy. Neuroimaging (volumetric, functional, and mo1684
protect against future occurrence of dementia and AD. Our findings suggest a role for BDNF in the biology and possibly in the prevention of dementia and AD, especially in select subgroups of women and older and more highly educated persons. JAMA Neurol. 2014;71(1):55-61. doi:10.1001/jamaneurol.2013.4781.
lecular) and cerebrospinal fluid analysis are leading biomarker tools, providing measures of brain atrophy, synaptic function, amyloid accumulation, and tau dysregulation.2 In addition to its diagnostic value and utility in the assessment for treatment effects, a blood biomarker could provide insight into disease mechanisms. Biomarkers are more essential as emphasis shifts from symptomatic disease on the AD spectrum (dementia and mild cognitive impairment) toward the earliest, asymptomatic stage of disease. This stage, now referred to as preclinical AD,3 antedates dementia by a decade or more and may represent an optimal stage at which to initiate disease-modifying interventions.4 Preclinical AD can be diagnosed in clinically normal older individuals by amyloid positron emission tomography (PET) scan or cerebrospinal fluid analysis.3
JAMA April 23/30, 2014 Volume 311, Number 16
Copyright 2014 American Medical Association. All rights reserved.
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From The JAMA Network Clinical Review & Education
Blood markers of risk and diagnosis could be valuable. Genotyping for the apolipoprotein E epsilon 4 (APOE4) allele, the primary genetic risk factor for sporadic AD, is widely used in AD research, although it has limited clinical utility because a significant portion of AD occurs in APOE4-negative individuals, and APOE4 is not rare in individuals who never show manifestation of AD. Measurement of amyloid peptides and fragments of tau (the primary constituents of the pathological lesions of the AD brain) in blood have been studied but with limited utility. Other blood biomarkers of limited value include measures of homocysteine and inflammatory markers, among others. However, to successfully establish effective early interventions, screening of the entire aging population may become appropriate, lending urgency to the search for bloodbased biomarkers. Much AD therapeutic research today focuses on amyloid accumulation in brain as a potential target for disease-modifying intervention. A leading screening tool is amyloid PET imaging, although this is expensive and may not be sensitive to the earliest stage of disease prior to accumulation of a fibrillar amyloid load in brain sufficient for a positive scan signal. Beyond amyloid, there are numerous plausible mechanisms involved in AD neurodegeneration that may represent targets for diagnostic and therapeutic study. Neuronal cells essential for synaptic function require exposure to neurotrophins, including nerve growth factor and brainderived neurotrophic factor (BDNF) 5 ; ongoing studies aim to increase brain neurotrophin exposure to slow the progression of synaptic failure. Brain-derived neurotrophic factor is a candidate modulator of AD risk. Alterations of brain levels of BDNF, linked to environmental factors such as physical activity, may influence neuronal vulnerability and therefore AD risk or progression. Delivery of BDNF to brain is an active area of translational research in AD,6 although not yet in human trials. Some prior studies have linked blood levels of BDNF to AD risk, prompting FHS investigators to explore the association between serum BDNF and risk of incident dementia and AD. The findings reported by Weinstein et al7 in JAMA Neurology support an association between serum BDNF and risk of dementia (n = 140 incident cases) and AD (n = 117 incident cases) in nondeARTICLE INFORMATION Author Affiliation: Department of Neurosciences, University of California, San Diego, La Jolla. Corresponding Author: Paul S. Aisen, MD, Department of Neurosciences, University of California, San Diego, 9500 Gilman Dr, M/C 0949, La Jolla, CA 92093 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
mented older individuals (N = 2131) followed up for up to 10 years. Higher levels of BDNF were associated with lower risk of incident disease overall, although subgroup analyses suggested that the association was restricted to individuals older than 80 years, women, and those with college degrees. The attenuated hazard ratios with increasing serum BDNF levels had less significance when adjusted for physical activity and homocysteine levels, both of which may influence AD risk and have been targets in therapeutic research. The implications of these confounding associations is unclear and suggest that interpretation of the primary findings may not be straightforward. Indeed, serum BDNF levels may reflect behavior altered by the earliest, preclinical stage of AD that is possibly characterized by subtle (clinically inapparent) changes in cognitive function and subjective concerns more than 10 years prior to diagnosis of the dementia of AD. This timeline suggests that the FHS data indicate an association between BDNF and progression of the neurobiology of AD rather than modulation of risk. Brain-derived neurotrophic factor remains a therapeutic target for AD. Studies are being done of both BDNF gene delivery to brain and physical exercise as an inducer of BDNF. The FHS report adds some further support to these approaches. Finding peripheral blood indicators of AD risk has led to a number of therapeutic trials aiming to modulate such risk, such as reducing homocysteine8 or inflammation,9 but with disappointing results. Pursuing measurement of BDNF, however, has particularly strong rationale and should continue. The findings are intriguing, but interpretation is complicated by a number of issues. What is the relationship of serum BDNF to brain levels? Levels of BDNF are influenced by other factors thought to modulate AD risk such as physical activity10 and caloric restriction; perhaps serum BDNF is an indirect indicator of such environmental issues rather than a direct modulator of risk. The data show a stronger relationship between serum BDNF and dementia than AD, suggesting that the role of BDNF may not be specific to AD mechanisms. It is very premature to consider peripheral BDNF measurement a guide for therapeutic maneuvers, but further study is warranted to determine the diagnostic and therapeutic significance of these data.
3. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292.
dementia: the Framingham Heart Study. JAMA Neurol. 2014;71(1):55-61.
4. Sperling RA, Jack CR Jr, Aisen PS. Testing the right target and right drug at the right stage. Sci Transl Med. 2011;3(111):11cm33.
9. Lyketsos CG, Breitner JC, Green RC, et al; ADAPT Research Group. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology. 2007;68(21):18001808.
REFERENCES
5. Lu B, Figurov A. Role of neurotrophins in synapse development and plasticity. Rev Neurosci. 1997;8(1):1-12.
1. Weinstein G, Wolf PA, Beiser AS, Au R, Seshadri S. Risk estimations, risk factors, and genetic variants associated with Alzheimer’s disease in selected publications from the Framingham Heart Study. J Alzheimers Dis. 2013;33(suppl 1):S439-S445.
6. Nagahara AH, Merrill DA, Coppola G, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med. 2009;15(3): 331-337.
2. Cummings JL. Biomarkers in Alzheimer’s disease drug development. Alzheimers Dement. 2011;7(3):e13-e44.
7. Weinstein G, Beiser AS, Choi SH, et al. Serum brain-derived neurotrophic factor and the risk for
jama.com
8. Aisen PS, Schneider LS, Sano M, et al; Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300(15):1774-1783.
10. Oliff HS, Berchtold NC, Isackson P, Cotman CW. Exercise-induced regulation of brain-derived neurotrophic factor (BDNF) transcripts in the rat hippocampus. Brain Res Mol Brain Res. 1998;61(1-2):147-153.
JAMA April 23/30, 2014 Volume 311, Number 16
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/14/2015
1685
From The JAMA Network
Serum Brain-Derived Neurotrophic Factor and the Risk for Dementia Paul S. Aisen, MD
JAMA NEUROLOGY Serum Brain-Derived Neurotrophic Factor and the Risk for Dementia: The Framingham Heart Study
related BDNF genetic variants to AD risk. This communitybased, prospective cohort study involved 2131 dementia-free participants aged 60 years and older (mean [SD] age, 72 [7] years; 56% women).
Galit Weinstein, PhD; Alexa S. Beiser, PhD; Seung Hoan Choi, MS; Sarah R. Preis, ScD, MPH; Tai C. Chen, PhD; Demetrios Vorgas, MSc; Rhoda
MAIN OUTCOMES AND MEASURES Ten-year incidence of
Au, PhD; Aleksandra Pikula, MD; Philip A. Wolf, MD; Anita L.
dementia and AD.
DeStefano, PhD; Ramachandran S. Vasan, MD; Sudha Seshadri, MD IMPORTANCE In animal studies, brain-derived neurotrophic
factor (BDNF) has been shown to impact neuronal survival and function and improve synaptic plasticity and long-term memory. Circulating BDNF levels increase with physical activity and caloric restriction, thus BDNF may mediate some of the observed associations between lifestyle and the risk for dementia. Some prior studies showed lower circulating BDNF in persons with Alzheimer disease (AD) compared with control participants; however, it remains uncertain whether reduced levels precede dementia onset. OBJECTIVE To examine whether higher serum BDNF levels in
cognitively healthy adults protect against the future risk for dementia and AD and to identify potential modifiers of this association.
RESULTS During follow-up, 140 participants developed dementia, 117 of whom had AD. Controlling for age and sex, each standard-deviation increment in BDNF was associated with a 33% lower risk for dementia and AD (P = .006 and P = .01, respectively) and these associations persisted after additional adjustments. Compared with the bottom quintile, BDNF levels in the top quintile were associated with less than half the risk for dementia and AD (hazard ratio, 0.49; 95% CI, 0.28-0.85; P = .01; and hazard ratio, 0.46; 95% CI, 0.24-0.86; P = .02, respectively). These associations were apparent only among women, persons aged 80 years and older, and those with college degrees (hazard ratios for AD: 0.65, [95% CI, 0.50-0.85], P = .001; 0.63 [95% CI, 0.47-0.85], P = .002; and 0.27 [95% CI, 0.11-0.65], P = .003, respectively). Brain-derived neurotrophic factor genetic variants were not associated with AD risk.
CONCLUSIONS AND RELEVANCE Higher serum BDNF levels may DESIGN, SETTING, AND PARTICIPANTS Framingham Study original
and offspring participants were followed up from 1992 and 1998, respectively, for up to 10 years. We used Cox models to relate BDNF levels to the risk for dementia and AD and adjusted for potential confounders. We also ran sensitivity analyses stratified by sex, age, and education, as well as
In view of the substantially increasing epidemic of Alzheimer disease (AD), efforts to find and explain genetic, biological, and environmental influences on the risk of AD are essential. The Framingham Heart Study (FHS) is the exemplar of long-term community-based studies and, despite some limitations involving generalizability, provides a rich opportunity for investigation of AD risk factors,1 including peripheral blood biomarkers of risk. The findings of such research can guide therapeutic trials, improving the likelihood of success in finding preventive and disease-slowing interventions. Biomarkers are critical to the accurate diagnosis and monitoring of AD because the clinical manifestations of the disease are not directly observable by clinicians and cognitive performance tests are variable and noisy. Neuroimaging (volumetric, functional, and mo1684
protect against future occurrence of dementia and AD. Our findings suggest a role for BDNF in the biology and possibly in the prevention of dementia and AD, especially in select subgroups of women and older and more highly educated persons. JAMA Neurol. 2014;71(1):55-61. doi:10.1001/jamaneurol.2013.4781.
lecular) and cerebrospinal fluid analysis are leading biomarker tools, providing measures of brain atrophy, synaptic function, amyloid accumulation, and tau dysregulation.2 In addition to its diagnostic value and utility in the assessment for treatment effects, a blood biomarker could provide insight into disease mechanisms. Biomarkers are more essential as emphasis shifts from symptomatic disease on the AD spectrum (dementia and mild cognitive impairment) toward the earliest, asymptomatic stage of disease. This stage, now referred to as preclinical AD,3 antedates dementia by a decade or more and may represent an optimal stage at which to initiate disease-modifying interventions.4 Preclinical AD can be diagnosed in clinically normal older individuals by amyloid positron emission tomography (PET) scan or cerebrospinal fluid analysis.3
JAMA April 23/30, 2014 Volume 311, Number 16
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/14/2015
jama.com
From The JAMA Network Clinical Review & Education
Blood markers of risk and diagnosis could be valuable. Genotyping for the apolipoprotein E epsilon 4 (APOE4) allele, the primary genetic risk factor for sporadic AD, is widely used in AD research, although it has limited clinical utility because a significant portion of AD occurs in APOE4-negative individuals, and APOE4 is not rare in individuals who never show manifestation of AD. Measurement of amyloid peptides and fragments of tau (the primary constituents of the pathological lesions of the AD brain) in blood have been studied but with limited utility. Other blood biomarkers of limited value include measures of homocysteine and inflammatory markers, among others. However, to successfully establish effective early interventions, screening of the entire aging population may become appropriate, lending urgency to the search for bloodbased biomarkers. Much AD therapeutic research today focuses on amyloid accumulation in brain as a potential target for disease-modifying intervention. A leading screening tool is amyloid PET imaging, although this is expensive and may not be sensitive to the earliest stage of disease prior to accumulation of a fibrillar amyloid load in brain sufficient for a positive scan signal. Beyond amyloid, there are numerous plausible mechanisms involved in AD neurodegeneration that may represent targets for diagnostic and therapeutic study. Neuronal cells essential for synaptic function require exposure to neurotrophins, including nerve growth factor and brainderived neurotrophic factor (BDNF) 5 ; ongoing studies aim to increase brain neurotrophin exposure to slow the progression of synaptic failure. Brain-derived neurotrophic factor is a candidate modulator of AD risk. Alterations of brain levels of BDNF, linked to environmental factors such as physical activity, may influence neuronal vulnerability and therefore AD risk or progression. Delivery of BDNF to brain is an active area of translational research in AD,6 although not yet in human trials. Some prior studies have linked blood levels of BDNF to AD risk, prompting FHS investigators to explore the association between serum BDNF and risk of incident dementia and AD. The findings reported by Weinstein et al7 in JAMA Neurology support an association between serum BDNF and risk of dementia (n = 140 incident cases) and AD (n = 117 incident cases) in nondeARTICLE INFORMATION Author Affiliation: Department of Neurosciences, University of California, San Diego, La Jolla. Corresponding Author: Paul S. Aisen, MD, Department of Neurosciences, University of California, San Diego, 9500 Gilman Dr, M/C 0949, La Jolla, CA 92093 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
mented older individuals (N = 2131) followed up for up to 10 years. Higher levels of BDNF were associated with lower risk of incident disease overall, although subgroup analyses suggested that the association was restricted to individuals older than 80 years, women, and those with college degrees. The attenuated hazard ratios with increasing serum BDNF levels had less significance when adjusted for physical activity and homocysteine levels, both of which may influence AD risk and have been targets in therapeutic research. The implications of these confounding associations is unclear and suggest that interpretation of the primary findings may not be straightforward. Indeed, serum BDNF levels may reflect behavior altered by the earliest, preclinical stage of AD that is possibly characterized by subtle (clinically inapparent) changes in cognitive function and subjective concerns more than 10 years prior to diagnosis of the dementia of AD. This timeline suggests that the FHS data indicate an association between BDNF and progression of the neurobiology of AD rather than modulation of risk. Brain-derived neurotrophic factor remains a therapeutic target for AD. Studies are being done of both BDNF gene delivery to brain and physical exercise as an inducer of BDNF. The FHS report adds some further support to these approaches. Finding peripheral blood indicators of AD risk has led to a number of therapeutic trials aiming to modulate such risk, such as reducing homocysteine8 or inflammation,9 but with disappointing results. Pursuing measurement of BDNF, however, has particularly strong rationale and should continue. The findings are intriguing, but interpretation is complicated by a number of issues. What is the relationship of serum BDNF to brain levels? Levels of BDNF are influenced by other factors thought to modulate AD risk such as physical activity10 and caloric restriction; perhaps serum BDNF is an indirect indicator of such environmental issues rather than a direct modulator of risk. The data show a stronger relationship between serum BDNF and dementia than AD, suggesting that the role of BDNF may not be specific to AD mechanisms. It is very premature to consider peripheral BDNF measurement a guide for therapeutic maneuvers, but further study is warranted to determine the diagnostic and therapeutic significance of these data.
3. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292.
dementia: the Framingham Heart Study. JAMA Neurol. 2014;71(1):55-61.
4. Sperling RA, Jack CR Jr, Aisen PS. Testing the right target and right drug at the right stage. Sci Transl Med. 2011;3(111):11cm33.
9. Lyketsos CG, Breitner JC, Green RC, et al; ADAPT Research Group. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology. 2007;68(21):18001808.
REFERENCES
5. Lu B, Figurov A. Role of neurotrophins in synapse development and plasticity. Rev Neurosci. 1997;8(1):1-12.
1. Weinstein G, Wolf PA, Beiser AS, Au R, Seshadri S. Risk estimations, risk factors, and genetic variants associated with Alzheimer’s disease in selected publications from the Framingham Heart Study. J Alzheimers Dis. 2013;33(suppl 1):S439-S445.
6. Nagahara AH, Merrill DA, Coppola G, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med. 2009;15(3): 331-337.
2. Cummings JL. Biomarkers in Alzheimer’s disease drug development. Alzheimers Dement. 2011;7(3):e13-e44.
7. Weinstein G, Beiser AS, Choi SH, et al. Serum brain-derived neurotrophic factor and the risk for
jama.com
8. Aisen PS, Schneider LS, Sano M, et al; Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300(15):1774-1783.
10. Oliff HS, Berchtold NC, Isackson P, Cotman CW. Exercise-induced regulation of brain-derived neurotrophic factor (BDNF) transcripts in the rat hippocampus. Brain Res Mol Brain Res. 1998;61(1-2):147-153.
JAMA April 23/30, 2014 Volume 311, Number 16
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a New York University User on 05/14/2015
1685
