[continued from previous message]

These observations provide further support for the previously reported finding that the personalized protocol for metabolic enhancement (note that the metabolic evaluation included parameters shown to affect Alzheimer's disease pathophysiology, such as
homocysteine [15], glucose [16], and inflammation [17], as well as numerous others as previously described [3]) in Alzheimer's disease leads to the reversal of cognitive decline in at least some patients with early Alzheimer's disease or its precursors,
MCI (mild cognitive impairment) and SCI (subjective cognitive impairment). To our knowledge, the magnitude of the improvements documented in patients 1 and 2 is unequaled in previous reports: in patient 1, the increase in hippocampal volume from 17th
percentile to 75th percentile supports the marked symptomatic improvement that he (and others) achieved on the protocol. In patient 2, quantitative neuropsychological testing demonstrated improvements of up to three standard deviations (CVLT-IIB, from
3rd percentile to 84th percentile), with multiple tests all showing marked improvements. These findings complement and support the marked subjective improvement already published for this patient [3].

It is noteworthy that these patients met criteria for Alzheimer's disease or MCI prior to treatment, but failed to meet criteria for either Alzheimer's disease or MCI following treatment—i.e., following treatment, most had returned to the normal range
for their cognitive testing. Furthermore, as noted in the initial description of the protocol used here [3], discontinuation of the protocol was associated with cognitive decline (here, in patient 1). It is not yet known for how many months or years the
marked improvements will be sustained, but loss of improvement in patients maintaining the protocol has not yet been observed, and follow-ups of up to four years have now occurred.

The hippocampal volumetric increase observed for patient 1 does not discriminate between the possibility that synaptic number increased, or glial cell number or volume increased, or endogenous stem cell survival increased, or neuronal cell number or
volume increased, or the vascular compartment increased, or some combination of these possibilities. This volumetric increase, and the marked symptomatic improvement that accompanied it, raises the question of whether it is possible that the patient's
diagnosis of mild cognitive impairment associated with Alzheimer's disease was incorrect. However, the diagnostic evaluation makes this possibility extremely unlikely: given the strong family history of dementia, the ApoE4 heterozygosity, markedly
positive amyloid PET scan, the FDG-PET scan characteristic of Alzheimer's disease with reduced glucose utilization in a temporoparietal distribution, the abnormal neuropsychological testing, and the MRI showing hippocampal volume at 17th percentile for
age, the possibility that the underlying pathological process was something other than Alzheimer's disease is remote. Thus it would be expected that hippocampal volume would decrease over time, and that cognitive decline would occur. Therefore, the
likelihood that his improvement was random and unrelated to the intervention is extremely low.

Similarly, for patient 2, it is highly unlikely that the diagnosis of Alzheimer's disease was incorrect: the ApoE4-positive genotype, the FDG-PET scan typical of Alzheimer's disease with temporoparietal reduction in glucose utilization, the pattern and
severity of quantitative neuropsychological abnormalities, and the well documented progressive nature of the deficits all provide strong support for the diagnosis of Alzheimer's disease. Furthermore, the severity of the abnormalities documented by the
quantitative neuropsychological assessment was also compatible with the diagnosis of Alzheimer's disease. The variations that may occur when different examiners perform the same set of quantitative neuropsychological tests is an obvious concern when
there is a significant change in the results of the tests in one subject. However, in this case, the same examiner performed the same set of tests in each instance, arguing against the possibility that the major improvement observed was simply the result
of examiner-related variability. The magnitude of the improvement also argued against this possibility.

In each of these cases, obvious subjective improvement, noted by the patient, his/her significant other, and his/her co-workers, was accompanied by clear, quantitated, objective improvement. In the cases of patients 1 and 2, the improvement was of a
magnitude not reported previously for patients with Alzheimer's disease. None of the 10 patients exhibited the cognitive decline that is characteristic of Alzheimer's disease, and the improvement experienced by all 10 has been sustained, with the longest
time on the program being four years.

It has been claimed that there is nothing that will prevent, delay, or reverse Alzheimer's disease (www.nih.gov/news-events/news-releases/independent-panel-finds-insufficient-evidence-support-preventive-measures-alzheimers-disease. Therefore, it is
typically recommended that the ApoE genotype, which represents the most important genetic risk factor for Alzheimer's disease, not be evaluated in asymptomatic individuals, and many physicians do not evaluate ApoE genotype even in symptomatic patients.
However, the examples described here complement and extend previously published data that argue that these claims are no longer valid. Thus, given the success of the therapeutic regimen used with these patients, it may be appropriate to evaluate the ApoE
genotype as part of prevention and early reversal of symptoms. Given the approximately 75 million Americans who are heterozygous for the ApoE ε4 allele, and the approximately seven million Americans who are homozygous, early identification and treatment
(presymptomatic or symptomatic) could potentially have a major impact on the prevalence of Alzheimer's disease-mediated cognitive decline.

Acknowledgements

I thank Dr. Rammohan Rao, Dr. Aida Lasheen Bredesen, and Dr. Alexei Kurakin for discussions, and Ms. Rowena Abulencia for preparing the manuscript.

Funding

I am grateful for support from James and Phyllis Easton, the NIH (AG16570, AG034427 and AG036975), the Mary S. Easton Center for Alzheimer's Disease Research at UCLA, the Douglas and Ellen Rosenberg Foundation, the Stephen D. Bechtel, Jr. Foundation, the
Joseph Drown Foundation, the Alzheimer's Association, the Accelerate Fund, the Buck Institute and Marin Community Foundation, the Michael and Catherine Podell Fund, Mr. Craig Johnson, Mr. Allan Bortel, Mr. Wright Robinson, Mr. Jeffrey Lipton, Mr.
Lawrence Dingus, and Ms. Michaela Hoag.

Conflict of Interest Statement

The author of this manuscript declares no conflict of interest.

References

1. James BD, Leurgans SE, Hebert LE, Scherr PA, Yaffe K and Bennett DA. Contribution of Alzheimer disease to mortality in the United States. Neurology. 2014; 82:1045-50.
2. Seshadri S, Drachman DA and Lippa CF. Apolipoprotein E epsilon 4 allele and the lifetime risk of Alzheimer's disease. What physicians know, and what they should know. Arch Neurol. 1995; 52:1074-79.
3. Bredesen DE. Reversal of cognitive decline: A novel therapeutic program. Aging (Albany NY). 2014; 6:707-17. doi: 10.18632/aging.100690.
4. Kurakin A and Bredesen DE. Dynamic self-guiding analysis of Alzheimer's disease. Oncotarget. 2015; 6:14092-14122. doi: 10.18632/oncotarget.4221.
5. Galvan V, Gorostiza OF, Banwait S, Ataie M, Logvinova AV, Sitaraman S, Carlson E, Sagi SA, Chevallier N, Jin K, Greenberg DA and Bredesen DE. Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc
Natl Acad Sci U S A. 2006; 103:7130-35.
6. Bredesen DE, John, V. Next generation therapeutics for Alzheimer's disease. EMBO Mol Med. 2013; 5:795-98.
7. Ross DE, Ochs, A.L., Seabaugh, J., Henshaw, T. NeuroQuant® revealed hippocampal atrophy in a patient with traumatic brain injury. J Neuropsychiatry Clin Neuroscience. 2012; 24:1:33.
8. Ahdidan J, Raji CA, DeYoe EA, Mathis J, Noe KO, Rimestad J, Kjeldsen TK, Mosegaard J, Becker JT and Lopez O. Quantitative Neuroimaging Software for Clinical Assessment of Hippocampal Volumes on MR Imaging. J Alzheimers Dis. 2015; 49:723-32.
9. Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011; 108:3017-22.
10. Fotuhi M, Lubinski B, Trullinger M, Hausterman N, Riloff T, Hadadi M, Raji CA. A personalized 12-week "Brain Fitness Program" for improving cognitive function and increasing the volume of hippocampus in elderly with mild cognitive impairement. The
Journal of Prevention of Alzheimer's Disease. 2016.
11. Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, Lossinsky AS, Graves MC, Gustavson A, Sayre J, Sofroni E, Suarez T, Chiappelli F, et al. Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer's disease patients. J Alzheimers
Dis. 2005; 7:221-232; 255-62.
12. Masoumi A, Goldenson B, Ghirmai S, Avagyan H, Zaghi J, Abel K, Zheng X, Espinosa-Jeffrey A, Mahanian M, Liu PT, Hewison M, Mizwickie M, Cashman J, et al. 1alpha,25-dihydroxyvitamin D3 interacts with curcuminoids to stimulate amyloid-beta clearance by
macrophages of Alzheimer's disease patients. J Alzheimers Dis. 2009; 17:703-17. 13. Bredesen DE. Metabolic profiling distinguishes three subtypes of Alzheimer's disease. Aging (Albany NY). 2015; 7:595-600. doi: 10.18632/aging.100801.
14. Bredesen DE. Inhalational Alzheimer's disease: an unrecognized - and treatable - epidemic. Aging (Albany NY). 2016; 8:304-13. doi: 10.18632/aging.100896.
15. Hooshmand B, Solomon A, Kareholt I, Leiviska J, Rusanen M, Ahtiluoto S, Winblad B, Laatikainen T, Soininen H and Kivipelto M. Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study. Neurology. 2010; 75:1408-14.
16. Yang Y, Wu Y, Zhang S and Song W. High glucose promotes Abeta production by inhibiting APP degradation. PLoS One. 2013; 8:69824.
17. Calsolaro V and Edison P. Neuroinflammation in Alzheimer's disease: Current evidence and future directions. Alzheimers Dement. 2016; 12:719-32.
DOWNLOAD PDF
CORRESPONDING AUTHOR
Dale E. Bredesen, MD
dbredesen@buckinstitute.org
KEYWORDS / RELATED PUBLICATIONS
neurodegeneration cognition biomarkers dementia neuropsychology imaging Alzheimer's disease Apolipoprotein E
TABLE OF CONTENTS
Abstract
Introduction
Results
Discussion
Acknowledgements
Funding
Conflict of Interest Statement
References
Copyright © 2016 Impact Journals, LLC
Impact Journals is a registered trademark of Impact Journals, LLC


http://www.aging-us.com/article/9R5JsRe8k4Jq7uTXj/text

--- SoupGate-Win32 v1.05
* Origin: fsxNet Usenet Gateway (21:1/5)

[continued from previous message]

These observations provide further support for the previously reported finding that the personalized protocol for metabolic enhancement (note that the metabolic evaluation included parameters shown to affect Alzheimer's disease pathophysiology, such as
homocysteine [15], glucose [16], and inflammation [17], as well as numerous others as previously described [3]) in Alzheimer's disease leads to the reversal of cognitive decline in at least some patients with early Alzheimer's disease or its precursors,
MCI (mild cognitive impairment) and SCI (subjective cognitive impairment). To our knowledge, the magnitude of the improvements documented in patients 1 and 2 is unequaled in previous reports: in patient 1, the increase in hippocampal volume from 17th
percentile to 75th percentile supports the marked symptomatic improvement that he (and others) achieved on the protocol. In patient 2, quantitative neuropsychological testing demonstrated improvements of up to three standard deviations (CVLT-IIB, from
3rd percentile to 84th percentile), with multiple tests all showing marked improvements. These findings complement and support the marked subjective improvement already published for this patient [3].

It is noteworthy that these patients met criteria for Alzheimer's disease or MCI prior to treatment, but failed to meet criteria for either Alzheimer's disease or MCI following treatment—i.e., following treatment, most had returned to the normal range
for their cognitive testing. Furthermore, as noted in the initial description of the protocol used here [3], discontinuation of the protocol was associated with cognitive decline (here, in patient 1). It is not yet known for how many months or years the
marked improvements will be sustained, but loss of improvement in patients maintaining the protocol has not yet been observed, and follow-ups of up to four years have now occurred.

The hippocampal volumetric increase observed for patient 1 does not discriminate between the possibility that synaptic number increased, or glial cell number or volume increased, or endogenous stem cell survival increased, or neuronal cell number or
volume increased, or the vascular compartment increased, or some combination of these possibilities. This volumetric increase, and the marked symptomatic improvement that accompanied it, raises the question of whether it is possible that the patient's
diagnosis of mild cognitive impairment associated with Alzheimer's disease was incorrect. However, the diagnostic evaluation makes this possibility extremely unlikely: given the strong family history of dementia, the ApoE4 heterozygosity, markedly
positive amyloid PET scan, the FDG-PET scan characteristic of Alzheimer's disease with reduced glucose utilization in a temporoparietal distribution, the abnormal neuropsychological testing, and the MRI showing hippocampal volume at 17th percentile for
age, the possibility that the underlying pathological process was something other than Alzheimer's disease is remote. Thus it would be expected that hippocampal volume would decrease over time, and that cognitive decline would occur. Therefore, the
likelihood that his improvement was random and unrelated to the intervention is extremely low.

Similarly, for patient 2, it is highly unlikely that the diagnosis of Alzheimer's disease was incorrect: the ApoE4-positive genotype, the FDG-PET scan typical of Alzheimer's disease with temporoparietal reduction in glucose utilization, the pattern and
severity of quantitative neuropsychological abnormalities, and the well documented progressive nature of the deficits all provide strong support for the diagnosis of Alzheimer's disease. Furthermore, the severity of the abnormalities documented by the
quantitative neuropsychological assessment was also compatible with the diagnosis of Alzheimer's disease. The variations that may occur when different examiners perform the same set of quantitative neuropsychological tests is an obvious concern when
there is a significant change in the results of the tests in one subject. However, in this case, the same examiner performed the same set of tests in each instance, arguing against the possibility that the major improvement observed was simply the result
of examiner-related variability. The magnitude of the improvement also argued against this possibility.

In each of these cases, obvious subjective improvement, noted by the patient, his/her significant other, and his/her co-workers, was accompanied by clear, quantitated, objective improvement. In the cases of patients 1 and 2, the improvement was of a
magnitude not reported previously for patients with Alzheimer's disease. None of the 10 patients exhibited the cognitive decline that is characteristic of Alzheimer's disease, and the improvement experienced by all 10 has been sustained, with the longest
time on the program being four years.

It has been claimed that there is nothing that will prevent, delay, or reverse Alzheimer's disease (www.nih.gov/news-events/news-releases/independent-panel-finds-insufficient-evidence-support-preventive-measures-alzheimers-disease. Therefore, it is
typically recommended that the ApoE genotype, which represents the most important genetic risk factor for Alzheimer's disease, not be evaluated in asymptomatic individuals, and many physicians do not evaluate ApoE genotype even in symptomatic patients.
However, the examples described here complement and extend previously published data that argue that these claims are no longer valid. Thus, given the success of the therapeutic regimen used with these patients, it may be appropriate to evaluate the ApoE
genotype as part of prevention and early reversal of symptoms. Given the approximately 75 million Americans who are heterozygous for the ApoE ε4 allele, and the approximately seven million Americans who are homozygous, early identification and treatment
(presymptomatic or symptomatic) could potentially have a major impact on the prevalence of Alzheimer's disease-mediated cognitive decline.

Acknowledgements

I thank Dr. Rammohan Rao, Dr. Aida Lasheen Bredesen, and Dr. Alexei Kurakin for discussions, and Ms. Rowena Abulencia for preparing the manuscript.

Funding

I am grateful for support from James and Phyllis Easton, the NIH (AG16570, AG034427 and AG036975), the Mary S. Easton Center for Alzheimer's Disease Research at UCLA, the Douglas and Ellen Rosenberg Foundation, the Stephen D. Bechtel, Jr. Foundation, the
Joseph Drown Foundation, the Alzheimer's Association, the Accelerate Fund, the Buck Institute and Marin Community Foundation, the Michael and Catherine Podell Fund, Mr. Craig Johnson, Mr. Allan Bortel, Mr. Wright Robinson, Mr. Jeffrey Lipton, Mr.
Lawrence Dingus, and Ms. Michaela Hoag.

Conflict of Interest Statement

The author of this manuscript declares no conflict of interest.

References

1. James BD, Leurgans SE, Hebert LE, Scherr PA, Yaffe K and Bennett DA. Contribution of Alzheimer disease to mortality in the United States. Neurology. 2014; 82:1045-50.
2. Seshadri S, Drachman DA and Lippa CF. Apolipoprotein E epsilon 4 allele and the lifetime risk of Alzheimer's disease. What physicians know, and what they should know. Arch Neurol. 1995; 52:1074-79.
3. Bredesen DE. Reversal of cognitive decline: A novel therapeutic program. Aging (Albany NY). 2014; 6:707-17. doi: 10.18632/aging.100690.
4. Kurakin A and Bredesen DE. Dynamic self-guiding analysis of Alzheimer's disease. Oncotarget. 2015; 6:14092-14122. doi: 10.18632/oncotarget.4221.
5. Galvan V, Gorostiza OF, Banwait S, Ataie M, Logvinova AV, Sitaraman S, Carlson E, Sagi SA, Chevallier N, Jin K, Greenberg DA and Bredesen DE. Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc
Natl Acad Sci U S A. 2006; 103:7130-35.
6. Bredesen DE, John, V. Next generation therapeutics for Alzheimer's disease. EMBO Mol Med. 2013; 5:795-98.
7. Ross DE, Ochs, A.L., Seabaugh, J., Henshaw, T. NeuroQuant® revealed hippocampal atrophy in a patient with traumatic brain injury. J Neuropsychiatry Clin Neuroscience. 2012; 24:1:33.
8. Ahdidan J, Raji CA, DeYoe EA, Mathis J, Noe KO, Rimestad J, Kjeldsen TK, Mosegaard J, Becker JT and Lopez O. Quantitative Neuroimaging Software for Clinical Assessment of Hippocampal Volumes on MR Imaging. J Alzheimers Dis. 2015; 49:723-32.
9. Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011; 108:3017-22.
10. Fotuhi M, Lubinski B, Trullinger M, Hausterman N, Riloff T, Hadadi M, Raji CA. A personalized 12-week "Brain Fitness Program" for improving cognitive function and increasing the volume of hippocampus in elderly with mild cognitive impairement. The
Journal of Prevention of Alzheimer's Disease. 2016.
11. Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, Lossinsky AS, Graves MC, Gustavson A, Sayre J, Sofroni E, Suarez T, Chiappelli F, et al. Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer's disease patients. J Alzheimers
Dis. 2005; 7:221-232; 255-62.
12. Masoumi A, Goldenson B, Ghirmai S, Avagyan H, Zaghi J, Abel K, Zheng X, Espinosa-Jeffrey A, Mahanian M, Liu PT, Hewison M, Mizwickie M, Cashman J, et al. 1alpha,25-dihydroxyvitamin D3 interacts with curcuminoids to stimulate amyloid-beta clearance by
macrophages of Alzheimer's disease patients. J Alzheimers Dis. 2009; 17:703-17. 13. Bredesen DE. Metabolic profiling distinguishes three subtypes of Alzheimer's disease. Aging (Albany NY). 2015; 7:595-600. doi: 10.18632/aging.100801.
14. Bredesen DE. Inhalational Alzheimer's disease: an unrecognized - and treatable - epidemic. Aging (Albany NY). 2016; 8:304-13. doi: 10.18632/aging.100896.
15. Hooshmand B, Solomon A, Kareholt I, Leiviska J, Rusanen M, Ahtiluoto S, Winblad B, Laatikainen T, Soininen H and Kivipelto M. Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study. Neurology. 2010; 75:1408-14.
16. Yang Y, Wu Y, Zhang S and Song W. High glucose promotes Abeta production by inhibiting APP degradation. PLoS One. 2013; 8:69824.
17. Calsolaro V and Edison P. Neuroinflammation in Alzheimer's disease: Current evidence and future directions. Alzheimers Dement. 2016; 12:719-32.
DOWNLOAD PDF
CORRESPONDING AUTHOR
Dale E. Bredesen, MD
dbredesen@buckinstitute.org
KEYWORDS / RELATED PUBLICATIONS
neurodegeneration cognition biomarkers dementia neuropsychology imaging Alzheimer's disease Apolipoprotein E
TABLE OF CONTENTS
Abstract
Introduction
Results
Discussion
Acknowledgements
Funding
Conflict of Interest Statement
References
Copyright © 2016 Impact Journals, LLC
Impact Journals is a registered trademark of Impact Journals, LLC


http://www.aging-us.com/article/9R5JsRe8k4Jq7uTXj/text

--- SoupGate-Win32 v1.05
* Origin: fsxNet Usenet Gateway (21:1/5)