Alzheimer’s Disease
Treatment Update
Monica K. Crane, MD
Associate Director
Cole Neuroscience Center,
Senior Assessment Clinic
Clinical Assistant Professor, Dept. of Medicine
AlzTN meeting version 11/20/2011
Non-pharmacologic treatment
Nonpharmacologic treatment for
Alzheimer’s Disease (AD)
Good physical health = Great
aging brain
 Regular physical exercise
 Positive emotions
 Positive relationships
 Limiting chronic stress
“Memory and the Aging Brain.” Steven W. Anderson, PhD
Thomas J. Grabowski, Jr. MD The University of Iowa. June 2003
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Exercise prevents the chronic
stress-adaptation failure in AD
•  Aerobic exercise
training increases
brain volume in aging
humans
Pereira AC, et al. An in vivo correlate of exercise-induces
neurogenesis in the adult dentate gyrus. PNAS. 2007;
104:5638-5643
Lautenschlager NT et al. Effect of physical activity on cognitive
function in older adults at risk for Alzheimer’s disease. JAMA,
2008;300:1077-1079.
Colcombe SJ et al. Aerobic exercise training increases brain
volume in aging humans. J Gerontol A Bio Sci Med SCi
2006;61:1166-1170.
Kramer AF et al. Exercise, cognition and the aging brain. J Appl
Physiol 2006;101:1237-1242.
How do health problems
affect my brain?
But
AD risk factors
Fixed Risk Factors
Modifiable Risk Factors
•
•
•
•
•  Lack of exercise
•  Smoking
•  High blood pressure and
heart disease
•  High cholesterol
•  Poorly controlled diabetes
•  Low education
Age
Family history
Genetics
Mild Cognitive Impairment
(MCI)
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FDA-approved Medications for
Alzheimer’s Disease
Cholinesterase inhibitors (ChEI)
Donepezil, Rivastigmine, Galatamine
ChEIs prevents the enzyme destruction of the
neurotransmitter acetylcholine (Ach)
–  Acetylcholine declines in AD; loss of cholinergic input to the
cortex from the basal forebrain.
– Donepezil:
•  selective acetylcholinesterase inhibitor
– Rivastigimine & Galatamine:
•  Inhibitor of acetylcholinesterase & butyrylcholinesterase.
Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR. Alzheimer’s disease and senile dementia: loss of
cholinergic neurons in the basal forebrain. Science 1982;215:1237-1239. (Zarate et al 2007; Muhonen et al 2008, Dodel et
al 2008; Maeng et al 2007; Ferguson et al 2007)
Cholinesterase inhibitors (ChEI)
Galatamine: (ER capsule), 8mg x 4 wks, 16mg x 4 wks,
then 24mg thereafter. Take w food. Also as BID dose.
Rivastigmine: Also FDA approved for dementia in
Parkinson’s disease/ Lewy Body Disease.
(Capsule) 1.5mg BID x 2 wks, 3.0mg BID x 2 wks, 4.5 mg BID x
2 weeks, then 6.0 mg BID thereafter. Take with food.
(Transdermal patch): 4.6 mg q 24hrs (5 cm2 size =9 mg), then
increase to 9.5mg/24 hrs after 4 weeks (10 cm2 size=18 mg).
Donepezil:5 mg daily x 4-6 weeks then increase to 10mg;
may increase to 23mg after 12 weeks. FDA has been petitioned
to rescind 23mg formulation.
(Zarate et al 2007; Muhonen et al 2008, Dodel et al 2008; Maeng et al 2007; Ferguson et al 2007, Valeo.
Neurology today 2011)
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Memantine (Noncompetitive glutamate Nmethyl-D-aspartate (NMDA)-receptor blocker)
–  FDA approved for moderate-severe AD.
–  Blocks the NMDA receptor calcium channels,
inhibiting the sustained, low-level influx of excitatory
calcium (Ca2+) ions into postsynaptic glutamatergic
neurons.
–  May have a neuroprotective effect by preventing the
negative consequences of persistent activation of
the neuron.
–  Dose 5mg/day wk1, 5mg BID wk2, 5mg qam and
10mg qpm wk 3, 10mg bid thereafter. ER available.
Source: Atri A, et al. Long-term Course and Effectiveness of Combination Therapy in
Alzheimer’s Disease. Alzheimer Dis Assoc Disord. 2008;22:209-221.
Combination Therapy: Memantine +
Cholinesterase inhibitors
§  NIH-sponsored analysis
of 382 patients over the
course of 15 years
§  Study supports
combination therapy:
§  Memantine +
Cholinesterase
inhibitors
NIH = National Institutes of Health.
Source: Atri A, et al. Alzheimer Dis Assoc Disord. 2008;22:209-221.
Investigational
drugs and vitamin
therapies
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NEGATIVE THERAPIES
DRUG
AN1792 Vaccine
MECHANISM OF ACTION
Abeta immunotherapy
Tramiprosate alzhemed - homotaurine
Abeta aggregation inhibitor
Latrepiridine (Dimebon)
Mitochondrial stabilizer – originally antihistamine
Tarenflurbil (Flurizan)
Semagacestat
Simvastatin
Gamma-secretase modulator
Gamma-secretase inhibitor
Possible membrane lipid modifier
Docosahexaenoic acid (DHA)
Possible membrane lipid modifier or
antioxidant
B12, B6 , Folic Acid, Vitamin E,
Omega-3 fatty acids, Ginko Biloba
Multiple theories, negative longitunidal
studies
Statins:
HMG CoA reductase inhibitors
Statin therapy
•  Evidence shows elective statin use may reduce AD
progression
–  Hyperlipidemia promotes Aβ production and deposition in
animal models of AD and cholesterol reduction reduce Aβ
deposition.
•  Large clinical trials show no efficacy in delaying progression
but NO increased AD risk.
•  Feb 2012: FDA warned that statins could cause “fuzzy”
thinking or reversible memory loss.
•  The evidence: USE statins for patients with heart or
cerebrovascular disease (regardless of AD status)
Sano M et al. A randomized, double-blind placebo controlled trial of simvastation to treat AD. Neurology
2011;77:556-563.
Siegel GJ et al. Statin therapy is associated with reduced neuropathologic changes of AD. Neurology 2008;71:383
Amarenco P, Labreuche J.Lipid management in the prevention of stroke: review and updated meta-analysis of statins
for stroke prevention.Lancet Neurology 2009;8:453 – 463.
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Supplements vs. food
Vitamins D versus
diet/ lifestyle C
•  Diet rich in antioxidants and vitamins beneficial but
NOT pills/ supplements!
•  Vitamin E 
–  No difference between placebo
•  High doses increase stroke risk
•  Increased relative risk of prostate cancer in men
•  Homocysteine lowering therapy (B-vitamins)  Folic
Acid B6, B12 – no benefit with supplements
–  The vitamins lower the homocysteine level but little else.
–  B12 and folic acid supplementation did not have any statistically
significant effect
Miller ER 3rd et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality.
Ann Intern Med. 2005;142:37-46.
Ford et al. Vitamins B12, B6, and folic acid for cognition in older men Neurology 2010;75 :1540-1547.
Vitamins D versus
diet/ lifestyle C
•  DHA L - Docosahexaenoic acid is an omega3
polyunsturated fatty acid found in fish.
–  component of synaptic plasma membranes
–  In animals models, DHA may affect the rate of signal
transduction, be neuroprotective.
–  NEGATIVE RCTs: no effect with supplementation.
•  Ginko biloba L
•  – marketed as a supplement that prevents or delays
cognitive decline
–  VERY LARGE Randomized contrlled trials were
negative
–  A numerically greater number of subjects treated with
ginko developed dementia as compared to placebo
Quinn JF et al. JAMA 2010;304:1903-1911.
DeKosky ST et al. JAMA. 2008;300:2253-2262.
Snitz BE et al. JAMA. 2009;302:2663-2670.
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Anti-inflammatory agents
•  Observational study showed daily ibuprofen use
(>5 YEARS) suppressed amyloid beta 1-42
production, decreased the risk of AD by 25-40%.
–  However, there was an increase risk of serious
adverse events (GI bleeding, other bleeding events).
–  Animal experience indicated that NSAIDs reduce
brain inflammatory markers such as activated
microglia and may reduce brain deposits of Aβ
•  No significant benefit found with prednisone,
diclofenac, rofecoxib, nimesulide or naproxen.
COX-2 inhibitors and nonacetylated agents not
effective.
Lim GP et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for AD. J Neurosci 200;20:5709-5714.
Salloway S, Mintzer J, Weiner MF, Cummings JL. Disease-modifying therapies in Alzheimer’s disease. Alzheimer’s Dementia.
2008;4:65-79.
Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer’s disease. Neurology.
2008;70:1672-1677.
Insulin Resistance and AD
•  Risk factor for AD: Type II diabetes
–  Impaired nsulin signaling in AD, contributing to the
neurodegenerative process.
•  Exendin-4 (or Exenatide)
–  Phase II trials: testing the effects of novel enzymeresistant analogues of the insulin-releasing incretin
hormone, glucagon-like peptide 1 (GLP-1).
•  Intranasal Insulin
–  Delayed memory was improved in the MCI group
receiving 20 IU of insulin (P < .05). Among insulintreated participants, no improvement in biomarkers.
Craft S, Baker LD, Montine TJ, et al Arch Neurol. 2011;Sept 12.
Caffeine may decrease level of beta-amyloid
in AD transgenic mice
•  AD mice received the equivalent
of 5 cups coffee/day for 2 months
•  End result: caffeinated AD mice
performed as well as normal mice
•  Caffeinated mice brains showed
~50% reduction in beta amyloid
•  Researchers suggested that
caffeine suppresses inflammatory
changes in the brain that lead to
an overabundance of beta
amyloid.
Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-β Levels in Aged Alzheimer's Disease Mice; Gary W
Arendash, Takashi Mori, Chuanhai Cao, Malgorzata Mamcarz, Melissa Runfeldt, Alexander Dickson, Kavon Rezai-Zadeh, Jun
Tan, Bruce A Citron, Xiaoyang Lin, Valentina Echeverria, and Huntington Potter; J Alzheimer's Disease, 2009:17:3.
2. Caffeine Suppresses Amyloid-β Levels in Plasma and Brain of Alzheimer's Disease Transgenic Mice; Chuanhai Cao, John R
Cirrito, Xiaoyang Lin, Lilly Wang, Deborah K Verges, Alexander Dickson, Malgorzata Mamcarz, Chi Zhang, Takashi Mori, Gary
W Arendash, David M Holzman, and Huntington Potter; J Alzheimer's Disease 2009; 17:3.
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The Cole Neuroscience
…what's
Clinic mantra is…
good for
your
BRAIN
is good for
your
heart.
Resources
Alzheimer’s Disease Education and
Referral Center
800-438-4380
http://www.nia.nih.gov/alzheimers
Government Web site
http://www.clinicaltrials.gov
Alzheimer’s Tennessee
http://www.alztennessee.org
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Intranasal Insulin
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Insulin dysregulation contributes to AD pathophysiology
Conclusion of study: Insulin resistance BAD for the brain (ie Diabetes is bad for
the brain) while normal insulin activity is good.
Small RCT evaluates the effects of intranasal insulin therapy on cognition,
function, cerebral glucose metabolism and cerebrospinal fluid biomarkers in
adults with amnestic mild cognitive impairment (aMCI) or AD.
3 groups: 36 receiving 20 IU, 38 receiving 40 IU, and 30 with placebo only, for 4
months. Compared with placebo, ubjects receiving 20 IU of insulin daily showed
improved delayed story recall, however no improvement was observed for
participants receiving 40 IU of insulin. Also, compared with the placebo group,
DSRS scores were preserved for both insulin treatment groups. Both insulin
doses also appeared to preserve general cognition (ADAS-cog) as well as
function(ADCS-ADL). The authors also found that participants with AD patients
had preserved function as compared with placebo.
Conversely, participants with aMCI showed no change regardless of treatment
assignment.
Stabilized or improved cognition, function and cerebral glucose metabolism for
adults with aMCI or AD,
Studies in progress
Nicotine and AD
Positive
Negative
•  Evidence that 6 months of
transdermal nicotine (15
mg/day) improves
cognitive test
performance, but not
clinical global impression
of change in nonsmoking
amnestic MCI pts.
•  Associated with an
increased risk of
Alzheimer’s disease
Nicotine treatment of mild cognitive impairment: A 6month double-blind pilot clinical trial Neurology January
10, 2012 78:91-101
•
Association of environmental tobacco smoke with
dementia and Alzheimer’s disease among never
smokers. Alzheimer's & Dementia: The Journal of
the Alzheimer's Association, Dec 2011.
•  Nicotine may also
increase the effect of
altered tau proteins,
causing brain tangles to
develop sooner
LaFerla, FM, Bennett DA, Borwell, RC, Steven H.
Ferris, SH Feb. 7-11, 2005, Proceedings of the
National Academy of Sciences
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