Treatment of Alzheimer’s disease: 2007 Update. Howard S. Kirshner, M.D. Vanderbilt University. Alzheimer’s disease Definition: NINCDS/ADRDA ’84, DSM IV. Acquired syndrome of memory and 2 other cognitive functions (aphasia, apraxia, agnosia, executive function) Progressive
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Howard S. Kirshner, M.D.
7th century BCAge-related mental deterioration recognized
1907AD first described by Dr. Alois Alzheimer
Early 1960sAwareness of AD as a single disease
Research into treatments continues
~200 ADGalen associates “morosis” (dementia) with old age
1978?Single entity established—senile dementia of the Alzheimer’s type (SDAT)
guidelines for AD
1994Brain inflammatory response identified as pathogenetic
Frontal lobe dementia
Progressive supranuclear palsy, many others
Lewy body dementias
Parkinson’s disease Diffuse Lewy body disease Lewy body variant of AD
and Alzheimer’s disease (AD)
AD and Lewybody dementias
Adapted with permission from Zurad E. Drug Benefit Trends. 2001;13:27-40.
Mild ADMMSE 20–23
Moderate ADMMSE 10–19
Severe ADMMSE 0–9
Loss of optimal
Use home appliance
Activities of daily living (ADLs)
Dispose of litter
Progressive loss of function
Adapted with permission from Galasko et al. Eur J Neurol. 1998;5(suppl 4):S9-S17.Functional Decline in AD
Primary somatic sensory cortex
Parietal-temporal-occipital association cortex
Primary visual cortex
Temporal lobeAD Symptoms Correlate With Affected Areas of the Brain
Cummings JL. Am J Psychiatry. 2000;157:4-15. Van Hoesen GW et al. Cereb Cortex. 2000;10:243-251.
This photo shows an Alzheimer amyloid plaque (white) surrounded by reactive astrocytes (brown) and a cluster of microglial cells (black) sitting on top
Amyloid is made up of A-beta peptides of amyloid, 40-42 amino acids
-secretaseProteolytic Cleavages of Amyloid Precursor Protein (APP) Produces A Peptide
Selkoe DJ et al. JAMA. 2000;283:1615-1617.
Rx largely disproved
Other compounds under investigation
Sano M, Ernesto C, Thomas RG, et al. N Engl J Med. 1997.
Bastianetto S, Ramassamy C, Dore S, et al. Eur J Neurosci. 2000.
Patients Who Switched From Placebo to Memantine Improved Relative to the Projected Rate of Decline
Mean Change From Baseline
in SIB Score (± SEM)
*OC analysis; †Memantine vs placebo; ‡Rate of decline between placebo group (weeks 1-28) and placebo-memantine group (weeks 28-52).
Sources: Ferris S, et al. Presented at the 16th Annual Meeting of the American Association for Geriatric Psychiatry; March 1-4, 2003; Honolulu, Hawaii. Data on file, Forest Laboratories, Inc.
Cummings JL, Back C. Am J Geriatr Psychiatry. 1998.
Drug inhibits AChE*Anticholinesterase:Mechanism of Action
Presynaptic nerve terminal
Postsynaptic nerve terminal
* Clinical significance of this mechanism is unknown.
Maelicke A, Albuquerque EX. Eur J Pharmacol. 2000;393:165-170. Nordberg A, Svensson A-L. Drug Safety. 1998;19:465-480.
Krall WJ, Sramek JJ, Cutler NR. Ann Pharmacother. 1999.
Cognitive Benefits in More Advanced AD (MMSE: 5-17)(also Winblad et al, Lancet 2006;367:1057-65) (Donepizil is FDA approved in advanced AD)
MMSE change from baseline
Adapted with permission from Feldman et al. Neurology. 2001;57:613-620.
See Appendix for study description and safety information (Moderate to Severe AD [MSAD]).
ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A.
Adapted from Mycek M et al. In: Harvey RA, Champe PC, eds. Pharmacology: Lippincott’s Illustrated Reviews. Philadelphia, Pa: JB Lippincott Co; 1992:35-44.
Mean Change in ADAS-CogScore From Baseline
Last Prescribed Dosage (mg/day)
Pooled study analysis involving approximately 2800 AD patients treated with either rivastigmine (1-12 mg/day) or placebo for 26 weeks in 4 phase III, randomized, double-blind, placebo-controlled trials.
Adapted from Proceedings, Satellite Symposium, IPA 9th Cong. Aug, 99, P11 * p < 0.05 v/s projected placebo