Prevention of Alzheimer’s Disease
Heidi D. Klepin
Resident Grand Rounds
November 28, 2000
Mrs K. is a 58 year old white female who presents to her primary care physicians office for a yearly
follow-up. She reports no problems in the last year with the exception of two episodes of poison ivy.
Her review of systems is negative with the exception of some mild arthritis in the hands.
FH: colon cancer, CAD
SH: married with 2 grown children. Does office work and remains very active physically and socially.
No tobacco. Social alcohol.
Medications: HRT which she cuts into quarters.
Labs: lipid normal
Health maintenance: encouraged patient to have screening colonoscopy, up to date on mammogram
At the end of the interview the patient says that she recently read in Prevention magazine that
vitamin E helped improve memory and prevent Alzheimer’s disease. She had also heard something
about Ginkgo biloba from a friend at work. She asks if she could be advised on what to take, if
anything, to prevent Alzheimer’s disease.
Clinical question: Are there any medications that have been proven to help prevent Alzheimer's
Table of Contents:
I. Definition of Alzheimer’s disease
IV. Rationale for prevention
V. Risk factors
VII. Anti-inflammatory medication
IX. Ginkgo biloba
Can we prevent it?
Heidi D. Klepin
November 28, 2000
Alzheimer’s disease is a progressive neurologic disorder characterized by memory loss, cognitive
dysfunction, personality changes and global functional decline. It is the most common type of dementia
accounting for atleast 60% of cases18. It typically develops insidiously and progresses gradually over
time. Classically, patients initially experience short term memory loss often with some impairmed
orientation, judgement, problem solving and perception which may be subtle and missed by family and
clinicians18. As the disease progresses patients become increasingly dysfunctional and eventually
completely dependent in IADLs and ADLs. Cognitive decline is often paired with behavioral
disturbance and mood disorders as well.
Alzheimer’s disease is both a clinical and pathological diagnosis. Currently the most accepted diagnostic
criteria for Alzheimer’s disease was introduced by the Work Group of the National Institute of
Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related
Disorders Association (NINCDS-ADRDA) which is listed below.
Table 1: Criteria for the Diagnosis of Alzheimer’s Disease
Probable Alzheimer’s Disease All of the following must be present:
- Dementia established by exam and objective testing
- Impairment in memory and atleast one other cognitive
function (ex. language and perception)
- Progressive worsening of memory and atleast one other
- No disturbance in consciousness
- Onest between 40 and 90 years of age
- Absence of another grain disorder or systemic disease
that might cause dementia
In addition the diagnosis may be supported by one of the
- Loss of motor skills
- Diminished independence in ADLs and altered patterns
- Family history of similar disorder
- Laboratory results consistent with the diagnosis (ex.
cerebral atrophy on CT scan)
Possible Alzheimer’s Disease - Fulfillment of the above criteria with variation in the
onset of symptoms or manifestations or in clinical
course; or a single, but gradually progressive, cognitive
impairment without and identifiable cause.
- Another brain disorder or systemic disease that is
sufficient to produce dementia, but that is not considered
to be the underlying cause of the dementia in the patient.
Definate Alzheimer’s disease - Fulfillment of the above clinical criteria and histiologic
evidence of Alzheimer’s disease based on the examination of
brain tissue at biopsy or autopsy. (NEJM Nov 25, 1999)
The histopathology of Alzheimer’s disease includes neuritic plaques (senile plaques), neurofibrillary
tangles, loss of synapses and neurons, granulovacular degeneration and amyloid angiopathy 2,4. The
neuritic plaques are extracellular lesions consisting of degenerating neuronal processes (neurites) and
abnormal deposits of amyloid protein 4. Neurofibrillary tangles are intraneuronal structures configured as
paired helical filaments consiting primarily of abnormallly phosphorylated tau protein 2,4. The
neurofibrallary tangles lead directly to cell death, although, cell death is not limited to only neurons
containing this classical finding of Alzheimer’s disease (AD)2. The evolution and distribution of plaques
and tanles in the brain is systematic in AD2,4 and correlates with the usual symptomatic progression of
disease. Of note neuritic plaques have also been seen in the normal aging process while neurofibrillary
tangle have been assiciated with other neurologic disorders including Parkinson’s disease , dementia
pugilistica, subacute sclerosing, panencephalitis and early onset epilepsy byt not normal aging2. Loss of
number of neurons and synapses is also classically seen in AD patients. One study reported a 45%
decrease in presynaptic terminal density at the time of autopsy2.
There is also evidence of inflammation within or adjacent to neuritic plaques2. Multiple acute phase
reactants have been detected as well as activation of the complement system 2. Inflammatory activity
may play a role in amyloid metabolism and subsequent cell death2. Research is currently underway
regarding the beneficial effects of anti-inflammatory medication and dementia.
Amyloid metabolism is felt by many researchers to be the central focus of AD pathologic changes in the
brain. Many studies in vitro and in vivo have demonstrated the toxic effects of abnormal accumulation of
amyloid protein on neuronal tissue2,4. The amyloid-beta protein is part of a larger molecule which itself
has not demonstrated neurotoxicity. Major catabolism of this protein (APP) does not liberate amyloid-
beta secondary to cleaving within the beta portion of the protein. A minor pathway requiring 2 cleavage
events liberates beta-amyloid. All genetic mutations that lead to an increased risk of AD as well as
normal aging and traumatic brain injury cause increased production of amyloid-beta 2. The mechanism
by which this protein exerts neurotoxic effects is not clear. It is hypothesized that amyloid-beta increases
production of H2O2 leading to oxidative cell damage and cell death2. The potential role of free radicals
has prompted research into the theraputic benefits of antioxidants. Amyloid beta protein also disturbs
calcium metabolism and increases the intrneuronal calcium concentrations that may lead to cell death by
activating intracellular proteases and lipases, abnormal phosphorylation of protein resulting in
neurofibrillary tangles and direct damage to cell mitochondria2. The potential role of calcium channel
blockers in AD is also being explored.
Neurotransmitter disturbances have been well documented in Alzheimer’s disease and have been the
focus of most drug related research. Acetylcholine (ACh) levels are consistently decreased in AD
patients. This is secondary to neuronal destruction in the nucleus basalis of Meynert in the basal
forebrain where most ACh is synthesized, which occurs early and consistently in AD. Choline
acetyltransferase (CAT) which synthesizes Ach is reduced by 58-90% in AD patients and correlates with
the severity of dementia2. The acetylcholinesterase inhibiters including tacrine and donepazil were
developed to target this aspect of AD pathology. Muscarinic (M1) and nicotinic cholinergic recepters
have also been found to be decreased in AD2. Other neurotransmitters not related to the cholinergic
system including serotonin, GABA, somatostatin, norepinephrine have been shown to be reduced in AD
as well and may play a role in cognitive dysfunction.
Alzheimer’s disease is the most common form of dementia in the United States. Is is estimated to affect
4 million people. The incidence of AD is estimated at 0.5% per year at age 65 and 8% per year after the
age of 85. Since average survival with disease is 10 years, the prevalence of AD increases from 3% at 65
years of age to approximately 47% at 85 years of age. The proprtion of the US poulation greater than 80
years old is expected to double in 10 years with significant implications for the number of patients
suffering from this disease.
In addition to the social and psychological stresses produced by this disease process, patients with AD are
at increased risk for many medical problems. They suffer from an increased incidence of neurologic
complications, infections, hip fractures and malnutrition. Specifically, these patients have been shown to
be at higher risk for stroke, myoclonus, urinary tract infection and aspiration pneumonia6. Furthermore,
as neurologic function declines most patients require increasingly intensive supervision and care, most
often resulting in nursing home placement.
The financial burden of AD is impressive. In 1991, the estimated cost of caring for and individual with
AD was $47,000 per year. The combined direct and indirect colst including medical care, loss of
productivity, resource loss and family care for all patients with AD in the US is estimated at 100 billion
dollard per year.
Alzheimer’s disease is already a significant public health problem and will continue to become more
prominent over the next few decades as the population ages. A recent paper by Brookmey et al.
Projected that the prevelance of AD would quadruple in the next 50 years. They used a prevalence
estimated of 2.3 million people with AD (1997) and projected a 3 fold increase in the number of patients
afflicted by the year 2047. They calculated that a delay in onset of disease by 5 years would decrease the
prevalence of AD by 1.15 million people 10 years later and 4 million people 50 years later. Even a 1
years delay in onset of symptoms could decrease the number of patients with AD by 210,000 at 10 years
and 770,000 at 50 years. The calculated economic benefit of such a preventative measure would be
about 10 billion dollars 10 years after initiation of intervention (using a yearly cost of $47,000 x 210,000
IV. Risk Factors
A. Mechanism of Action
The benefit of estrogen on cognitive function and potential role for estrogen in the treatment and
prevention of dementia has intrigued scientists for years. Basic science research has provided the
groundwork for recent clinical trials. Multiple mechanisms have been proposed which might contribute
to a decreased risk of dementia and specifically AD.
Animal models have shown that chronic estrogen deficiency affects behavior and cognitive function,
specifically decreasing performance on tasks of memory and learning16. This has been associated with
decreased cholinergic activity and is improved with estrogen replacement. Estrogen appears to modulate
mutiple neurotransmitters within the brain. It has been shown to increase choline acetyltransferase,
increase release of acetylcholine and prolong survival of cholinergic neurons. Estrogen has also been
shown to decrease monoamine oxidase activity which is results in decreased catabolism of
In vitro studies have also shown that estrogen stimulates neurite growth and synapse formation 17.
In vitro studies have shown that estrogen increases metabolism of amyloid precurser protein (APP) into
nontoxic peptides, which could have signigicant impact on Alzheimer’s disease pathology17. Estrogen
may also influence inflammatory repsonses via effects on interleukin-6, a cytokine postulated to
participate in neuritic plaque formation17.
Estrogen improves regional blood flow in the brain and may be protective against cerebral ischemia 17.
Estrogen may also influence genetic predispostition to Alzheimer’s disease. Studies have suggested that
estrogen modulates expression of apolipoprotein E gene and may supress the expression apo E-4 in
Summary of pathophysiologic benefits of estrogen
• increased cholinergic activity
• decreased catabolism of catecholamines secondary to inhibition of MAO
• stimulation of neurite growth and synapse formation
• decreased production of toxic beta-amyloid protein
• antiinflammatory effect
• improved regional blood flow
• supression of apoE-4 expression
C. Clinical Trials
The effect of estrogen on cognition has been the subject of numerous trials. This paper will consider
trials that looked at the effect of estrogen directly on cognition as well as studies that addressed the
association between estrogen and AD directly.
There have been 7 large observational trials addressing the effect of estrogen on cognitive function.
Conclusions: Effect of estrogen on cognitive function
• Contradicory results with no consistantly reproducible benefit of estrogen use on cognitive function
• Prospective trials did not show improvement in cognitive decline with estrogen use
Observational trials limited by lack of randomizatiom and potential inherent differences between study