A. Introduction

1. AD is most common form of dementia (~65%) in USA and Western Europe
2. Progressive dementia affecting memory, affect, behavior, gait, and autonomic system
   1. Degeneration of (cholinergic) neurons in cortex and hippocampus
   2. Mild cognitive impairment (MCI) may be prodromal phase of dementia [44]
3. Early (<60 years) and Late Onset forms of AD exist
4. Late onset (>65 years) represents over 95% of cases
   1. Prevalence increases with age, to ~250/1000 patients age >90 years
   2. Women have slightly higher age-adjusted prevalence than men
5. Prevention
   1. Screening for AD may lead to 2-7 month improvement with current treatments [11]
   2. Participation in cognitively stimulating activities reduces incidence of AD by 7-30% [64,80]
   3. Exercise at least 3 times per week associated with ~40% reduced incidence of dementia in 65 year old persons without baseline dementia
   4. Long-term cognitive training in older adults (without AD) prevents loss of everyday functions, fosters improvements in activities of daily living [91]
6. Median survival after onset of dementia in >65 year olds is ~3.3 years [56]
7. Median survival after AD diagnosis: 4.2 years men, 5.7 years for women [15]
8. Increasing incidence of AD mixed with vascular dementia ("mixed dementia")

B. Clinical Presentation

1. Memory loss, usually recent memory is affected first [12]
2. Parietal Stage disease
   1. Aphasia: language deficiency
   2. Apraxia: cannot perform learned motor movements
   3. Agnosia: cannot recognize words or what is happening in environment
3. Limbic System Changes
   1. Anosmia (loss of smell)
   2. Anterograde and retrograde memory loss
   3. Mood disorders: depression most common
   4. Delusions and other psychoses
   5. Seizures: late onset but uncommon in AD
4. Psychiatric / Behavioral changes
   1. Affect essentially all persons with AD at some point in their disease
   2. Depression and/or depressive symptoms occur in >85% of patients
   3. Agitation and wandering are seen in nearly all patients
   4. Frank psychosis with delusions, often paranoid, and hallucinations
   5. Visual hallucinations more common than auditory
5. After 3-4 years, gait changes
6. Autonomic systems failures in late stage disease
7. Neurological Functions Preserved in AD
   1. Sensation - even with real pain
   2. Fine motor movement

C. Pathology [5]

1. Underlying problem is apoptotic neuronal cell loss leading to progressive brain dsyfunction
   1. Believed that AD is initiated and then progresses from neuron to neuron
   2. Initially in limbic areas, then progresses to parietal part of brain
   3. Possible that some agent enters nose initially and travels to other brain parts
2. Selective Loss of Cholinergic Neurons
   1. Choline acetyltransferase (CAT) and acetylcholinesterase (AChE) are markers of cholinergic neurons
   2. Specific defects in cholinergic neurons were found in moderate severe AD on autopsy
   3. Specific cholinergic neuron loss by histology was not found in early AD on autopsy
   4. Reduced AChE levels found in positron emission tomographic (PET) scans of AD patients versus controls
   5. Reduced CAT levels are also found in AD versus normal persons
3. Neuronal Loss Primarily in Limbic Brain Areas
   1. Posterior Cingulate Gyrus
   2. Parietal Areas
   3. Temporal Areas
   4. Prefrontal Regions (later phase)
4. Amyloid plaques and Neurofibrillary Tangles (NFT) are hallmarks of AD
5. Amyloid (Senile or Neuritic) Plaques [18]
   1. Aggregates of ß-amyloid 1-42 (insoluble) derived from APP (chr 21) with other proteins
   2. Tau protein is found in these plaques
   3. Ubiquitin and other proteins involved in degredation
   4. ApoE (Apo E4 is particularly prevalent) promotes amyloid 1-42 deposition
   5. Alpha-1 antichymotrypsin and fragment of alpha-synuclean
   6. Plaques appear to precede NFT in AD and probably induce them
   7. Inflammatory reaction can be visualized by special PET scanning [58]
   8. Plaques and tangles can visualized by PET-FDDNP imaging [4]
6. Neurofibrillary Tangles (NFT)
   1. Tau proteins (coded on chromosome 17q21-22) involved in microtubule structures
   2. NFT consist of hyperphosphorylated, misfolded, tau proteins
   3. These abnormal tau proteins form misshapen helical fillaments
   4. Mutations in tau genes have not been described in AD
   5. Tau mutations found in frontotemporal dementia with parkinsonism (Pick's Disease)
7. AD with Lewy Bodies
   1. Lewy bodies are classically associated with Parkinson's disease
   2. They are rounded, eosinophilic intracytoplasmic neuronal inclusions

D. Pathophysiology of Common AD [1,5]

1. Unclear Etiology
   1. Genes involved in some forms of AD have been found
   2. Overall, disease involves abnormal protein structure and degradation
   3. Senile (amyloid) plaques and NFT are found
   4. Unclear which of these (or both) is causative
   5. Oxidative injury through free radicals (including lipid peroxides) may play a role [51]
   6. Early and late onset forms of AD appear to have distinct genetic components
   7. Early microglial activation associated with inflammation [58]
2. Late Onset AD Most Common
   1. Usually occurs with autonomic dysfunction
   2. Vascular disorders appear to contribute directly to AD [10]
   3. Apo E e4 allele, hypercholesterolemia, high blood pressure independent risks for AD [10,71]
   4. A chromosome 12 gene also variably linked to late onset familial AD [7,8,9]
   5. Single intronic mutation in ubiquilin 1 (UBQLN1) gene on chromosome 9 associated with increased AD risk [17]
   6. Ubiquilin 1 interacts with presenilins 1 and 2 and promotes their accumulation
   7. Dementia rate in relatives of black AD patients higher than for white AD patients [63]
3. Apolipoprotein E (ApoE) Overview
   1. Three alleles of Apo E (chromosome 19) in humans: ApoE e2, e3, e4
   2. ApoE protein is produced in astrocytes and binds to LDL-receptor
   3. ApoE is transported into neurons; binds to ß-amyloid where e2 and e3 forms protect against neuronal toxicity
   4. ApoE e4 has the highest affinity for ß-amyloid of all Apo E variants
   5. Deposition of ß-amyloid protein (tangles) is highest in persons with the e4 allele [54]
   6. Polymorphisms in ApoE promoter correlate with brain amyloid deposition [54]
   7. Asymptomatic ApoE e4 heterozygotes have reduced glucose metabolism by PET scan in areas of brain most affected by AD
   8. Asymptomatic ApoE e4 homozygotes have increased brain activation during memory tasks compared to ApoE e3 homozygotes (assessed by functional MRI) [48]
4. ApoE Alleles and AD Risk
   1. Homozygous Apo E4 has an increased odds ratio for AD of 2-10 fold in whites [13,14]
   2. Role of ApoE e4 in development of AD in non-whites is controversial [13,14,16]
   3. Overall ~25% of e4 heterozygotes will develop AD
   4. Polymorphism (-491T to A) in ApoE promoter region correlates with AD risk
   5. Promoter polymorphism -491A appears to increase production of Apo E protein [54]
   6. Inflammation (with TNFa) may interact with specific ApoE alleles
   7. ApoE e2 form appears to be protective for late onset AD
   8. Presence of ApoE e4 variant increases risk for non-AD types of dementia [19]
   9. Tumor necrosis factor alpha (TNFa) promoter polymorphism (CT or TT) associated with
5. 7X increase risk of AD in patients with Apo E4 [53]
   1. Elevated levels of plasma apolipoprotein(a) is synergistic with ApoE e4 for risk of late onset AD; lack of apolipoprotein(a) was associated with reduced risk of AD [47]
6. ß-Amyloid Precursor Protein (APP) [18,20]
   1. Normal APP (chr 21) is processed by alpha-, beta- and gamma-secretases
   2. Alpha secretases include TNFalpha converting enzyme (TACE) cleaves most N terminus
   3. ß-secretase cleaves N-terminus of APP into Aß1-40 or Aß1-42 forms
   4. ß-secretase also called ß-amyloid cleaving enzyme, a membrane anchored aspartyl protease
   5. APP is cleaved at C-terminus by gamma-secretasegb
   6. Presenilin 1 appears to enhance gamma-secretase cleavage of APP
   7. APP is abnormally processed and deposited in AD by ß-secretase (and then gamma-secretase)
   8. Alpha-secretase cleaves APP to form sAPPalpha, which is neuroprotective
   9. ß- or gamma-secretase inhibitors are being evaluated in AD
   10. Stimulators of alpha-secretase (to increase sAPPalpha formation and reduce Aß) being sought
7. Aß Peptides in AD [18,46]
   1. Aß1-42 is more prone to aggregation and is found earlier in AD course
   2. Aß 1-40 and Aß 1-42 levels correlate with progressive levels of cognitive decline
   3. Both soluble Aß and insoluble (plaque-based) Aß are increased in AD
   4. Aß 1-42 peptide appears to be the earliest plaque-deposited form of APP in AD
   5. Aß 1-42 oligomers are toxic to neurons, and enhance toxicity of other neurotoxins
   6. Insoluble ß-amyloid is probably biologically intert and probably does not cause dementia
   7. Vaccinations of AD patients targeting Aß peptides can lead to plaque clearing but no improvement in cognition [95]
8. Homocysteine (HC) [65]
   1. HC levels inversely correlated with cognitive function
   2. HC is a vascular toxin
   3. Relative risk of AD was ~2X for HC level >14µmol/L
   4. AD risk increased with increasing HC across all subgroups
   5. Reduction in homocysteine levels with folate, vitamins B6 and B12 may reduce AD Risk
9. Role of Inflammation in AD
   1. Amyloid plaques are inflammatory
   2. Inflammation associated with activation of microglial cells (visualized by PET) [58]
   3. Reduction in prevalance of AD in rheumatoid arthritis patients correlated with length of use on nonsteroidal anti-inflammatory drugs (NSAIDS) [62]
10. Smoking and AD [21]
    1. Smoking increases overall risk of AD about 2 fold
    2. Risk increase primarily in patients without ApoE e4 genotype
11. Presence of cerebrovascular disease in early AD significantly worsens cognitive function [40]

E. Early Onset AD

1. Defined as onset of AD in <60 year olds
2. Very early onset AD defined as onset in <40 year olds
3. Early Onset AD Genetics [22]
   1. Chromosome 21 - Amyloid Precursor Protein (APP)
   2. Chromosome 14 - Presenilin 1 Gene
   3. Chromosome 1 - Presenilin 2 Gene
   4. Contributing Factors: Family History, Downs Syndrome (trisomy 21)
   5. Trisomy 21 (Downs Syndrome) increases risk of early onset AD (increased APP levels)
4. Presenilin 1 (PS1)
   1. PS1 gene mutations found in ~50% of very early onset (<40 years) AD
   2. Over 35 different missense mutations in PS1 have been found in AD
   3. PS1 mutations Gly206Ala common in Hispanic Caribbean early onset AD [60]
   4. PS1 may be involved in Notch signalling pathway in endosomes and Golgi complex
   5. PS1 found in amyloid plaques; may enhance processing of APP (gamma-secretase)
5. Presenilin 2 (PS2)
   1. PS2 mutations found in <1% of early onset AD
   2. Protein has high degree of homology to PS1

F. Diagnosis [2,3]

1. Definitive diagnosis currently only available with brain biopsy or autopsy
2. Use of specific clinical and laboratory criteria for probable AD has a specificity of ~90%
3. Probable AD [24]
   1. Typical history of AD: insidious onset of symptoms, gradual progression
   2. Cognitive loss documented by neuropsychological tests
   3. Rule out other diseases in differential diagnosis (see below)
4. Components of Diagnosis
   1. Clinical History
   2. Neuropsychological Examination such as mini-mental state exam (MMSE)
   3. Physical Examination - neurological exam for focal defects (suggest vascular disease)
   4. Laboratory Evaluation - rule out other causes of dementia
   5. Neuroimaging - recommended for initial diagnostic and possibly monitoring purposes
5. Clinical History and Neuropsychological Exam [12]
   1. Based on DSM-3R or DMS-4 parameters
   2. Symptoms by history (especially from family)
   3. Caution interpreting family reporting as symptom reports are often minimized or explained away by family members
   4. MMSE "Mental Status Exam "
   5. MMSE 10-18 moderate to moderately severe AD; 20-26 mild AD
   6. Ruling out other causes of dementia is difficult with currenlty available tests
6. Dementia and Functional Assessment Scales [43]
   1. Useful as primary outcome measures to assess cognitive performance / clinical change
   2. Alzheimer's Disease Assessment Scale - Score 0 (no impairment) to 70 (severe)
   3. ADAS declines 8-10% per year
   4. Clinical Global Impression of Change Scale - Score 1 (improvement) to 7 (worsening)
   5. CGICS declines ~19% per year
   6. Clinical Interview Based Impression of Change - Score 1 to 7
   7. CIBIC declines 1.4% in 6 months
   8. The MMSE is used primarily in screening for AD and other mental disorders
7. Physical Examination
   1. Focal neurologic deficits suggest vascular cause(s) of or contribution to dementia
   2. Parkinsonism (rigidity, gait disturbance) suggests Parkinson's disease or dementia with Lewy body disease (see below)
   3. Clues to systemic illnesses or infections associated with dementia may be found
   4. Supranuclear cataracts - promoted by cytosolic Aß peptide in AD patients [75]
8. Routine Laboratory Evalation
   1. Rule out other causes of dementia as well as factors in delirium
   2. Complete blood count ± differential
   3. Electrolytes including calcium and phosphorus levels
   4. Blood chemistry with liver and renal function tests
   5. Thyrotropin (TSH) levels to rule out thyroid disease
   6. Vitamin B12 levels to rule out deficiency (associated with mental status changes)
   7. Serologic test for syphilis
9. Selective Laboratory Evaluation in Appropriate Patients
   1. Inflammatory Disease - C-reactive protein or erythrocyte sedimentation rate
   2. Heavy metal screen
   3. HIV Testing
   4. Toxicology Screen: drug abuse or surruptitious drug use
   5. Electroencephalogram (EEG) rarely useful except for CJD and delirium
   6. Neuroimaging (PET scans) and Metabolic Imaging Studies (see below)
10. Clinical diagnosis of AD is incorrect in 6-20% of cases [1,2,23]
    1. Majority of these patients had Parksinon's disease or cerebrovascular disease
    2. Other patients had Pick's disease, diffuse Lewy-Body disease, or other diseases
    3. No CNS-related diagnosis could be made in ~12% of the incorrect AD patients
11. Routine ApoE Genotyping [23]
    1. Not currently recommended for screening or routine diagnosis of AD
    2. An e4 allele occurs in ~65% of patients with non-familial (tissue proven) AD
    3. However, of all dementia patients who had an e4 allele, 93% had AD
    4. Apo e4 allele found in ~75% (sensitivity) of patients with AD
    5. An ApoE e4 alele is highly predictive for AD in patients with memory problems
    6. ApoE genotyping should be considered in many patients with memory problems
    7. Finding ApoE e4 hetero- or homozygosity increases specificity of AD diagnosis
12. ß-Amyloid 1-42 and Tau in Cerebrospinal fluid (CSF) [76]
    1. CSF tau levels are elevated in most AD patients
    2. Other CSF disorders can increase tau (mean 587 versus 244 pg/mL)
    3. Most AD patients have reduced levels of CSF ß-amyloid 1-42 (mean 183 versus 491 pg/mL)
    4. Optimal diagnostic cutoff points lead so sensitivity, specificity >90%
13. Positron emission tomography (PET) with amyloid- plaque/tangle specific agent FDDNP may differentiate between mild cognitive impairment (MCI), AD, and normal brain [4]
14. Great need for diagnostic and monitoring tests for AD [1,22]
    1. Improve prognostic accuracy
    2. Monitor drug efficacy during treatment
    3. Enhance new drug development

G. Imaging Studies

1. All patients with possible AD should undergo CT or MRI scans to rule out other disorders
2. Atrophy
   1. Temporal lobes shrink with disease, so pool of CSF increases
   2. Shrinkage in hippocampus (memory center) and amygdala also most common
   3. Digital Subtraction / Positional Matching MRI can be used to quantitate progress of AD
3. Metabolic Imaging
   1. Positron Emission Tomography (PET) [61]
   2. Single photon emission computed tomography (SPECT) is being used as well [2]
4. PET Scans [41]
   1. With 18F-flurodeoxyglucose can be used to assess regional brain metabolism
   2. PET scans show reduced acetylcholinesterase levels in AD compared with normals
   3. In early AD, bilateral temporal and parietal metabolic defects seen
   4. In more advanced disease, reduced bilateral frontal metabolism seen
   5. PET scanning of patients presenting with dementia symptoms provides >90% sensitivity and ~75% specificity for AD and other neurodenegerative diseases
   6. PET with FDDNP, which binds to plaques and tangles, can be used to distinguish between normal brain, MCI, and AD in early studies [4]
   7. Consider PET in all patients with cognitive symptoms of dementia

H. Differential Diagnosis of Dementia

1. Neurodegenerative Diseases
   1. Alzheimer's Disease (AD)
   2. Dementia with Parkinson's Disease
   3. Dementia with Huntington's Chorea
   4. Spongiform Encephalopathies (mainly CJD)
   5. Corticobasal ganglionic degeneration
2. Vascular Dementia
   1. Vascular disease appears to play a role in AD
   2. Non-AD vascular dementia shows multiple cerebral infarctions
   3. Also called Bindswanger's Disease
   4. Overall, however, incidence of vascular dementia is rarer than previously thought
3. Diffuse Lewy Body Disease - may be second most common cause of dementia [26]
4. Frontoemporal Dementia (Pick's Disease)
5. Korsakoff Syndrome

I. Therapeutic Considerations [24,43]

1. Overview
   1. Acetylcholinesterase inhibitors (ACh-I) show cognitive benefits in mild to moderate AD
   2. Memantine has shown activity in moderate and severe disease
   3. Cognitive activities delay onset and progression of AD [64]
   4. Excercise with behavioral therapy improves physical health and depression in AD [82]
   5. Vitamin E and selegeline have shown some efficacy in retarding disease progression
   6. Increased Vit E, and possibly Vit C and ß-carotene intake from foods associated with reduced AD risk [69,70]
   7. Behavioral and psychiatric manifestations are treated symptomatically
   8. Collaborative care with interdisciplinary team superior to standard care [88]
2. AChE-I are Effective in Mild to Moderate AD [24,25,36,37,74,83]
   1. Efficacy demonstrated primarly in measures of cognition and activities of daily living (ADL) for 3-12 months
   2. Cholinesterase inhibitors and/or memantine should be considered for any patient with dementia, though clinically meaningful responses occur in <25% of patients [36,37]
   3. AChE-I show mean 3-4 mean improvement in ADAS-Cog over 3-6 months [37]
   4. Donepezil
   5. Rivastigmine
   6. Galantamine
   7. Tacrine
   8. Activity of AChE-I wains over time due to down-regulation of AChE and reduced acetylcholine production as disease progresses
   9. Minimal efficacy over 5 years compared with placebo [83]
   10. AChE-I are most effective agents currently available
3. Donepezil (Aricept®) [30,31,43]
   1. Centrally active, non-competitive, selective central AChE-I
   2. Prevents degradation of endogenous ACh leading to increased brain levels
   3. Approved for sympatomic treatment of mild to moderate AD
   4. Dose 5mg po qhs initially, increase to 10mg po qhs after 4-6 weeks if tolerated
   5. Improves cognition and global function in AD f Also effective for moderate to severe AD [67]
   6. In 6-month study in severe AD (MMSE of 1-10), doses of 5-10mg po qd showed improved severe impairment batery score, and less reduction in ADCS-ADL severe score [87]
   7. Adding memantine to denepezil improves all measure of functions in AD patients [34]
   8. Donepezil 10mg po qhs slightly delayed onset of AD in patients with MCI [85]
   9. Donepezil had clear beneficial effects in mild to moderate AD on behavioral and psychological symptoms of dementia [86]
   10. Unlike tacrine, has no significant liver problems
   11. Peripheral cholinergic side effects: nausea, diarrhea, vomiting
4. Rivastigmine (Exelon®) [39,49]
   1. AChE-I with improvement in cognition and global function
   2. Doses of 6-12mg po qd are effective as other agents
   3. Some reduced deterioration rate
   4. Provided modest improvement in mood and cognition in Lewy Body Dementia [52]
   5. Showed ~3 point improvement in cognitive scale over 6 months in Parkinson's Disease [84]
   6. Exelon Patch is now approved for mild to moderate Alzheimer's or Parkinson's Diseases [93]
   7. Patch is begun at 4.6mg (5cm2) x 4 weeks, then increase to 9.5mg (10cm2) patch
   8. If transitioning from oral dose 6-12mg/day, then 9.5mg patch is used 24 hours after last dose
   9. One patch is applied daily to upper or lower back, chest, or upper arms
5. Galantamine (Reminyl®) [57,89]
   1. Competitive, reversible, AChE-I
   2. Modulates nicotinic acetylcholine receptors as well (unclear if this matters)
   3. Effective in 6 month studies; activity apparent for >2 years
   4. Effective (24mg qd) in patients with probable vascular dementia or AD combined with cerebrovascular disease [68]
   5. Initial dose 4mg po bid, increase to 8-12mg bid (8mg bid maximum with renal failure)
6. Metrifonate (trichlorfon) [42]
   1. Drug is metabolized to an active AChE-I called dichlorvos
   2. Dose of 50mg po qd improves cognitive, behavioral, and psychiatric symptoms
   3. Generally well tolerated
7. Eptastigmine [43]
   1. Reversible inhibitor of AChE-I
   2. Effective in 24 week trials in AD
   3. Sinus bradycardia and dose dependent granulocytopenia occur
   4. Clinical studies have been discontinued due to these side effects
8. Tacrine (Cognex®) [32]
   1. First approved centrally acting AChE-I
   2. Approved for mild to moderate AD
   3. Side effects including liver function abnormalities are problematic
   4. In general, donepezil or other ACh-I is strongly recommended over tacrine [1,30]
9. Memantine (Axura®, Namenda®) [73,81]
   1. NMDA antagonists block glutamate activity at NMDA receptors
   2. Memantine is an uncompetitive NDMA antagonist
   3. Memantine 10mg po qd-bid reduced clinical deterioration in moderate to severe AD
   4. When added to donepazil, improves cognition, global outcomes, memory, behavior [34]
   5. Very well tolerated with mild dizziness, headache, constipation
   6. Avoid combination with amantadine (Symmetrel®)
10. Ginko Biloba Extract (EGb761)
    1. Safely and modestly improves AD, about equal to tacrine [29]
    2. However, no benefit on overall memory in patients >60 years after 6 weeks [72]
11. Dimebon [94]
    1. Antihistamine agent with allergy applications
    2. Unclear mechanism; may have mitochondrial pore stabilization function
    3. In 26-week trial 20mg po tid dimebon improved ADAS-Cog 4 points versus placebo
    4. Patients given dimebon had 1.9 point ADAS-Cog improvement over their baseline
    5. Generally well tolerated, with dry mouth (14%) and depressed mood/depression (14%)
    6. Completion rates at 26 weeks better for dimebon than placebo
12. Selegiline and Vitamin E (Tocopherol) [38]
    1. Selegiline (Deprenyl®) is a long acting monoamine oxidase type B (MAO-B) inhibitor
    2. Selegiline is used in the treatment of early Parkinson's Disease (5-10mg/day)
    3. Each of these agents showed weak ability to slow progression of AD in one study [38]
    4. Combination therapy did not show any additive benefit, and data are weak
    5. Vitamin E 2000 IU/d showed no ability to slow progression from MCI to AD [85]
    6. Selegiline showed small short-term improvement in activities of daily living in AD [35]
13. Use of statin anticholesterol agents associated with 50-70% reduction in dementia risk [50]
14. Hormone (Estrogen) Replacement Therapy (ERT/HRT)
    1. Prospective randomized studies found ERT/HRT associated with increased incidence of dementia [77] and small increase in cognitive decline [78]
    2. HRT use over 4 years did not improve cognitive function in postmenopausal women with cardiovascular disease [79]
    3. Estrogen for one year did not prevent decline in mild to moderate AD [45]

J. Experimental Disease Altering Treatments [1,2]

1. Beta and gamma-secretase inhibitors being evaluated
2. Vaccination
   1. Vaccine targeted against Aß1-42 lead to encephalitis in 6% of subjects [3]
   2. This vaccine showed clearing of ß-amyloid plaque over time, but no improvement in dementia [95]
   3. Therefore, plaque may not be pathogenic
3. Nonsteroidal antiinflammatory drugs (NSAIDs) naproxen or rofecoxib showed no benefit on AD progression [28] despite initial positive results [62]
4. Hydroxychloroquine (Plaquenil®) 200-400mg qd had no benefit in early AD [59]
5. Anti-apoptotic agents (neurotrophic factors, others)
6. Agents which block abnormal phosphorylation of Tau proteins
7. Agents which block synthesis or release of ApoE e4

K. Treatment of Psychiatric and Behavioral Problems [1,33,43]

1. Depression
   1. Selective serotonin reuptake inhibitors (SSRI) are first line
   2. Sertraline (Zoloft®) or escitalopram (Lexapro®) are preferred with few side effects and drug interactions
   3. Paroxetine (Paxil®) should be avoided as it has significant anticholinergic activity
   4. Fluoxetine (Prozac®) has a very long half-life and many drug-drug interactions
   5. Atypical antidepressants are also reasonable as alternative first line agents
   6. Venlefaxine (Effexor®) has serotonin and norepinephrine (NE) reuptake blocking actions
   7. Buproprion (Wellbutrin®) has dopaminergic and NE enhancing actions and may be useful for patients where apathy is a major component
   8. Tricyclic antidepressants (TCA) should not be used because of anticholinergic and cardiovascular side effects
2. Psychosis (± Agitation) [90]
   1. Overall, adverse effects mitigate most improvements seen with atypical antipsychotics [90]
   2. Olanzapine or respiridone are both effective for aggressive and/or psychotic patients with dementia but discontinuation rates are high [47,90]
   3. Any agents with significant dopamine blocking activities should be avoided
   4. Classical neuroleptics such as haloperidol have very high incidences of dyskinesia
   5. Resperidone has demonstrated efficacy for the psychosis and agitation in AD, but it too has significant extrapyramidal side effects and no clear net benefit [43,90]
   6. Clozapine (Clozaril®) is effective for the treatment of AD associated psychosis
   7. Clozapine requires biweekly monitoring of leukocyte (neutrophil) counts
   8. Therefore, it is reasonable to assess the efficacy of these agents first in patients with AD and a significant psychotic component
   9. Antipsychotic use must be re-evaluated every 3-6 months for efficacy and safety
   10. Cholinesterase inhibitors may have some benefit on psychotic behaviors in AD
3. Agitation
   1. Must rule out treatable medical causes unrelated to AD
   2. Thorough evaluation of all pharmacologic treatments is also required:
   3. Prescription and over the counter drugs should always suspected causes of agitation
   4. Many drugs cause unusual or paradoxical reactions in the elderly
   5. Antipsychotics are effective for agitation in ~20% of AD patients
   6. Benzodiazepines should be avoided in the elderly (often cause pardoxical agitation)
   7. Acetylcholine enhancing agents may be effective for treatment of agitation
   8. Donepezil of no benefit for agitation in AD patients [92]
4. Sleep Disorders
   1. Avoid benzodiazapines
   2. Avoid antihistamines such as diphenhydramine (Benadryl®) which is anticholinergic
   3. Chloral hydrate may be used for short term treatment
   4. Zolpidem (Ambien®) at low doses (such as 5mg po qhs) should be considered

References

1. Blennow K, de Leon MJ, Zetterberg H. 2006. Lancet. 369(9533):387
2. Clark CM and Karlawish JHT. 2003. Ann Intern Med. 138(5):400
3. Cummings JL. 2004. NEJM. 351(1):56
4. Small GW, Kepe V, Ercoli LM, et al. 2006. NEJM. 355(25):2652
5. Selkoe DJ. 2004. Ann Intern Med. 140(8):627
6. Zandi PP, Carlson MC, Plassman BL, et al. 2002. JAMA. 288(17):2123
7. Rogaeva E, Premkumar S, Song Y, et al. 1998. JAMA. 280(7):614
8. Wu WS, Holmans P, Wavrant-DeVrieze F, et al. 1998. JAMA. 280(7):619
9. Pericak-Vance MA, Bass MP, Yamaoka LH, et al. 1997. JAMA. 278(15):1237
10. Casserly I and Topol E. 2004. Lancet. 363(9415):1139
11. US Preventive Services Task Force. 2003. Ann Intern Med. 138(11):925
12. Karlawish JHT and Clark CM. 2003. Ann Intern Med. 138(5):411
13. Slooter AJ, Tang MX, van Duijn CM, et al. 1997. JAMA. 277(10):818
14. Evans DA, Beckett LA, Field TS, et al. 1997. JAMA. 277(10):822
15. Larson EB, Shadlen MF, Wang L, et al. 2004. Ann Intern Med. 140(7):501
16. Tang MX, Stern Y, Marder K, et al. 1998. JAMA. 279(10):751
17. Bertram L, Hiltunen M, Parkinson M, et al. 2005. NEJM. 352(9):884
18. Merlini G and Bellotti V. 2003. NEJM. 349(6):583
19. Haan MN, Shemanski L, Jagust WJ, et al. 1999. JAMA. 282(1):40
20. Lippa CF, Nee LE, Mori H, St George-Hyslop P. 1998. Lancet. 352(9134):1117
21. Ott A, Slooter AJC, Hofman A, et al. 1998. Lancet. 351(9119):1840
22. Growdon JH. 1999. Arch Neurol. 56:281
23. Mayeux R, Saunders AM, Shea S, et al. 1998. NEJM. 338(8):506
24. Kawas CH. 2003. NEJM. 349(11):1056
25. Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, van den Bussche H. 2005. BMJ. 331:321
26. Beal MF and Vonsattel JP. 1998. NEJM. 338(9):603 (Case Record)
27. Yaffe K, Sawaya G, Lieberburg I, Grady D. 1998. JAMA. 279(9):688
28. Aisen PS, Schafer KA, Grundman M, et al. 2003. JAMA. 289(21):2819
29. La Bars PL, Katz NM, Berman N, et al. 1997. JAMA. 278:1327
30. Donepezil. 1997. Med Let. 39(1002):53
31. Rogers SL, Doody RS, Mohs RC, Friedhoff LT. 1998. Arch Intern Med. 158(9):1021
32. Tacrine. 1993. Med Let. 35(905):87
33. Sink KM, Holden KF, Yaffe K. 2005. JAMA. 293(5):596
34. Tariot PN, Farlow MR, Grossberg GT, et al. 2004. JAMA. 291(3):317
35. Wilcock GK, Birks J, Whitehead A, Evans JG. 2002. Int J Geriatric Psychiatry. 17:175
36. Qaseem A, Snow V, Cross JT Jr, et al. 2008. Ann Intern Med. 148(5):370
37. Raina P, Santaguida P, Ismaila A, et al. 2008. Ann Intern Med. 148(5):379
38. Sano M, Ernesto C, Thomas RG, et al. 1997. NEJM. 336(17):1216
39. Rosler M, Anand R, Cicin-Sain A, et al. 1999. Brit Med J. 318:633
40. Esiri MM, Nagy Z, Smith MZ, et al. 1999. Lancet. 354(9182):919
41. Costa DC, Pilowsky LS, Eli PJ. 1999. Lancet. 354(9184):1107
42. Raskind MA, Cyrus PA, Ruzicka BB, Gulanski BI. 1999. J Clin Psychiatry. 60:318
43. Mayeux R and Sano M. 1999. NEJM. 341(22):1670
44. Ritchie K and Touchon J. 2000. Lancet. 355(9199):225
45. Mulnard RA, Cotman CW, Kawas C, et al. 2000. JAMA. 283(8):1007
46. Naslund J, Haroutunian V, Mohs R, et al. 2000. JAMA. 283(12):1571
47. Mooser V, helbecque N, Miklossy J, et al. 2000. Ann Intern Med. 132(7):533
48. Bookheimer SY, Strojwas JH, Cohen MS, et al. 2000. NEJM. 343(7):450
49. Rivastigmine. 2000. Med Let. 42(1089):93
50. Jick H, Zornberg GL, Jick SS, et al. 2000. Lancet. 356(9242):1627
51. Pratico D and Delanty N. 2000. Am J Med. 109(7):577
52. McKeith I, Del Ser T, Spano P, et al. 2000. Lancet. 356(9247):2031
53. McCusker SM, Curran MD, Dynan KB, et al. 2001. Lancet. 357(9254):436
54. Lambert JC, Mann D, Goumidi L, et al. 2001. Lancet. 357(9256):608
55. LeBlanc ES, Janowsky J, Chan BKS, Nelson HD. 2001. JAMA. 285(11):1489
56. Wolfson C, Wolfson DB, Asgharian M, et al. 2001. NEJM. 344(15):1111
57. Galantamine. 2001. Med Let. 43(1107):53
58. Cagnin A, Brooks DJ, Kennedy AM, et al. 2001. Lancet. 358(9280):461
59. Van Gool WA, Weinstein HC, Scheltens PK, Walstra GJM. 2001. Lancet. 358(9280):455
60. Athan ES, Williamson J, Ciappa A, et al. 2001. JAMA. 286(18):2257
61. Silverman DHS, Small GW, Chang CY, et al. 2001. JAMA. 286(9291):2120
62. In't Veld BA, Ruitenberg A, Hofman A, et al. 2001. NEJM. 345(21):1515
63. Green RC, Cupples LA, Go R, et al. 2002. JAMA. 287(3):329
64. Wilson RS, Mendes de Leon CF, Barnes LL, et al. 2002. JAMA. 287(6):742
65. Seshadri S, Beiser A, Selhub J, et al. 2002. NEJM. 346(7):476
66. Schneider RK and Levenson JL. 2002. Ann Intern Med. 136(4):298
67. Feldman H, Gauthier S, hecker J, et al. 2001. Neurology. 57:613
68. Erkinjuntti T, Kurz A, Gauthier S, et al. 2002. Lancet. 359(9314):1283
69. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. 2002. JAMA. 287(24):3223
70. Morris MC, Evans DA, Bienias JL, et al. 2002. JAMA. 287(24):3230
71. Kivipelto M, Helkala EL, Laakso MP, et al. 2002. 137(3):149
72. Solomon RR, Adams F, Silver A, et al. 2002. JAMA. 288(7):835
73. Reisberg B, Doody R, Stoffler A, et al. 2003. NEJM. 348(14):1333
74. Trinh NH, Hoblyn J, Mohanty S, Yaffe K. 2003. JAMA. 289(2):210
75. Goldstein LE, MuffatJA, Cherny RA, et al. 2003. Lancet. 361(9365):1258
76. Sunderland T, Linker G, Mirza N, et al. 2003. JAMA. 289(16):2094
77. Shumaker SA, Legault C, rapp SR, et al. 2003. JAMA. 289(20):2651
78. Rapp SR, Espeland MA, Shumaker SA, et al. 2003. JAMA. 289(20):2663
79. Grady D, Yaffe K, Kristof M, et al. 2002. Am J Med. 113(7):543
80. Verghese J, Lipton RB, Katz MJ, et al. 2003. NEJM. 348(25):2508
81. Memantine. 2003. Med Let. 45(1165):73
82. Teri L, Gibbons LE, McCurry SM, et al. 2003. JAMA. 290(15):2015
83. AD2000 Collaborative Group. 2004. Lancet. 363(9427):2105
84. Emre M, Aarsland D, Albanese A, et al. 2004. NEJM. 351(24):2509
85. Petersen RC, Thomas RG, Grundman M, et al. 2005. NEJM. 352(23):2379
86. Holmes C, Wilkinson D, Dean C, et al. 2006. Ann Intern Med. 144(6):424
87. Winblad B, Kilander L, Eriksson S, et al. 2006. Lancet. 367(9516):1057
88. Callahan CM, Boustani MA, Unverzagt FW, et al. 2006. JAMA. 295(18):2148
89. Rockwood K, Fay S, Song X, et al. 2006. CMAJ. 174(8):1099
90. Schneider LS, Tariot PN, Dagerman KS, et al. 2006. NEJM. 355(15):1525
91. Willis SL, Tennstedt SL, Marsiske M, et al. 2006. JAMA. 296(23):2805
92. Howard RJ, Juszczak E, Ballard CG, et al. 2007. NEJM. 357(14):1383
93. Exelon Patch. 2008. Med Let. 50(1282):21
94. Doody RS, Gavrilova SI, Sano M, et al. 2008. Lancet. 372(9634):207
95. Holmes C, Boche D, Wilkinson D, et al. 2008. Lancet. 372(9634):216