1. The Management of Alzheimer’s Disease
Laurel Coleman, MD
Maine Medical Center
Portland, Maine

2. Management of Alzheimer’s Disease
Manage cognitive symptoms
Increased quality of life for patient and family
Manage BPSD
Although there is no current cure for Alzheimer’s disease, both nonpharmacological and pharmacological interventions are needed to optimally treat the cognitive, behavioral and psychological symptoms in patients with the disease. When coordinated with support services, outcomes for the patient, family and caregiver can be improved.
Support patient/family

3. Pharmacologic Options for AD
Cognitive enhancers
2 classes
Cholinesterase inhibitors (ChEIs)
NMDA-receptor antagonist
Do not cure the disease or reverse cognitive impairment
Can improve cognition and functional ability
Reduce the rate of decline 9-12 months (ChEIs)
Delay in nursing home placement was months (ChEIs)
Rate of decline. [Farlow et al. Eur Neurol. 2000;44: Doody et al. Arch Neurol. 2001;58: Raskind et al. Neurology. 2000;54: Winblad et al. Neurology. 2001;57: ]
NH placement . [Geldmacher et al. JAGS. 2003;51: Lopez et al. Neurol Neurosurg Psychiatry. 2002;72: Knopman et al. Neurology. 1996;47: ]
Cholinesterase inhibitors delay the breakdown of acetylcholine released into synaptic clefts and so enhance cholinergic neurotransmission
Memantine may prevent excitatory neurotoxicity by binding to the NMDA receptor and normalizing the influx of magnesium and calcium into the synapse???

4. Management of Alzheimer’s Disease: Cognitive Enhancers
*Available in generic
Drug Name
 Dosage form
Dosage range
Minimum titration interval (as tolerated)
Indication
Donepezil
(Aricept)
Tablet*, orally disintegrating tablet*
5 mg – 23 mg QD
4 weeks 5 mg  10 mg
3 months
10 mg  23 mg
Mild to severe
Galantamine (Razadyne®)
Tablet/oral solution*
Extended-release capsule*
4 mg – 12 mg BID
8 mg – 24 mg ER QD
4 weeks
Mild to moderate
Rivastigmine (Exelon®)
Capsule*
Patch
1.5 mg – 6 mg BID
4.6 mg – 9.5 mg QD
2 weeks
Memantine (Namenda®)
Tablet*, oral solution*
5 mg – 10 mg QD
1 week
Mod to severe
Cholinesterase inhibitors - Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. The evidence from one large trial shows fewer adverse events associated with donepezil compared with rivastigmine. [Birks 2006]
When prescribing any of these medications it is important discuss reasonable expectations and goals of therapy with families and caregivers.
For best results, these medications should be titrated to the highest tolerated dose.
Alternative dosage forms may improve compliance.
Aricept [product information]. Woodcliff Lake, NJ: Eisai Corp; 2010.
Razadyne [product information]. Titusville, NJ: Ortho-McNeil Neurologics; 2011.
Exelon [product information]. East Hanover, NJ; Novartis Corp; 2009.
Aricept® package insert. Razadyne® package insert. Exelon® package insert.

5. Pharmacologic Options for AD Common Side Effects
Cholinesterase inhibitors (Donepezil, galantamine, rivastigmine)
NMDA-receptor antagonist
(Memantine)
Nausea
Vomiting
Diarrhea
Weight loss
Loss of appetite
Muscle weakness
Vivid dreams/nightmares (donepezil)
Dizziness
Headache
Constipation
Confusion
ChEIs
The most common reason for discontinuing a ChEI is gastrointestinal disturbances, such as nausea, vomiting and diarrhea that may result in anorexia and weight loss.
Cardiovascular side effects include dizziness, syncope and bradycardia
Incontinence, leg cramps and sleep disturbances also may occur.
Side effects associated with cholinesterase inhibitors occur primarily during the dose-escalation phase of therapy and seem to be transient.
If patient is not tolerating a cholinesterase inhibitors, switching to another agent may minimize side effects.
Aricept® package insert. Razadyne® package insert. Exelon® package insert.

6. Switching ChEIs Lack or loss of therapeutic benefit
Immediate switch No washout needed
Washout period of
1-2 weeks before starting another agent
Tolerability issues
Try an alternate dosage form before switching
Noncompliance

7. Discontinuation of Therapy
Data for optimal duration of treatment as disease progresses is limited
Modest cognitive and functional benefits associated with continued therapy with (donepezil) in moderate to severe AD1
Discontinuation associated with adverse behavioral changes and reduced participation in activites2
Consider discontinuation in the following situations:
Inability to tolerate multiple ChEIs
No improvement or greater than expected decline after one or more therapeutic trials
End-stage dementia
Appropriate time to discontinue therapy is controversial
Howard et al. New Engl J Med. 2012;366:
Daiello et al. Am J Geriatr Pharmacother. 2009;7:74-83.

8. Impact of Coexisting Medical Conditions
2.4 conditions/pt
HTN 82%
DM 39%
CAD 21%
CHF 14%
Stroke 10%
Many people with Alzheimer’s disease and other dementia also have other serious chronic conditions.
Interactions between dementia and these coexisting conditions can make care difficult.
The comorbid condition or its treatment can worsen cognitive impairment and cognitive impairment can exacerbate serious medical conditions and complicate treatment.
Accurate information about the prevalence of coexisting medical conditions in people with dementia is difficult to obtain (Maslow 2004)
Dementia is often undiagnosed or undocumented diagnosis
Clinical studies may exclude PWD who have coexisting conditions
PWD complain about symptoms unrelated to their cognitive impairment much less often than the nondemented controls (McCormick – 20)
Cognitive
Impairment
Prevalence of coexisting conditions in PWD
Schubert CC, et al. J Am Geriatr Soc. 2006;54(1):104–109.

9. Impact of Coexisting Medical Conditions
PWD in primary care average 5.1 medications/pt1 
50% take ≥1 anticholinergic medications
Medications with anticholinergic activity
Impairs cognition acutely (delerium) and chronically2
Anticholinergic burden
Interfere with the therapeutic effect of ChEIs3
The use of drugs with anticholinergic activity has been an integral part of the routine treatment of common conditions such as asthma, urinary incontinence, and various psychiatric disorders.
Medications with anticholinergic activity negatively affect the cognitive performance of older adults. Recognizing the anticholinergic activity of certain medications may represent a potential tool to improve cognition.
Anticholinergic use may interfere with cholinesterase inhibitors
These effects may be due to an accumulation of multiple medications with anticholinergic activity (anticholinergic burden) rather than one drug with strong anticholinergic effects.
1. Schubert CC, et al. J Am Geriatr Soc. 2006;54(1):104–109.
2. Campbell N, et al. Clin Interv Aging. 2009;4:225–233.
3. Lu C, Tune LE. Am J Geriatr Psychiatry. 2003;11(4):458–461.

10. Behavioral and Psychological Symptoms of Dementia (BPSD)
Apathy
Depressive symptoms
Anxiety
Agitation/irritability/ aggression
Psychotic symptoms
Delusions
Hallucinations
Disinhibition
Euphoria
Loss of appetite
Sleep disturbances
Stereotyped behaviors (eg, pacing, wandering, rummaging, picking
Many people with Alzheimer’s and their families find behavioral symptoms to be the most challenging effects of the disease.
BPSD contributes to caregiver burden, cognitive impairment, functional decline and costs of care.
Agitation, aggression, depression and psychosis are the leading causes for assisted living or nursing facility placement. [Yaffe et al.JAMA.2002;287:2090. Gauthier et al. IntJGeriatrPsychiatry. 2008;23:537.
60%-90% of patients will have BPSD at some point (higher in institutional settings). [Lyketsos et al. JAMA. 2002;288: Mega et al. Neurology. 1996;46: Steinberg et al. Int J Geriatr Psychiatry. 2008;23: Zuidema et al. J Geriatr Psychiatry Neurol. 2007;20: Haupt M, Kurz A, Janner M. A 2-year follow-up of behavioural and psychological symptoms in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2000; 11: ]
The presence of one or more APOE e4 alleles is a significant predictor of the incidence of delusions. [Scarmeas et al. Neurology. 2002;58: ]
Leaving patients’ behavioral and pyschological symptoms of dementia untreated has been associated with caregiver burnout, nursing home placement, poor management of comorbid conditions, and excess health care costs. [Steele C, Rovner B, Chase GA, Folstein M. Psychiatric symptoms and nursing home placement of patients with Alzheimer’s disease.AmJ Psychiatry. 1990; 147: Cohen-Mansfield J. Assessment of disruptive behavior/agitation in the elderly: function, methods, and difficulties. J Geriatr Psychiatry Neurol. 1995;8: Ballard C, Neill D, O’Brien J, McKeith IG, Ince P, Perry R. Anxiety, depression and psychosis in vascular dementia: prevalence and associations. J Affect Disord. 2000;59: ]
Tampi et al. Clinical Geriatrics. 2011;19:41-46.

11. Managing BPSD Identify triggers Make adjustments Modify as needed
Observe symptom timing and frequency
Look for environmental triggers, eg noise, lighting
Investigate potentially treatable causes, eg pain
Make adjustments
Address medical causes
Adapt environment
Adapt caregiving
Modify as needed
Early recognition and treatment of BPSD helps to decrease morbidity, reduce the costs and burden of caring for these patients, and improve patient and carepartner quality of life.
The first step to reduce or stabilize BPSD is to identify the trigger. Determining when the behavior occurs and how often is often helpful.
Behaviors are a form of communication, especially if the person with dementia cannot communicate in other ways. They may be a response to a symptom of illness, a stressful environment or an unmet need.
Common causes include the following;
Environmental triggers, such as excessive stimulation, dim lighting, or changing caregivers
Medical causes, such as bowel impaction, infection, or untreated pain.
Medication side effects
Inability to communicate (understand or be understood)
Correctly identifying what triggered the behavior can help in selecting the best intervention.

12. Managing BPSD Nonpharmacological Interventions
Use the “3 Rs”—repeat, reassure, redirect
Simplify the environment, task, routine
Anticipate unmet needs
Allow adequate rest between stimulating events
Use cues
Encourage physical activity
Other interventions
A key principle of intervention is redirecting the person’s attention, rather than arguing or being confrontational. Additional strategies include:
Simplifying the environment, tasks and routine
Anticipating unmet needs, such as hunger, thirst, full bladder
Allowing adequate rest between stimulating events
Using cues or reminders
Encouraging physical activity
Other interventions with limited evidence of efficacy include: music therapy, bright light treatment, aromatherapy, sleep hygiene.

13. Managing BPSD: Pharmacologic Interventions
Drug class
Chemical name
Dosage range (mg)
Side effects of class
Antipsychotics
Aripiprazole*
Haloperidol
Risperidone*
Quetiapine*
Olanzapine*
2.5-15
0.5-5
0.25-2
25-200
Sedation, EPS, NMS, metabolic syndrome, QTc prolongations, increased risk of CVE and mortality
Antidepressants
Fluoxetine
Citalopram
Paroxetine
Sertraline
Trazadone
10-80
10-60
10-50
Anxiety, headaches, sedation, GI symptoms, sexual dysfunction
Mood stabilizers
Carbamazepine
Divalproex sodium
Oxcarbazepine
Sedation, gait and balance issues, falls, liver dysfunction, hyperammonemia, thrombocytopenia
*2nd-generation antipsychotics
When nonpharmacological interventions fail or the BPSD endangers the safety of the patient or others, pharmacological treatment may be needed.
The FDA has not approved any medication for the treatment of BPSD.
The antipsychotics, especially the second generation agents, are the most commonly prescribed medications for BPSD.
They have demonstrated modest benefits in senior patients with dementia, which should be weighed against their considerable risks of adverse events, including heart failure and sudden death.
The cognitive enhancers (cholinesterase inhibitors and memantine) have been shown to improve neuropsychiatric and functional outcomes.
Other alternatives to treat BPSD are antidepressants and mood stabilizers (anticonvulsants).
Antidepressants are generally well tolerated in persons with dementia [Henry et al. Am J Alzheimers Dis Other Demen ], but evidence is variable.
Mood stabilizers may be effective in some patients, but their side effects often limit use. [Konovalov et al.IntPsychogeriatr ]
Adapted from Tampi et al. Clin Geriatr. 2011;19:31-32.

14. Education of Patient and Family
Alzheimer’s Disease
Education of Patient and Family

15. Education of Patient and Family
Safety issues:
Home environment
Driving
Medication adherence
Financial exploitation
Elder abuse
Address future needs: financial planning, advanced directives, power of attorney
Safety hazards at home
Household accidents, eg, kitchen fire, power tools
Falls
Impaired judgement, visual perception, and spatial perception significantly increase the risk of falls in people wie AD and other dementias. [194, 195]
Falls are a major cause of serious injury and emergency department visits in the elderly population [196]
Wandering
Prevalence of wandering among people with dementia varies widely in clinical in studies– from 12% to 63% in the community. [Rowe et al. Am J Alz Dis Oth Dement. 2010;25: Klein et al. Int J Geriatr Psych. 1999;14: Calkins et al. J Alz Care & Related Dis Research. 1991; 6: Sayva et al. B J Psych. 2009; 194: Rolland et al. Alzheimer’s Dis Assoc Disord. 2007;21: Hope et al. Int J Geriatr Psychiatry. 1994;9: Ter et al. JAGS. 1988;36:1-6.]
Due to different definitions of wandering. It has been used to describe a multitude of behaviors, including pacing, entering other people’s rooms, talking about going home, getting lost on a walk, or attempting to leave against advice. Wandering also may be defined by whether the movement is purposeful (looking for something to eat) vs no identifiable purpose (pacing). Because of this, wandering statistics are difficult to discern.

16. Education of Patient and Family Medications
Define treatment success
Symptomatic benefit in
Cognition
Physical function and ADLs
Behavior
Increases time to nursing home placement
Discuss length of therapy
Adequate trial is 6 months
Safety hazards at home
Household accidents, eg, kitchen fire, power tools
Falls
Impaired judgement, visual perception, and spatial perception significantly increase the risk of falls in people wie AD and other dementias. [194, 195]
Falls are a major cause of serious injury and emergency department visits in the elderly population [196]
Wandering
Prevalence of wandering among people with dementia varies widely in clinical in studies– from 12% to 63% in the community. [Rowe et al. Am J Alz Dis Oth Dement. 2010;25: Klein et al. Int J Geriatr Psych. 1999;14: Calkins et al. J Alz Care & Related Dis Research. 1991; 6: Sayva et al. B J Psych. 2009; 194: Rolland et al. Alzheimer’s Dis Assoc Disord. 2007;21: Hope et al. Int J Geriatr Psychiatry. 1994;9: Ter et al. JAGS. 1988;36:1-6.]
Due to different definitions of wandering. It has been used to describe a multitude of behaviors, including pacing, entering other people’s rooms, talking about going home, getting lost on a walk, or attempting to leave against advice. Wandering also may be defined by whether the movement is purposeful (looking for something to eat) vs no identifiable purpose (pacing). Because of this, wandering statistics are difficult to discern.
Cummings JL. Am J Geriatr Psychiatry. 2003;11(2):131–145.
Doody RS, et al. Arch Neurol. 2001;58(3):427–433.

17. Impact on Caregivers Tasks Change Over Time
Early stage
Help with IADLS, eg, paying bills and preparing meals
Cope with mood swings and reluctance to engage
Mid stage
Help with ADLS, eg, dressing and toileting
Cope with increased memory loss, sleep disturbances, wandering, loss of driving
Late stage
Help with all personal care
Cope with unresponsiveness and end-of-life issues

18. Education of Patient and Family Alzheimer’s Association
24/7 Nationwide Helpline
Information and referral in 170 languages
Current reliable information for healthcare professionals, people with dementia, family members and caregivers
300 local offices
Information and referral
Support groups
Care consultation
Safety services
Education, local conferences

19. Clinical Trials
>120 clinical studies in the US are recruiting participants
Slow recruitment is a barrier to discovering new treatments
Alzheimer’s Association TrialMatch™
Connect potential participants with appropriate clinical studies
Access via phone or online
Confidential
Free
There are more than 120 clinical studies in the US, exploring new approaches to treatment, caregiving and prevention, as well as risk factors and epidemiology.
Difficulty recruiting and retaining study participants is the second-greatest barrier to progress.
It’s second only to inadequate funding of Alzheimer’s research.
To surmount barriers to recruitment, Alzheimer's Association TrialMatch was launched in July 2010.
The heart of the this free service is a managed and regularly updated database of Alzheimer-related clinical studies currently recruiting participants.
TrialMatch users:
Access TrialMatch online or call the Alzheimer's Association toll-free Contact Center
Identify themselves as a potential participant, caregiver, physician, or researcher
Create a password-protected account
Complete a confidential profile detailing key information that will help match a prospective participant to a clinical trial:
- Age
-Sex
- Geographic location and distance able to travel
- Clinical diagnosis
- Current Alzheimer’s medications
- Other medical conditions
- Educational level

20. Understanding prevention research
Much evidence comes from large epidemiological studies that show associations, not proof
Study results apply to populations, not individuals
Large randomized studies for many prevention strategies unlikely
Cost prohibitive
Can Alzheimer's be prevented? There are no clear cut answers yet for the following reasons:
Much of our current evidence comes from large epidemiological studies such as the Honolulu-Asia Aging Study, the Nurses' Health Study, the Adult Changes in Thought Study and the Kungsholmen Project, so a direct cause and effect cannot be determined, only associations.
Insights about potentially modifiable risk factors apply to large population groups, not to individuals. An individual can do everything “right” and still have Alzheimer’s disease.
It is unlikely that many prevention strategies will be tested in large, double-blind, randomized trials due to ethical and logistical reasons.
Example: Definitively testing the impact of exercise on Alzheimer’s risk would require a huge trial enrolling thousands of people and following them for may years. The expense and logistics of such a trial would be prohibitive, and it would require some people to go without exercise, a known health benefit.

21. Prevention Factors with a consistent association
Heart-head connection
Preventative drug treatments
Physical exercise
Diet
Social connections
Intellectual activity
Head trauma prevention
Can Alzheimer's be prevented? It's a question that continues to intrigue researchers and fuel new investigations. There are no clear cut answers yet — partially due to the need for more large-scale studies — but promising research is under way. As the number of people affected by Alzheimer's rises, the effort to find prevention strategies continues to gain momentum.

22. Prevention Factors with a consistent association
Increased risk of AD
Decreased risk of AD
Conjugated equine estrogen with progesterone*
Diabetes
Depression
Smoking
Physical activity
Mediterranean diet
Cognitive engagement
In 2010, the NIH published an NIH Consensus Development Conference Statement on Preventing Alzheimer’s Disease and cognitive decline.
Gerontologists, neurologists, geneticists and nutritionists made up the panel that evaluated 25 reviews and 250 primary research studies.
The modifiable factors listed here have shown a consistent association with the presence or absence of Alzheimer’s disease or cognitive decline.
The panel concluded there was moderate evidence that associated carriers of the ApoE4 gene or individuals receiving conjugated estrogen with progesterone were at an increased risk of AD.
The panel rated the evidence low for the remaining associated factors.
Ratings mostly are a reflection of the quantity of evidence, not the quality.
Too few randomized controlled trials
The panel considered many of the studies too short, lasting less than a full year.
Lack of standardization made comparison of outcomes across studies impossible.
*Moderate evidence, all other factors had low evidence

23. The Future of Alzheimer’s Disease
Earlier recognition
Dependent on reliable biomarkers
New medications
Current medications only address symptoms
New medications in development
Disease-modifying therapy
Combination disease-modifying and symptomatic therapy
Prevention
The prevailing thought is to start treatment early in the disease process to increase the chance of successful treatment.
Early diagnosis is dependent on reliable biomarkers.
Biomarkers under investigation include: structural, functional and molecular brain imaging, cerebrospinal fluid (CSF) proteins; tau, beta-amyloid and other biomarkers in blood and other areas of the body; genetic risk profiling.
There are no validated biomarkers currently, and they are used almost exclusively in research.
Current approved drug treatments for Alzheimer disease (donepezil, rivastigmine, galantamine, and memantine) provide symptomatic relief, but do not arrest the disease process.
In the last 10 years, drug discovery has been directed towards disease-modifying therapies that would slow or halt the progressions of Alzheimer’s.
The most effective way of reducing the incidence of Alzheimer’s disease is prevention. Although there is no proven way to prevent the diseases, a wide variety of preventative strategies are under investigation, from lifestyle measures to pharmacological treatments.

24. Alzheimer's Disease Progression
Beta-amyloid and neurofibrillary tangle formation begins in pre-clinical phase
Cell death
Pre-Clinical
MCI
Probable AD
Deposition of beta-amyloid and hyperphosphorylated tau proteins begin years before clinically detectable symptoms of Alzheimer’s disease appear.
This long preclinical phase of AD provides a critical opportunity for potential intervention with preventative and disease-modifying therapy.
TIME
Asymptomatic
Clear cognitive deficits
Aβ=Beta-amyloid
AD=Alzheimer’s disease MCI=Mild cognitive impairment
Mild cognitive deficits
Adapted from Shaw et al. Nature Reviews Drug Discovery. 2007;6:

25. Targets for Future Therapies
-secretase inhibitors
-secretase inhibitors
Monoclonal antibodies
Tau protein
Inflammation
Insulin resistance
Beta-amyloid is the chief component of plaques, one hallmark Alzheimer's brain abnormality.
We now have a detailed understanding of how this protein fragment is clipped from its parent compound amyloid precursor protein (APP) by two enzymes — beta-secretase and gamma-secretase.
Researchers are developing medications aimed at virtually every point in amyloid processing. This includes blocking activity of both enzymes; preventing the beta-amyloid fragments from clumping into plaques; and even using antibodies against beta-amyloid to clear it from the brain. 
Tau protein is the chief component of tangles, the other hallmark brain abnormality.
Researchers are investigating strategies to keep tau molecules from collapsing and twisting into tangles, a process that destroys a vital cell transport system.
Inflammation is another key Alzheimer's brain abnormality.
We’ve learned a great deal about molecules involved in the body's overall inflammatory response and are working to better understand specific aspects of inflammation most active in the brain. These insights may point to novel anti-inflammatory treatments for Alzheimer's disease.
Insulin resistance and the way neurons process insulin may be linked to Alzheimer's disease.
Researchers are exploring the role of insulin in the brain and closely related questions of how neurons use glucose. These investigations may reveal strategies to support cell function and stave off Alzheimer-related changes.

26. Emerging Treatments for AD
 A production
 A  aggregation
 A  clearance
 tau aggregation or phosphorylation
Cholinergic drugs
Other
It is an exciting and busy time in Alzheimer’s disease research with hundreds of potential therapies being tested at various stages of the research process, and many more being developed.
Disease-modifying drugs in development include medications to reduce beta-amyloid production, prevent beta-amyloid aggregation, promote beta-amyloid clearance, decrease tau aggregation or phosphorylation and other approaches.
It is unlikely that a single cure will be found because Alzheimer’s disease is likely to be caused by several factors.
As our understanding of the diseases progresses, other potential drug targets will be discovered.
The Global Alzheimer’s Association Interactive Network (GAAIN), a collaboration between the Alzheimer’s Association, the Laboratory of Neuro Imaging (LONI) at UCLA, the Italian National Centre for Alzheimer’s Disease, and Intel Corporation announced plans to develop a cloud-enabled database infrastructure that would allow researchers worldwide to have access to continually updated data reflecting the latest in Alzheimer’s research.
The increased collaboration between basic researchers, clinical researchers and pharmaceutical companies across the globe has the potential to accelerate research significantly.

27. Clinical Trials Failed Phase 2 Moving to Phase III Phase III AN-1792
ACC-01
Lu AE58054
Solanezumab
Bapineuzumab
Crenezumab
EVP-6124
IVIg
Dimebon
Rosiglitazone
Semagacestat
Tarenflurbil
Tramiprosate
Bapineuzumab and solanezumab are monoclonal antibodies.
Bapineuzumab did not show benefits on tests of cognition and function in mild-moderate AD, and studies have been discontinued.
Recent results released from 2 Phase 3 clinical studies of solanezumab showed the drug did not meet cognitive and functional endpoints in either study.
Pooled analysis, however, showed a statistically significant slowing of cognitive decline in patients with mild-moderate AD.
Immunoglobulin, or IVIg, originally was used to treat immune deficiency disorders.
IVIg may contribute to beta amyloid clearance by suppressing harmful inflammation and mitigating the toxicity of the plaque.
At the Alzheimer’s Association International Conference in July, IVIg was reported to stabilize AD symptoms for 3 years. This included no decline on measures of cognition, memory, daily functioning and mood.
 A Phase 3 trial is in progress and, in less than one year, we'll have more definitive data on the efficacy of 18 months of IVIG treatment.“
Two previous studies, showed short-term immunoglobulin administration in patients with AD was well tolerated, promoted a decrease of total Aβ CSF concentrations, and increased plasma total Aβ concentrations [Relkin NR, et al. Neurobiol Aging Nov;30(11): Epub 2008 Feb 21. PubMed PMID: Dodel RC, et al. J Neurol Neurosurg Psychiatry Oct;75(10): PubMed PMID: ; PubMed Central PMCID: PMC ], with evidence of improvement or stabilization of cognitive functions. Preliminary data from a phase II RCT confirmed the positive effects on cognition, and a phase III study is ongoing .
Crenezumab is focused on prevention rather than treatment, and is recruiting cognitively healthy individuals for its phase II study.
AN-1792 – Vaccine – phase II clinical trial showed improvement in memory and function, but the trials was discontinued after about 6% of participants developed meningoencephalitis.
Dimebon – showed promise early, but Phase II and III studies failed.
Semagacestat – gamma-secretase inhibitor that hurt patients more than helped them by producing more beta amyloid and speeding up Alzheimer’s disease.
Tarenflurbil is a gamma-secretase modulator. It is believed to reduce the production of the toxic amyloid beta in favor of shorter forms of the peptide. Negative results were announced regarding tarenflurbil in July 2008 and further development was canceled.