Alzheimer’s Disease


More than 47 million people in the world are living with this disease.

Presently the most prevalent cause of dementia worldwide.

The disease was first described by Alois Alzheimer in 1906!


Alzheimer’s disease is the most common form of dementia, and two thirds of individuals with Alzheimer’s disease in the USA are female.


Alzheimer’s disease ranks as the fifth leading cause of death for women (6.1% of deaths), whereas it is the seventh for men (2.6%.


Caucasian and Japanese carriers of two APO E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles.

Differentiating Alzheimer’s disease from other causes of dementia is more easily done in the early stage of disease, as dementias in the late stage of disease have similar manifestations.

5.5 million people in the U.S. have this disease.

Prevalence is highest among blacks at 14%, followed by Hispanics at 12%, and Caucasians at 10%.

Prevalence in American Indian and Alaskans 9%, Asian and Pacific Islanders 8.4%.

Global memory problems affecting trivial and important events and interferes with the activities of daily living.

Begins approximately 10-15 years before any symptoms manifest.

An acquired disorder of cognitive and behavioral impairment that markedly interferes with social and occupational functioning.

An incurable disease with a long and progressive course.

Evolves over years before dementia is recognized, and pathophysiological changes and may be present in some individuals who appear to have normal cognition or only minimal impairment during a preclinical phase.

Its most common clinical presentation is a slow onset and gradually progressive loss of memory, typically with inability to learn new information and particularly auto biographical information such as recent events in one’s life.

Has an extended preclinical phase characterized by imaging and CSF biomarker changes, with subtle memory decline beginning more than a decade before the emergence of symptomatic memory loss.

higher amounts of amyloid, beta proteins can be detected in the CSF as long as 18 years earlier people later diagnosed with Alzheimer’s disease.

It heralds in the beginning of mild cognitive impairment stage.

Two defining pathological hallmarks are extracellular amyloid plaques and intracellular tau protein tangles.

An amyloid enabled tauopathy.

The accumulation of amyloid-beta peptide in the form of amyloid plaques in the brain is an early event in Alzheimer’s disease that leads to  eurodegeneration with cognitive  and functional impairment. 

Amyloid plaques are described as diffuse or neuritic.

The amyloid hypothesis postulates that ABeta aggregation triggers a cascade of pathophysiologic events, including synaptic and network dysfunction, neuroinflammation, and aggregation and spread of P-tau tangles.

The spread of tangles is associated with synaptic loss and neurodegeneration, culminating in cognitive decline and dementia:by binding Abeta aggregates, monoclonal antibodies facilitate Abeta clearance from the brain, potentially mitigating, both direct and downstream effects of Abeta and slow cognitive decline.

It preferentially affects brain networks involved in episodic memory.

Episodic memory loss includes forgetting appointments or forgetting to pay bills or to take medication and typically a person with AD repeats questions and conversations

Both types or seen individuals without dementia, but they may indicate an increased risk of progression to dementia.

Neuritic plaque is associated with cognitive impairment, whereas with diffuse plaques the relationship is tenuous.

A second and meuropathological homework of AD is the presence of intracellular neurofibrillary tangles that contain hyperphosphoralated protein.tau protein.

It is proposed that ABeta triggers taunpathology with the complex and synergistic interaction between the two manifesting in later stage disease leading to progression of AD.

Apolipoprotein E epsilon allele is prevalent and potent risk factor.

Individuals with two ε4 alleles have up to 20 times the risk of developing AD.

Criteria for diagnosing dementia of AD include: insidious onset of months to years, clearcut history of progression of cognitive decline, with affirmation by neuropsycholigical testing, and evident amnestic presentation involving impairment of episodic memory such as the ability to learn and retain new information, or nonamnestic presentation involving of the cognitive domains such as language, executive functioning and problem-solving on history and physical examination.

Accounts for more than 70% of all cases of dementia.

Disease onset is usually after the age of 70 years, but the prevalence increases exponentially after the age of 65 and exceeds 25% over the years.

Cerebrovascular disease is the most frequent comorbid condition with AD.

Costs of care in 2010 estimated more than $172 billion.

Hypothesized to begin decades before first symptoms appear.

Cognitive deficits such as anomia, agnosia and apraxia and an insidious onset in as many as 80% of patients.

Diagnosis requires that a patient have cognitive loss of two or more domains, such as memory, language calculations, orientation, and judgment and must be os sufficient severity to cause social or occupational disability.

The only certain way to determine if a person indeed had the disease was to perform a biopsy on the patient’s brain to find distinctive spots on the brain that show the buildup of amyloid plaque. 

To diagnose the disease in patients with memory loss and dementia based on symptoms, and as many as 20% of patients diagnosed with the disease are found after examination of the brain following death not to have had the condition.

A patient with preclinical AD may appear completely normal on physical exam and mental status testing.

It Is known that specific regions of the brain such as the entorhinal cortex, and hippocampus begin to be affected 10-20 years before symptoms appear.

Signs of mild AD can include: memory loss, confusion, delay in accomplishing daily chores, impaired executive decision making, impaired decision making and judgement, loss of spontaneity, lack of initiative, mood alterations, increased anxiety and personality changes.

The symptoms of moderate stage AD can include: increasing memory loss and confusion, a shortened attention span, difficulty recognizing friends and family, difficulty with language, reading, writing, working with numbers, difficulty organizing thoughts and thinking logically, incapability to learn new things, inability to cope with new situations, agitation, anxiety, irritability, emotional lability, wandering, repetitious speech, repetitious movements, muscle twitches, hallucinations, delusions, paranoia, loss of inhibitions and impulse control, increased vulgarity, and motor and perceptual abnormalities.

Severe Alzheimer disease patients do not recognize family or friends and cannot communicate.

Severe Alzheimer disease patients are completely dependent on others for care, and lack a sense of self.

Severe Alzheimer disease associated with weight loss, lethargy, incontinence of urine and stool, seizures, skin infections, difficult swallowing, moaning, confinement to bed, increased risk of aspiration pneumonia and death.

Among the most common symptoms are agitation, aggression, delusions and hallucinations.

Agitation which includes anxiety, irritability, motor restlessness, abnormal behavior of pacing, shouting, wandering, and aggressive behavior in 24% of patients in the community and 48% of those in care facilities.

Behavioral and psychological symptoms frequently precipitate a transition to institutionalization.

Commonly associated with psychosis or agitation.

Of psychotropic medications, only antipsychotic agents indicate superiority over placebo for psychotic and agitated-aggressive behavior in patients with dementia: they are however associated only with low-moderate efficacy.

Mortality among dementia patients receiving antipsychotic medications is on the average 1.6-1.7 times as high in patients with dementia than among patients with placebo.

Leads to death within 3-9 years.

The mainstay of drug treatment for anxiety are atypical neuroleptics drugs with only modest efficacy, and with side effects including stroke and death.

Most common form of dementia, especially among the elderly.

Meta-analyses reports a reduced aggregate risk of cancer in patients with AD.

Cerebral plaques laden with beta-amyloid peptide and dystrophic neurites in neocortical terminal fields as well as prominent neurofibrillary tangles in medial temporal lobe structures are significant pathological features of this process.

The prevalence of beta amyloid pathology rises steeply with advancing age and has high rates of comorbid positivity in nonAlzheimers disease neurodegenerative disorders and cognitively normal elderly individuals.

The two key features of AD in the brain are plaques of amyloid beta peptides and neurofibrillary tangles consisting of tau protein.

The protein fragment beta-amyloid is found 10-20 years before dementia or even mild cognitive impairment is diagnosed.

The two features above combine to block communication between neurons and cause destruction of neurons and brain atrophy.

How plaques and tangles cause dysfunction and degeneration of neurons or glial cells is presently unknown.

Plaques develop in the hippocampus, a structure that encodes memories, and in other areas of the cerebral cortex that are used in thinking and making decisions.

Atrophy of the affected brain regions, includes degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.

Whether plaques themselves cause AD or whether they are a by-product of the AD process is still unknown.

Loss of neurons and white matter, amyloid angiopathy, inflammation and oxidative damage may be present.

Increase in AD pathology in the oldest old is primarily mixed AD and infarct pathology

Beta amyloid peptides consist of 36-43 amino acids, which originate from proteolysis of the amyloid precursor protein by enzymes.

Beta amyloid peptides accumulate due to an end balance between production and clearance and may be in initiating factor in AD.

The earliest recognize pathological event is cerebral amyloid-beta aggregation, which may be present up to 20 years before the onset of dementia.

Monomers of beta amyloid peptides40 are more prevalent than aggregation prone and damaging beta amyloid peptide42 species.

Evidence exists that beta amyloid peptide 42 is toxic to cells (Selkoe DJ).

Moderate seafood consumption is correlated with a lesser burden of brain Alzheimer disease neuropathology in APOE e4 carriers.


Caucasian and Japanese carriers of two APO E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. 

Plasma amyloid measurements have indicated that lower levels of beta-amyloid 42 and 42/40 are associated with increased risk of developing Alzheimer’s disease

Lower plasma amyloid 42/40 is associated with greater cognitive decline among elderly persons without dementia over nine years, and this is associated with those with low measures of cognitive reserve (Yaffe K et al).

Inflammation is commonly seen among the histologic features of brains of patients with Alzheimer’s disease.

Inflammation is an early event in the brains of patients with Alzheimer’s disease, and the expression of genes associated with inflammation in the brain is increased with aging.

Inflammation is a downstream effect of amyloidgenesis, which provides a trigger for inflammatory response in AD.

TREM2 variants have a significant association with AD disease (Jonsson T et al, Guerreiro R et al).

Accounts for 50-56% of cases of dementia at autopsy and clinical studies.

Often coexists with vascular dementia and referred to as mixed dementia.

Significant overlap in risk factors with vascular dementia including hypertension, diabetes and apoE4 genotype.

Plasma clusterin, apolipoprotein J, is significantly associated with a prevalence and severity of Alzheimer’s disease at baseline, but not the risk of incident disease (Schrijvers EMC et al).

Lean muscle mass may reduce risk of AD.

Seizures are more frequent in Alzheimer’s disease and patients with epilepsy have a greater risk of developing Alzheimer’s disease.

Presently 5.5 million Americans have Alzheimer’s disease and the number of cases is expected to quadruple by 2050.

Accounts for than $100 billion per year expenditures with an average expense per year of $27,000.

Disrupts circadian rhythms increasing motor activity at night by phase delaying body temperature.

Advancing age is the major risk factor, with a doubling of risk every five years after the age of 65.

1275 new cases diagnosed per year per 100,000 persons older than 65 years.

Alzheimer’s disease combined with vascular intracerebral disease accounts for 13-17% of cases of dementia.

Accounts for 50-75% of all cases of dementia.

20% of patients develop severe dementia.

Odds of having AD after the age of 85 years is one in three.

Average duration of illness from time of onset to death is 8-10 years.

Progression of disease accompanied by a decline in cholinergic neurotransmission, and extent of dysfunction correlates with level of cognitive impairment.

Cholinesterase inhibitors are the most effective drugs for treatment.

Delusions, hallucinations and aggressive behavior affects more than 50% of patients.

Loss of acetylcholine is the primary neurotransmitter deficit in Alzheimer’s disease.

Some studies show elevated homocysteine levels in such patients.

Hypertension a risk factor.

Mid-life obesity associated with an increased risk of AD, and late life weight-loss is known to proceed clinical onset of AD.

Black and Hispanic people are disproportionately affected by Alzheimer’s disease.

Higher levels of leptin at baseline is prospectively associated with lower incidence of AD and dementia(Lieb W).

Leptin and insulin act to decrease hyperphosphorylation of tau, the primary component of the neurofibrillary tangle, the second major histopathological finding in Alzheimer’s disease.

Local accumulation of proteins that misfold and polymerize into fibrils that cause cellular and tissue destruction.

Senile plaques develop between neurons and neurofibrillary tangles develop within neurons.

Cerebral plaques laden with beta-amyloid peptide and dystrophic neurites in neocortical terminal fields as well as prominent neurofibrillary tangles in medial temporal lobe structures are significant pathological features of this process.

Loss of neurons and white matter, amyloid angiopathy,inflammation and oxidative damage may be present.myeloid

ABeta amyloid peptides consist of 36-43 amino acids, which originate from proteolysis of the amyloid precursor protein by enzymes.

ABeta amyloid peptides accumulate beginning 15-30 years before symptom onset.

Monomers of Abeta amyloid peptides40 are more prevalent than aggregation prone and damaging beta amyloid peptide42 species.

Evidence exists that beta amyloid peptide42 is toxic to cells (Selkoe DJ).

ABeta can self aggregate into multiple oligomers.

Beta-amyloid can grow into fibrils and arrange themselves into Beta-pleated sheets forming insoluble fibers of amyloid plaques.

Neurofibrillary tangles are made up in part by a protein, tau, which links to form filaments, the density of which in neurons of the brain is directly related to the severity of dementia.

Neurofibrillary tangles compromise microtubular function and eventually destroy the neuron.

Inflammation around plaques destroy surrounding neurons.

Cerebral hypoperfusion is detected by positron emission tomography (PET) in early stages.

Plaques are composed of beta-amyloid polypeptides formed as a result of disorders of processing beta-amyloid and its precursor protein.

The disease probably caused by a combination of genetic predisposition and environmental factors.

Patients with hypertension and elevated cholesterol have an increased risk.

Patients with diabetes mellitus may be at higher risk of developing Alzheimer’s disease.

People with poor sleep have a higher risk of developing Alzheimer’s disease.

More than 160 highly penetrant mutations in three genes APP, PSEN and PSEN2 associated with early onset familial disease.

APP (amyloid precursor protein), presenilin 1, and 2 Variants appear to be fully penetrant and result in a AD disease with an early onset, in most cases before age 60

Apolipoprotein E gene is associated with increased risk of late-onset Alzheimer’s.

Epsilon4 allele of the apolipoproteins E gene is known to increase the risk of Alzheimer’s disease.

Genetic variants on chromosome 9q22 increase risk.

Accumulation of a form of amyloid A’ peptide which results from the cleavage of the amyloid precursor protein, the gene for which is on chromosome 21.

Pathological changes of Alzheimer’s found in the brains of adult patients with trisomy 21 Down’s syndrome).

Associated with elevated homocysteine levels.

Habitual exercise is associated with significant risk reduction in Alzheimer’s disease.

Patients have elevated CSF tau protein and tau phosphrylated at threonine 181 (P-tau) and decreased levels of B-amyloid 42.

CSF levels of biomarkers ABamyloid42, T-tau, and P-tau can predict which patients with mild cognitive impairment will develop AD (Mattsson).

Forbetaben F18 injection (Neuraceq) is an agent for imaging amyloid in patients being evaluated for AD with positron emission tomography (PET) scanning.

Other PET imaging tracers, florbetapir (Amyvid) and flutemetamol (Vizamyl), are approved for PET imaging.

The imaging agent Forbetaben accurately detects moderate to frequent plaques in the brain.

PET Flortaucipir tracer has affinity for tau aggregates formed AD and in a trial had an estimated sensitivity of 89.9% and specificity of 90.6% for Alzheimer’s disease versus other neurodegenerative diseases.

Flortaucipir Fv18 (Tauvid) is a radioactive diagnostic agent for adults with cognitive impairment indicated for PET imaging to estimate the density and distribution of aggregated tau neurofibrillary tangles.

The Lumipulse G beta amyloid ratio test is an in vitro diagnostic biomarker test for the early detection of amyloid plaques in Alzheimer’s disease.

Alzheimer’s Disease Assessment Scale has a 70 point range and patients generally have a 6-7 point deterioration per year.

Cholinesterase inhibitors most frequently prescribed drugs.

Four present cholinesterase inhibitor agents tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (Reminyl).

Cholinesterase inhibitors do not prevent eventual development of severe disease.

Many patients with mild cognitive impairment have neurologic morphological changes as AD patients and the annual rate of AD diagnosis for patients with minimal cognitive impairment is 10-15%.

Acetylcholinesterase inhibitors for treatment include: donepezil, gallantamine, or rivastigmine.

769 patients with mild cognitive impairment randomly given donepezil 10 mg daily, 2000 IU of vitamin E, or placebo for 36 months did not record differences in dementia and cognition by the end of the study (Petersen).

Rivastigmine given to prevent mild cognitive impairment from progressing over 4 years was associated with negative findings (Feldman).

Preliminary results from galantamine studies have been negative.

Memantine (Namenda) a N-methyl-D aspartate receptor antagonist with donepezil slow cognitive and functional deterioration in moderate to severe disease.

Memantine as single therapy has positive global function and cognition effects in moderate the severe disease.

The  number of nicotinic receptors in the brain are reduced in Alzheimer’s disease, even in the absence of a general decrease in the number of neurons.

Recommended treatment in severe AD is cholinesterase inhibitor combined with meantime as recommended cost-effective option for management compared with cholinesterase inhibitors alone.

With moderate AD disease menmantine therapy is not cost effective compared with cholinesterase inhibitors alone.

In a study of community dwellers treated with donepezil for at least 3 months and have moderate or severe AD than assigned to donzepil, discontinue donezepil, discontinue donezepil and start memantine, or continue donezepil and start memantine: treatment with donezeil was associated with significant cognitive benefits over 12 months (Howard R et al).

Tarenflurbil a selective AB42 lowering agent modulates gamma-secretase activitity and reduces AB42 production in favor of shorter less toxic forms of AB, such as AB37 and 38.

Phase 2 trial of tarenflurbil in mild to moderate AD slowed decline more than did placebo (Wilcock GK).

In a phase three randomized double blind, placebo controlled study of patients with mild AD comparing tarenflurbil 800 mg BID there was no slowing of cognitive decline or loss of activities of daily living, and the study included 1649 participants (Green RC).

Risk factors associated with Alzheimer’s disease that can be modified to decrease by one in three cases of A.D. include:diabetes, hypertension, obesity, lack of physical activity, smoking, depression, and lack of education (Barnes DE et al).

Physical inactivity is one of the seven risk factors for Alzheimer’s disease.

Acetylcholine esterase inhibitors inhibit the brain acetylcholine esterase enzyme promoting relative increase in acetylcholine abundance at the synaptic cleft for cholinergic transmission.

In meta-analysis acetylcholine esterase inhibitors was associated with 2.4 points lower decline for a cognition outcome: this improvement is equivalent to about six months of decline from natural studies of Alzheimer’s disease dementia, but the magnitude of clinical benefit is uncertain.

The efficacy of anti-cholinesterase inhibitors is similar among the individual drugs donepezil, rivastigmine, and galantamine.

Aducanumab what is the first Abeta targeting monoclonal antibody to show reductions in plaques is measured by Abeta positron emission tomography.

Donanemab IV every 4 weeks resulted in a 25-30% less decline in placebo or in the Alzheimer’s disease rating  score in a 1.5 year trial.

Donanemab aims at removal of ABeta amyloid plaques.

Donanemab can improve the removal of amyloid from the brain and had less worsening in patients cognition and function.

It is estimated that these monoclonal antibodies may slow progression of disease by 1/4 to a half a year.

Aducanumab approved to lower brain amyloid, and improve neurological function.

Combining focused ultrasound to one side of the brain with infusions of Aducanumab cleared more amyloid beta plaque from those regions in the ones that were targeted with medication alone. Participants in the study, experienced a 32% reduction in amyloid beta levels.

In a trial targeting brain amyloid in a familial Paisa mutation group with early onset Alzheimer’s disease, there was no clinical benefit after 6-8 years of treatment with crenezumab.

Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to a beta soluble protofibrils reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function and placebo at 18 months, but was associated with adverse events.

Lecanemab study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months; supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).

The drug also affected function, with a 37% decrease compared to placebo on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.

Results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.

APOE4 individuals have a higher risk of brain edema and amyloid  related imaging abnormalities when treated with monoclonal antibody agents.

APOE genotaping is recommended prior to Abeta targeting monoclonal antibody treatments.

Brexpiprrazole antipsychotic approved for agitation related to Alzheimer’s disease.

Solanezumab, which targets monomeric amyloid in persons with elevated brain amyloid did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with pre-clinical Alzheimer’s disease (A4 study team).

Gantenenerumab a monoclonal antibody to amyloid beta in a phase 3 trial among patients with early Alzheimer’s disease led to lower amyloid plaque burden than placebo, but was not associated with slower clinical decline.




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