Author

Gabriel Bucurescu, MD, MS  Staff Neurologist, Neurology Service, Philadelphia Veterans Affairs Medical Center Gabriel Bucurescu, MD, MS is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, and American Epilepsy SocietyDisclosure: Nothing to disclose.

Apr 11, 2011http://emedicine.medscape.com/article/1134817-medication

Background

Uremia describes the final stage of progressive renal insufficiency and the resultant multiorgan failure. It results from accumulating metabolites of proteins and amino acids and concomitant failure of renal catabolic, metabolic, and endocrinologic processes. No single metabolite has been identified as the sole cause of uremia. Uremic encephalopathy (UE) is one of many manifestations of renal failure (RF).

Pathophysiology

The exact cause of UE is unknown. Accumulating metabolites of proteins and amino acids affect the entire neuraxis. Several organic substances accumulate, including urea, guanidine compounds, uric acid, hippuric acid, various amino acids, polypeptides, polyamines, phenols and conjugates of phenols, phenolic and indolic acids, acetoin, glucuronic acid, carnitine, myoinositol, sulfates, phosphates, and middle molecules. Levels of some of the guanidine compounds, including guanidinosuccinic acid, methylguanidine, guanidine, and creatinine, increase in patients with uremia who are or who are not receiving dialysis. Endogenous guanidino compounds have been identified to be neurotoxic.[1]

Patients with terminal RF have >100-fold increases in levels of guanidinosuccinic acid and guanidine, 20-fold increases in levels of methylguanidine, and 5-fold increase in levels of creatinine in various regions of the brain. Disturbance in the kynurenic pathway, by which tryptophan is converted to neuroactive kynurenines, has also been implicated. Levels of 2 kynurenines, 3-hydroxykynurenine and kynurenine, are elevated in rats with chronic renal insufficiency; these changes lead to alterations in cellular metabolism, cellular damage, and eventual cell death. Kynurenine can induce convulsions.

Abnormalities that may be associated with UE include acidosis, hyponatremia, hyperkalemia, hypocalcemia, hypermagnesemia, overhydration, and dehydration. Acute renal injury has been found in mice with increased neuronal pyknosis and microgliosis in the brain. Acute renal injury also led to increased levels of the proinflammatory chemokines keratinocyte-derived chemoattractant and G-CSF in the cerebral cortex and hippocampus, as well as increased expression of glial fibrillary acidic protein in astrocytes. Acute renal injury led to both soluble and cellular inflammation in the brain, affecting the CA1 region of the hippocampus foremost. Acute renal injury leads to increase in brain microvascular leakage.[2, 3]

No single abnormality is precisely correlated with the clinical features of UE. Increased levels of glycine, organic acids (from phenylalanine), and free tryptophan and decreased levels of gamma-aminobutyric acid (GABA) in the CSF may be responsible for early phases of the disorder. In rats with RF, brain levels of creatine phosphate, adenosine triphosphate (ATP), and glucose are increased, whereas levels of adenosine monophosphate (AMP), adenosine diphosphate (ADP), and lactate are decreased. This finding

suggests that the uremic brain uses less ATP and produces less ADP, AMP, and lactate than healthy brains, consistent with a generalized decrease in metabolic function.

Transketolase, found mainly in myelinated neurons, is a thiamine-dependent enzyme of the pentose phosphate pathway; it maintains axon-cylinder myelin sheaths. Plasma, CSF, and low-molecular-weight (< 500 Da) dialysate fractions from patients with uremia substantially inhibit this enzyme. Erythrocyte transketolase activity is lower in nondialyzed patients than in dialyzed patients. Guanidinosuccinic acid can inhibit transketolase.

Synaptosome studies of uremic rats have shown altered function of the sodium ATP and other metabolic pumps. Methylguanidine can induce a condition similar to UE that includes seizures and uremic twitch-convulsive syndrome. Guanidinosuccinic acid can also inhibit excitatory synaptic transmission in the CA1 region of the rat hippocampus, an effect that may contribute to cognitive symptoms in UE.

Guanidinosuccinic acid, methylguanidine, guanidine, and creatinine inhibited responses to GABA and glycine (inhibitory amino acids) in cultured mouse neurons. Guanidino compounds (GCs) inhibit nitric oxide synthase (NOS) modulators in vivo and in vitro. Accumulation of asymmetric dimethylarginine (ADMA), a NOS inhibitor, has been observed in patients with uremia; this accumulation induces hypertension and possibly increases ischemic vulnerability to the uremic brain.

UE involves many hormones, levels of several of which are elevated. Such hormones include parathyroid hormone (PTH), insulin, growth hormone, glucagon, thyrotropin, prolactin, luteinizing hormone, and gastrin. In healthy dogs, high levels of PTH produce CNS changes like those seen in uremia. PTH is thought to promote the entry of calcium into neurons, which leads to the changes observed.

A combination of factors, including increased calcium and decreased GABA and glycine activity, leads to a distorted balance of excitatory and inhibitory effects that contributes to systemic changes associated with UE.

Epidemiology

Frequency

United States

The prevalence of UE is difficult to determine. UE may manifest in any patient with end-stage renal disease (ESRD), and directly depends on the number of such patients. In the 1990s, more than 165,000 people were treated for ESRD, compared with 158,000 a decade earlier. In the 1970s, the number was 40,000. As the number of patients with ESRD increased, presumably so did the number of cases of UE. On a yearly basis, 1.3 per 10,000 patients develop ESRD.

For related information, see Medscape's End-Stage Renal Disease Resource Center.

International

The worldwide prevalence is unknown. In western Europe and in Japan, ie, countries with healthcare systems similar to that of the United States, statistics parallel to those of United States are expected. In general, the care of patients with UE depends on costly intensive care and dialysis that is not available in developing nations.

Mortality/Morbidity

RF is fatal if untreated.

UE reflects worsening renal function, with symptoms worsening as RF progresses. If untreated, UE progresses to coma and death.

Patients need aggressive care to prevent complications and maintain homeostasis. They depend on intensive care and dialysis. In the United States, more than 200,000 patients are currently receiving hemodialysis.

Race

RF is more common in African Americans than in other races. Of all patients in the Medicare ESRD treatment program in 1990, 32% were African American, though African Americans account for only 12% of the US population. The overall incidence of ESRD is 4 times greater in African Americans than in whites.

Sex

Incidences are equal in men and woman.

Age

People of all ages can be affected, but the fastest growing group with ESRD is the elderly, ie, persons older than 65 years. RF has a proportionally increased prevalence in this group compared with any other age group.

History Uremic encephalopathy (UE) is a consequence of renal failure (RF). Symptoms begin insidiously and are often noticed not by the patients but by their family

members or caregivers.

In many cases, impairment of the nervous system provides the first indication of metabolic derangements.

Symptoms may progress slowly or rapidly.

Changes in sensorium include loss of memory, impaired concentration, depression, delusions, lethargy, irritability, fatigue, insomnia, psychosis, stupor, catatonia, and coma.

Patients may complain of slurred speech, pruritus, muscle twitches, or restless legs.

Physical

Physical findings are variable and depend on the severity of the encephalopathy. Neurologic findings range from normal to a comatose state. Cases of Wernicke syndrome associated with UE have been described in the literature, and Wernicke syndrome has been observed in patients with UE, dialysis dementia, or dialysis disequilibrium syndrome.

Findings include the following: o Myoclonic jerks, twitches, or fasciculations (ie, uremic twitch-convulsive syndrome

postulated by Adams et al in 1997)

o Asterixis

o Dysarthria

o Agitation

o Tetany

o Seizures, usually generalized tonic-clonic

o Confusion, stupor, and other alterations in mental status

o Coma

o Sleep disorders

Some patients undergoing long-term dialysis acquire dialysis encephalopathy (or dialysis dementia), which is a subacute, progressive, and often fatal disease.[4] Aluminum toxicity either from aluminum phosphate salts or from aluminum in the dialysate were linked to the pathogenesis of dialysis dementia. Starting in the early and mid 1980s, aluminum was actively removed from the dialysate with a large reduction in the incidence of dialysis dementia.

o Dialysis encephalopathy is believed to be part of a multisystem disease that includes encephalopathy, osteomalacic bone disease, proximal myopathy, and anemia.

o Symptoms include dysarthria, apraxia, personality changes, psychosis, myoclonus, seizures and, finally, dementia.

o In most cases, the condition progresses to death in 6 months.

Dialysis disequilibrium syndrome occurs in patients receiving hemodialysis.

o Symptoms include headache, nausea, emesis, blurred vision, muscular twitching, disorientation, delirium, hypertension, tremors, and seizures.

o The condition tends to be self-limited and subsides over several hours.

o Dialysis disequilibrium syndrome is attributed to a reverse urea effect. Urea is cleared more slowly from the brain than from the blood, an effect that causes an osmotic gradient leading to the net flow of water into the brain and to transient cerebral edema.

Complications of renal transplantation can lead to UE. This occurrence has become more common as more patients are receiving renal transplants.

o This condition is characterized by edema of the white matter.

o Patients are at risk for primary brain lymphoma and opportunistic infections because of long-term immunosuppression.

Rejection encephalopathy has been observed in patients undergoing transplantation. They have systemic features of acute graft rejection, more than 80% of whom have symptoms in the first 3 months after transplantation. Overall prognosis is good, with rapid recovery after treatment of the rejection episode. The presumed pathology is cytokine production secondary to the rejection process.

Uremic polyneuropathy is the most common neurologic complication of RF.

Causes The exact cause of UE is unknown. Accumulation of metabolites and, perhaps, imbalance in excitatory and inhibitory

neurotransmitters are possible etiologies.

PTH and abnormal calcium control have also been identified as possible important contributing factors.

Differentials Alzheimer Disease Alzheimer Disease in Individuals With Down Syndrome

Aphasia

Apraxia and Related Syndromes

Complex Partial Seizures

Dementia in Motor Neuron Disease

Dementia With Lewy Bodies

EEG in Dementia and Encephalopathy

EEG in Status Epilepticus

Frontal and Temporal Lobe Dementia

Generalized EEG Waveform Abnormalities

Huntington Disease

Intracranial Hemorrhage

Normal Pressure Hydrocephalus

Pick Disease

Status Epilepticus

Subdural Hematoma

Tonic-Clonic Seizures

Transient Global Amnesia

Background

In 1901, a German psychiatrist named Alois Alzheimer observed a patient at the Frankfurt Asylum named Mrs. Auguste D. This 51-year-old woman suffered from a loss of short-term memory, among other behavioral symptoms that puzzled Dr. Alzheimer. Five years later, in April 1906, the patient died, and Dr. Alzheimer sent her brain and her medical records to Munich, where he was working in the lab of Dr. Emil Kraeplin. By staining sections of her brain in the laboratory, he was able to identify amyloid plaques and neurofibrillary tangles.[1]

A speech given by Dr. Alzheimer on November 3, 1906 was the first time the pathology and the clinical symptoms of presenile dementia (later to be renamed Alzheimer disease [AD]) were presented together. Alzheimer published his findings in 1907.[2]

AD is an acquired cognitive and behavioral impairment of sufficient severity that markedly interferes with social and occupational functioning. It is an incurable disease with a long and progressive course. AD not only has detrimental effects on the patient but tends to take a significant toll on patients’ families and caretakers as well.

The most common form of dementia, AD affects about 4.5 million people in the United States alone, and that number is projected to exceed 13 million by the year 2050.[3] Economically, it is a major public health problem. In the United States, the cost of caring for patients with dementia was $144 billion per year in 2009. The most recent data available on the cost for healthcare and long-term care services per patient, from 2004, show that the average yearly cost was about $33,007.[4]

In the past 15-20 years, dramatic progress has been made in understanding the neurogenetics and pathophysiology of AD (see Pathophysiology). Four different genes have been associated with AD, and others are likely to be discovered. The mechanisms by which altered amyloid and tau protein metabolism, inflammation, oxidative stress, and hormonal changes may produce neuronal degeneration in AD are being identified, and rational pharmacological interventions based on these discoveries are being developed.

Currently, an autopsy or a brain biopsy is the only ways to make a definitive diagnosis of AD, although the diagnosis is usually made clinically from the history and findings on Mental Status Examination (see Workup).

Symptomatic therapies are the only treatments available for AD. The standard medical treatments include cholinesterase inhibitors and partial N -methyl-D-aspartate (NMDA) antagonists. Psychotropic medications are often used to treat secondary symptoms of AD, such as depression, agitation, and sleep disorders (see Treatment and Management).

For related information, see Alzheimer’s Disease: Slideshow.

Anatomy

Healthy neurons have an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A special kind of protein, tau, makes the microtubules stable.

In AD, tau is changed chemically. It begins to pair with other threads of tau, and they become tangled together. When this happens, the microtubules disintegrate, collapsing the neuron’s transport system (see the image below). This may result first in malfunctions in communication between neurons and later in the death of the cells.

Healthy neurons. Image courtesy of NIH.

Pathophysiology

AD affects the 3 processes that keep neurons healthy: communication, metabolism, and repair. This disruption causes certain nerve cells in the brain to stop working, lose connections with other nerve cells, and finally die. The destruction and death of these nerve cells causes the memory failure, personality changes, problems in carrying out daily activities, and other features of the disease.

The anatomic pathology of Alzheimer disease includes neurofibrillary tangles (NFTs); senile plaques (SPs; also known as beta-amyloid plaques) at the microscopic level; and cerebrocortical atrophy, which predominantly involves the association regions and particularly the medial aspect of the temporal lobe. NFTs and SPs, which were described by Alois Alzheimer in his original report on the disorder in 1907,[2]

are now universally accepted as a hallmark of the disease.

Considerable attention has been devoted to elucidating the composition of NFTs and SPs to find clues about the molecular pathogenesis and biochemistry of AD. The main constituent of NFTs is the microtubule-associated protein tau (see Anatomy). In AD, hyperphosphorylated tau accumulates in the perikarya of large and medium pyramidal neurons. Somewhat surprisingly, mutations of the tau gene result not in AD but in some familial cases of frontotemporal dementia.

Since the time of Alois Alzheimer, SPs have been known to include a starch like (or amyloid) substance, usually in the center of these lesions, which is surrounded by a halo or layer of degenerating (dystrophic) neurites and reactive glia (both astrocytes and microglia).

One of the most important advances in recent decades has been the chemical characterization of this amyloid protein, the sequencing of its amino acid chain, and the cloning of the gene encoding its precursor protein (on chromosome 21). These advances have provided a wealth of information about the mechanisms underlying amyloid deposition in the brain, including information about the familial forms of AD. (See Amyloid hypothesis versus tau hypothesis.)

Although the amyloid cascade hypothesis has gathered the most research dollars, other interesting hypotheses have been proposed, including the mitochondrial cascade hypothesis.[5]

In addition to NFTs and SPs, many other lesions of AD have been recognized since Alzheimer’s original papers were published. These include the granulovacuolar degeneration of Shimkowicz; the neuropil

threads of Braak et al[5] ; and neuronal loss and synaptic degeneration, which are thought to ultimately mediate the cognitive and behavioral manifestations of the disorder.

Neurofibrillary tangles and senile plaques

Plaques are dense, mostly insoluble deposits of protein and cellular material outside and around the neurons. Plaques are made of beta-amyloid (AB), a protein fragment snipped from a larger protein called amyloid precursor protein (APP). These fragments clump together and are mixed with other molecules, neurons, and non-nerve cells (see the images below).

Amyloid plaques. Image courtesy of NIH

APP is associated with the cell membrane, the thin barrier that encloses the cell. After it is made, APP sticks through the neuron's membrane, partly inside and partly

outside the cell. Image courtesy of NIH. Enzymes (substances that cause or speed up a chemical reaction) act on the APP and cut it into fragments of protein, one of which

is called beta-amyloid. Image courtesy of NIH. The beta-amyloid fragments begin coming together into clumps outside the cell, then join other molecules and non-nerve cells to form insoluble plaques. Image courtesy of NIH.

In AD, plaques develop in the hippocampus, a structure deep in the brain that helps to encode memories, and in other areas of the cerebral cortex that are used in thinking and making decisions. Whether AB

plaques themselves cause AD or whether they are a byproduct of the AD process is still unknown. It is known that changes in APP structure can cause a rare, inherited form of AD.

Tangles are insoluble twisted fibers that build up inside the nerve cell. Although many older people develop some plaques and tangles, the brains of patients with AD have them to a much greater extent, especially in certain regions of the brain that are important in memory.

NFTs are initially and most densely distributed in the medial aspect and in the pole of the temporal lobe; they affect the entorhinal cortex and the hippocampus most severely. As AD progresses, NFTs accumulate in many other cortical regions, beginning in high-order association regions and less frequently in the primary motor and sensory regions.

SPs also accumulate primarily in association cortices and in the hippocampus. Plaques and tangles have relatively discrete and stereotypical patterns of laminar distribution in the cerebral cortex, which indicate predominant involvement of corticocortical connections.

Although NFTs and SPs are characteristic of AD, they are not pathognomonic. NFTs are found in several other neurodegenerative disorders, including progressive supranuclear palsy and dementia pugilistica. SPs may occur in normal aging. Therefore, the mere presence of these lesions is not sufficient to support the diagnosis of AD. These lesions must be present in sufficient numbers and in a characteristic topographic distribution to fulfill the current histopathologic criteria for AD.

Some authorities believed that NFTs, when present in low densities and essentially confined to the hippocampus, were part of normal aging. However, the histologic stages for AD that Braak et al formulated include an early stage in which NFTs are present at a low density in the entorhinal and perirhinal (ie, transentorhinal) cortices.[6] Therefore, even small numbers of NFTs in these areas of the medial temporal lobe may be abnormal.

In contrast, there is consensus that the presence of even low numbers of NFTs in the cerebral neocortex with concomitant SPs is characteristic of AD.

Amyloid hypothesis versus tau hypothesis

A central but controversial issue in the pathogenesis of AD is the relationship between amyloid deposition and NFT formation. Evidence shows that abnormal amyloid metabolism plays a key pathogenic role. The fibrillar form of AB has been shown to be neurotoxic to cultured neurons at high concentrations.

Apoptosis (self-regulated cell destruction) is one possible mechanism of cellular death in AD. Cultured cortical and hippocampal neurons treated with AB protein exhibit changes characteristic of apoptosis, including nuclear chromatin condensation, plasma membrane blebbing, and internucleosomal DNA fragmentation. The fibrillar form of AB has also shown to alter the phosphorylation state of tau protein.

The identification of several point mutations within the APP gene in some patients with early-onset familial AD and the development of transgenic mice exhibiting cognitive changes and NPs also incriminate AB in AD. The APOE E4 allele, which has been linked with significantly increased risk for developing AD, may promote inability to suppress production of amyloid, increased production of amyloid, or impaired clearance of amyloid with collection outside of the neuron. Having 1 copy of the APOE E4 allele increases the risk of developing AD perhaps 4 times compared with all other alleles, and having 2 copies of the E4 allele increases the risk up to 10 times.

Autopsies have shown that patients with 1 or 2 copies of the APOE E4 allele tend to have more amyloid. Additional evidence comes from recent experimental data supporting the role of presenilins in AB metabolism as well as findings of abnormal production of AB protein in presenilin-mutation familial Alzheimer disease.

Although very popular, the amyloid hypothesis is not uniformly accepted. Dementia severity correlates better with the number of neocortical NFTs than with NPs. Tau is a protein that stabilizes neuronal microtubules. The APOE E2 allele, the least prevalent of the 3 common APOE alleles, is associated with the lowest risk of developing AD,[7] with a lower rate of annual hippocampal atrophy and higher CSF β-amyloid and lower phosphotau, suggesting less AD pathology.[8] The E3 allele confers intermediate risk of developing AD, with less risk than the E4 allele. The E3 allele, which is more common than the E2 allele, may protect tau from hyperphosphorylation, and the E2 allele’s effect on tau phosphorylation is complex.

Destabilization of the microtubular system is speculated to disrupt the Golgi apparatus, in turn inducing abnormal protein processing and increasing production of AB. In addition, this destabilization may decrease axoplasmic flow, generating dystrophic neurites and contributing to synaptic loss.

Go to Alzheimer Disease and APOE-4 for complete information on this topic.

Granulovacuolar degeneration and neuropil threads

Granulovacuolar degeneration occurs almost exclusively in the hippocampus. Neuropil threads are an array of dystrophic neurites diffusely distributed in the cortical neuropil, more or less independently of plaques and tangles. This lesion suggests neuropil alterations beyond those merely due to NFTs and SPs and indicates an even more widespread insult to the cortical circuitry than that visualized by studying only plaques and tangles.

Cholinergic neurotransmission and Alzheimer disease

The cholinergic system is involved in memory functions, and cholinergic deficiency and has been implicated in the cognitive decline and behavioral changes of AD. Activity of the synthetic enzyme choline acetyltransferase (CAT) and the catabolic enzyme acetylcholinesterase are significantly reduced in the cerebral cortex, hippocampus, and amygdala in patients with AD.

The nucleus basalis of Meynert and diagonal band of Broca provide the main cholinergic input to the hippocampus, amygdala, and neocortex, which are lost in patients with AD. Loss of cortical CAT and decline in acetylcholine synthesis in biopsy specimens have been found to correlate with cognitive impairment and reaction time performance.

Because cholinergic dysfunction may contribute to the symptoms of patients with AD, enhancing cholinergic neurotransmission constitutes a rational basis for symptomatic treatment.

Oxidative stress and damage

Oxidative damage occurs in AD. Such studies have demonstrated that an increase in oxidative damage selectively occurs within the brain regions involved in regulating cognitive performance. Increased levels of oxidative damage occur in patients with mild cognitive impairment (MCI), which is believed to be one of the earliest stages of AD and is a condition that is devoid of dementia or the extensive neurofibrillary pathology and neuritic plaque deposition observed in AD.

Oxidative damage potentially serves as an early event that then initiates the development of cognitive disturbances and pathological features observed in AD. A decline in protein synthesis capabilities occurs in the same brain regions that exhibit increased levels of oxidative damage in patients with MCI and AD. Protein synthesis may be one of the earliest cellular processes disrupted by oxidative damage in AD.[9]

Oxidative stress is believed to be a critical factor in normal aging and in neurodegenerative diseases such as Parkinson disease, amyotrophic lateral sclerosis, and AD. Formation of free carbonyls and thiobarbituric acid-reactive products, an index of oxidative damage, are significantly increased in AD brain tissue compared with age-matched controls. Plaques and tangles display immunoreactivity to antioxidant enzymes.

Multiple mechanisms exist by which cellular alterations may be induced by oxidative stress, including production of reactive oxygen species (ROS) in the cell membrane (lipid peroxidation). This in turn impairs the various membrane proteins involved in ion homeostasis such as N-methyl-D-aspartate receptor channels or ion-motive adenosine triphosphatases.

The subsequent increase in intracellular calcium, along with the accumulation of ROS, damages various cellular components such as proteins, DNA, and lipids and may result in apoptotic cellular death. Increased intracellular calcium may also alter calcium-dependent enzyme activity such as the implication of protein kinase C in amyloid protein metabolism and the phosphorylation of tau.

The involvement of calcium in AD has suggested that blocking the increase in free intracellular calcium may diminish neuronal injury. However, clinical trials of nimodipine, a lipophilic calcium channel blocker that is mediated through inactivation of voltage-dependent L-type (long-lasting) calcium channels, have yielded generally disappointing results in patients with AD.

The apoptotic pattern of cellular death seen in oxidative stress is similar to that produced by AB peptide exposure, and AB neurotoxicity is attenuated by antioxidants such as vitamin E. AB may induce its toxicity by engaging several binding sites on the membrane surface. The receptor for advanced glycation end products (RAGE) may be one of these receptors. RAGE is a member of the immunoglobulin superfamily of cell surface molecules known for its capacity to bind advanced glycation end products.

RAGE is also expressed in a variety of other cell types, including endothelial cells and mononuclear phagocytes. Activation of this receptor is believed to trigger cellular oxidative reactions. In addition, RAGE has been shown to mediate the interaction of beta amyloid protein with glial cells, which may be one of the first steps in the inflammatory cascade (see Inflammatory reactions below).

Inflammatory reactions

Inflammatory and immune mechanisms may play a role in the degenerative process in AD. Reactive microglia are embedded in neuritic plaques. Increased cytokines are seen in the serum, cortical plaques, and neurons of patients with AD compared with aged-matched control subjects. Interestingly, the anti-inflammatory cytokine transforming growth factor beta 1 (TGF-β1) has recently been found to promote or accelerate the deposition of amyloid.

Classical complement pathway fragments are also found in the brains of patients with AD, and amyloid may directly activate the classical complement pathway in an antibody-independent fashion.

One study by Finch et al found an association between AD and the major histocompatibility complex, located on chromosome 6.[10] The age at onset of AD was significantly lower in patients carrying the A2 allele.

Whether markers of immune and inflammatory processes actively participate in the neurodegenerative process or instead represent an epiphenomenon remains unclear. Brain specimens from elderly patients with arthritis treated with nonsteroidal anti-inflammatory drugs (NSAIDs) have similar numbers of senile plaques as control brains.

However, less microglial activation is seen in the brains of the patients with arthritis. This suggests that although NSAIDs may not impede senile plaque formation, they may delay or prevent clinical symptoms by limiting the associated inflammation.

As mentioned above, RAGE has been shown to mediate the interaction of amyloid and glial cells, producing cellular activation and an inflammatory response with cytokine production, chemotaxis, and haptotaxis. The expression of this receptor appears to be upregulated in neurons, vasculature, and microglia in affected regions of AD brains. The unrelated class A scavenger receptor (Class A SR) also mediates the adhesion of microglial cells to amyloid fibrils. Senile plaques contain high concentrations of microglia that express class A SRs.

RAGE and class A SRs may represent novel pharmacologic targets for diminishing the inflammatory and oxidative reactions associated with AD.

Clusterin

Clusterin, a plasma protein, plays an important role in the pathogenesis of AD. In a recent study, clusterin was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. This important study suggests that alterations in amyloid chaperone proteins could be a relevant peripheral signature of AD.[11]

Presenilins

A significant proportion of early-onset autosomal-dominant AD cases have been linked to a candidate gene on chromosome 14 (14q24.3) called presenilin-1 (PS1) and a candidate gene on chromosome 1 called presenilin-2 (PS2). The 2 putative products of these candidate genes, PS1 and PS2, share substantial amino-acid and structural similarities, suggesting that they may be functionally related. In addition, the expression patterns of PS1 and PS2 in the brain are similar, if not identical.

Both PS1 mRNA and PS2 mRNA are detectable only within neuronal populations. Immunochemical analyses indicate that PS1 localizes to intracellular compartments such as the endoplasmic reticulum and Golgi complex that are involved in similar functions. Recent evidence supports the role of presenilins in AB metabolism. Mice deficient in the expression of PS1 exhibit dramatic decrease in proteolytic cleavage of the transmembrane domain of APP by secretase.

PS1 is immunoreactive with neuritic plaques (NP). Both asymptomatic and demented subjects carrying the PS1 mutation have increased production of the amyloidogenic AB 42/43 isoform in skin fibroblasts and plasma. Prominent deposition of AB 42/43 is found in many brain regions of patients with PS1 mutations. These findings, in suggesting that inhibiting presenilin function might decrease AB amyloid production, offer new therapeutic avenues.

Estrogen loss

Some studies have shown that estrogen loss may lead to cognitive decline and neuronal degeneration, and the expression of nerve growth factor and brain-derived neurotrophic factor mRNA is also decreased. Estrogen has also been shown to exert cytoprotective effects and to prevent amyloid toxicity in human neuroblastoma cell cultures; however, a randomized clinical trial of estrogen in cognitively normal women aged 65 and older with a first-degree relative with AD showed that estrogen therapy might actually increase the risk of stroke and dementia.[12]

Etiology

The cause of AD is unknown. Several investigators now believe that converging risk factors trigger a pathophysiologic cascade that, over decades, leads to Alzheimer pathology and dementia.

The following risk factors for Alzheimer-type dementia have been identified[13, 14, 15, 16] :

Advancing age Family history

Apolipoprotein E epsilon 4 genotype

Obesity

Insulin resistance

Vascular factors

Dyslipidemia

Hypertension

Inflammatory markers

Down syndrome

In addition, epidemiology studies have suggested some possible risk factors (such as aluminum[17, 18] and previous depression) and some protective factors (education,[19, 20] , anti-inflammatory drugs). Moderate-to-severe head trauma appears to be linked to the development of AD as well as other forms of dementia later in life. A study that followed over 7,000 US veterans from World War II showed that those who had sustained head injuries had twice the risk of developing dementia later in life, with veterans who suffered more severe head trauma being at an even higher risk. The study also found that the presence of the apolipoprotein E gene and sustaining head trauma seemed to act additively to increase the risk of developing AD, although there was no direct correlation.[21]

Insulin resistance

A small study by Baker et al implies that insulin resistance as evidenced by decreased cerebral glucose metabolic rate measured by a specific type of positron emission tomography (PET) scan may be useful as an early marker of AD risk, even before the onset of MCI.[22] The PET scan revealed a qualitatively different activation pattern in patients with prediabetes or type 2 diabetes mellitus during a memory encoding task compared with healthy individuals who were not insulin resistant. Although their results

were not statistically significant due to the small number of subjects (n=23) in the study, this certainly warrants further study because it may lead to a noninvasive test that could help to quantify risk for development of AD in presymptomatic patients.

A similar study was performed in a much larger population of 3,139 participants to investigate the association of diabetes mellitus with an increased risk of AD and to assess whether the risk is constant over time.[23] A different measure of insulin resistance was calculated, using the homeostasis model assessment. They found a similar association between insulin resistance and AD over 3 years, which then disappeared after that time. Disturbances in insulin metabolism may not cause neurological changes but may influence and accelerate these changes, leading to an earlier onset of AD.

Genetic causes

Although most cases of AD are sporadic (ie, not inherited), familial forms of AD do exist; however, they account for less than 7% of all cases.

Mutations in genes coding for 3 proteins unequivocally cause AD. These genes (which code for amyloid precursor protein [APP, on chromosome 21], for PS1 [on chromosome 14], and for PS2 [on chromosome 1]) all lead to a relative excess in the production of the stickier 42-amino acid form of the AB peptide over the less sticky 40-amino acid form.

This beta-pleated peptide is postulated to have neurotoxic properties and to lead to a cascade of events (as yet incompletely understood) that results in neuronal death, synapse loss, and the formation of NFTs and SPs, among other lesions. Nonetheless, the mutations that have been found to date account for less than half of all cases of early-onset AD. Other than the apolipoprotein E epsilon 4 (APOE E4) genotype, no polymorphisms in other genes have been consistently found to be associated with late-onset AD.

Genetic factors associated or potentially associated with AD are summarized in Tables 1 and 2.

Table 1. Genetic Factors Associated With Alzheimer Disease (Open Table in a new window)

Chromosome Gene Defect Onset Putative Mechanisms

21 APP Early Increased production of AB 42

19 APOE E4 Late Tau hyperphosphosphorylation Impaired production/

-polymerzation/ clearance of AB

14 PS-1 Early Early increased production of AB 42

1 PS-2 Early Early altered AB metabolism

Table 2. Other Locus or Susceptibility Genes Potentially Associated with Alzheimer Disease (Open Table in a new window)

Chromosome Gene Onset Putative Mechanisms

12 Unidentified Late Unknown

6 HLA A2 Late Possible relationship with immune system and inflammatory response

14 a1-antichymotrypsin A allele

Late AB aggregation

12 LRP Late Endocytosis of APOE/APP

APP mutations

The observation that patients with Down syndrome (trisomy 21) develop cognitive deterioration and typical pathological features of AD by middle age led to the discovery of the APP gene on chromosome 21. Simultaneously, a locus segregating with a minority of early-onset familial AD kindreds was mapped to this chromosome in the same region as the APP gene. Go to Alzheimer Disease in Individuals With Down Syndrome for complete information on this topic.

Subsequently, several missense mutations within the APP gene that resulted in amino acid substitutions in APP were identified in these FAD kindreds. Such mutations appear to alter the previously described proteolytic processing of APP, generating amyloidogenic forms of AB. Skin fibroblasts from subjects carrying APP mutations produce increased AB 42/43. Increased plasma concentration of AB 42/43 is also seen in these patients regardless of age, sex, or clinical status. Interestingly, some patients with sporadic AD may exhibit similar elevations of plasma AB 42/43.

PS1 and PS2 mutations

In cases of early-onset autosomal-dominant AD cases, 50-70% appear to be associated with a locus (AD3) mapped by genetic linkage to the long arm of chromosome 14 (14q24.3). Numerous missense mutations have been identified on a strong candidate gene, called PS1. At the same time, another autosomal dominant locus responsible for early-onset AD was localized to chromosome 1. Two mutations were identified on the candidate gene, designated PS2.

The physiological role of presenilins and the pathogenic effects of their mutations are not yet well understood. (See Pathophysiology.)

APOE E4 allele

The gene encoding the cholesterol-carrying apolipoprotein E (APOE) on chromosome 19 has been linked to early-onset familial and sporadic AD. The gene is inherited as an autosomal codominant trait with 3 alleles. This article focuses on the allele that may have a direct correlation to AD.

APOE E4 gene “dose” is correlated with increased risk and earlier onset of AD.[10] Persons with 2 copies of the APOE E4 allele (4/4 genotype) have significantly greater risk of developing AD than persons with other APOE subtypes. Mean age at onset is significantly lower in the presence of 2 APOE E4 copies. A collaborative study has suggested that APOE E4 exerts its maximal effect before the age of 70.

Many APOE E4 carriers do not develop AD, and many patients with AD do not have this allele. Therefore, the presence of an APOE E4 allele does not secure the diagnosis of AD, but instead, the APOE E4 allele acts as a biological risk factor for the disease, especially in those younger than 70 years.

Epidemiology

United States statistics

Using 2000 US Census results, Hebert et al estimated that about 4.5 million people in the United States had AD.[3] These researchers calculated that by 2030, an estimated 7.7 million Americans aged 65 and older will have AD and that by 2050, that number will rise to more than 13 million.

According to a 2010 report, AD affects approximately 5.3 million people in the United States.[4] A larger number of individuals have decreased cognitive function (eg, mild cognitive impairment); this condition frequently evolve into a full-blown dementia, thereby increasing the number of affected persons. The statistical projections cited in this report indicate that the number of persons affected by the disorder in the United States could range from 11 to 16 million by the year 2050.[4]

The lifetime risk of AD is estimated to be 1:4-1:2. More than 14% of individuals older than 65 years have AD, and the prevalence increases to at least 40% in individuals older than 80 years.

International statistics

Prevalence rates of AD similar to those in the United States have been reported in industrialized nations. The prevalence of dementia in subjects 65 years and older in North America is approximately 6-10%, with AD accounting for two-thirds of these cases. If milder cases are included, the prevalence rates double. Countries experiencing rapid increases in the elderly segments of their population have rates approaching those in the United States.

The World Health Organization’s review in 2000 on the Global Burden of Dementia[24] reported that an integrative analysis of 47 surveys across 17 countries suggested that approximate rates for dementia from any cause are under 1% in persons aged 60-69 years, rising to about 39% in persons 90-95 years old. The prevalence doubles with every 5 years of age within that range, with few differences taking into account secular changes, age, gender, or place of living.

AD has become nearly twice as prevalent as vascular dementia (VaD) in Korea, Japan, and China since transition in the early 1990s. American and European studies consistently reported AD to be more prevalent than VaD. They found a dementia prevalence rate among Chinese aged 50 years and older on the islet of Kinmen for this age group of 11.2 per 1,000. AD accounted for 64.6% and VaD for 29.3%. These results, together with previous studies in Chinese populations, suggest that the rates of AD in the Chinese are low compared with those in whites.

In Nigeria, the prevalence of dementia was low. Indian studies were contradictory, with both AD and VaD being more prevalent in different studies.

Age distribution for Alzheimer disease

The prevalence of AD increases with age. AD is most prevalent in individuals older than 60 years. Some forms of familial early-onset AD can appear as early as the third decade, but this represents a subgroup of the less than 10% of all familial cases of the disease.

More than 90% of cases of AD are sporadic and occur in individuals older than 60 years. However, of interest, results of some studies of nonagenarians and centenarians suggest that the risk may decrease in individuals older than 90 years. If so, age is not an unqualified risk factor for the disease, but further study of this matter is needed.

Savva et al found that the association between dementia and the pathological features of AD (eg, neuritic plaques, diffuse plaques, tangles) is stronger in younger old persons (ie, age 75 years) than in older old persons (ie, 95 years). These results were achieved by assessing 456 brains donated to the population-based Medical Research Council Cognitive Function and Ageing Study from persons 69-103 years of age at death.

These results demonstrate that the relationship between cerebral atrophy and dementia persist into the oldest ages, but the strength of association between pathological features of AD and clinical dementia diminished. It is important to take age into account when assessing the likely effect of interventions against dementia on the population.[11]

Sex distribution for Alzheimer disease

AD affects both men and women; however, Plassman et al found the risk of developing AD to be significantly higher in women than in men, primarily due to women’s higher life expectancy.[25]

Prevalence of Alzheimer disease by race

AD and other dementias are more common in African Americans than in whites. According to the Alzheimer’s Association, in the population aged 71 and older, African Americans are almost 2 times as likely to have AD and other dementias than whites (21.3% of African Americans vs 11.2% of whites). The number of Hispanic patients studied in this age group was too small to determine the prevalence of dementia in this population.

In individuals age 65 and older, 7.8% of whites, 18.8% of African-Americans, and 20.8% of Hispanics have AD or other dementias, and the prevalence of AD and other dementias is higher in older versus younger age groups.[4]

Prognosis

AD is initially associated with memory impairment that progressively worsens. Over time, patients with AD can display anxiety, depression, insomnia, agitation, and may become violent and paranoid. Eventually the patient with AD loses all bodily function, including the ability to walk and swallow; feeding is possible only by gastrointestinal tube. Difficulty swallowing may lead to aspiration pneumonia.

The time from diagnosis to death varies from as little as 3 years if the patient is older than 80 years when diagnosed to as long as 10 or more years if the patient is younger. The primary cause of death is intercurrent illness, such as pneumonia.

In the United States, AD is frequently considered a leading cause of death. In 2006, AD was the seventh leading cause of death[26] ; however, AD as an underlying cause of death is frequently underreported.[27]

Patient Education

When counseling patients following a diagnosis of AD, it is essential to involve the patient’s family and others who will play a supporting role in the discussion. It is important to emphasize that not only the patient, but also those who support him or her, will likely experience reactions of sadness and anger, and that these are normal reactions to such a catastrophic diagnosis.

As the patient’s symptoms become more pronounced, a dialogue must be opened regarding the patient’s wishes for care when he or she is no longer able to make the necessary choices. Durable power of attorney should be discussed, with particular attention to who will make decisions for both medical and financial issues. Medical advance directives should be considered while the patient is still able to participate in the decision-making process.

As the patient continues to decline, family members should be careful to select qualified and trustworthy individuals to be involved in the day-to-day management of the patient. Any suspicions of elder abuse should be immediately addressed.

Throughout the course of the illness, it is important that the family be counseled to continue to treat the patient as a competent adult as much as possible, despite the patient’s decreasing ability to care for himself or herself.

The following resources may be helpful to share with patients and their families:

MedlinePlus -Alzheimer’s Disease The National Institute on Aging -General Information on Alzheimer’s Disease

Caring for Someone with Alzheimer’s (video series)

The National Alzheimer’s Association

For patient education resources, see eMedicine’s Dementia Center as well as Alzheimer Disease, Alzheimer Disease in Individuals With Down Syndrome, Dementia Overview, and Dementia Medication Overview.

Approach Considerations

Clinical guidelines such as those described earlier are used. (See Diagnosis.) The main focus of these diagnostic guidelines consists of verifying the initial finding of mild, slowly progressive memory loss, confirming that additional spheres of cognition are also compromised, and ruling out other possible causes for dementia (eg, cerebrovascular disease, cobalamin [vitamin B-12] deficiency, syphilis, thyroid disease).

A combination of clinical examination and ancillary imaging studies (eg, computed tomography [CT], magnetic resonance imaging [MRI], and, in selected cases, single-photon emission CT [SPECT] or positron emission tomography [PET]) and laboratory tests may be used. At the Alzheimer’s Association International Conference on Alzheimer’s Disease (AAICAD) in July 2010, operational research criteria

were presented to define preclinical AD, mild cognitive impairment due to AD, probable AD, and possible AD, involving PET imaging, cerebrospinal fluid (CSF) Aß42 and tau levels, and genetic analysis in order to facilitate future studies. These criteria were not intended to serve as diagnostic criteria for clinical purposes.

Lab Studies

Laboratory workup can be performed to rule out other conditions that may cause cognitive impairment. Current recommendations from the American Academy of Neurology (AAN) include measurement of the cobalamin (vitamin B-12) level and a thyroid function screening test. Additional investigations are left to the physician, to be tailored to the particular needs of each patient. Initial test results that require further investigation include the following:

Abnormalities in complete blood cell count and cobalamin (vitamin B-12) levels require further workup to rule out hematologic disease

Abnormalities found in screening of liver enzyme levels require further workup to rule out hepatic disease

Abnormalities in thyroid-stimulating hormone (TSH) levels require further workup to rule out thyroid disease

Abnormalities in rapid plasma reagent (RPR) require further workup to rule out syphilis

There is a possible link between vitamin D deficiency and cognitive impairment.[30, 31] However, vitamin D deficiency has not been identified as a reversible cause of dementia.

Brain MRI or CT Scanning

AAN recommendations indicate that structural neuroimaging with either a noncontrast CT or MRI scan is appropriate in the initial evaluation of patients with dementia, in order to detect lesions that may result in cognitive impairment (eg, stroke, small vessel disease, tumor).[32] In patients with Alzheimer disease (AD), brain MRIs or CT scans can show diffuse cortical and/or cerebral atrophy, but these findings are not diagnostic of AD.

In clinical research studies, atrophy of the hippocampi (structures important in mediating memory processes) on coronal MRI is considered a valid biomarker of AD neuropathology. Nonetheless, measurement of hippocampal volume is not used in routine clinical care in the diagnosis of AD.

Go to Imaging of Alzheimer Disease for complete information on this topic.

SPECT or PET scanning

Brain scanning with SPECT or PET is not recommended for the routine workup of patients with typical presentations of AD. These modalities may be useful in atypical cases or when some form of frontotemporal dementia is a more likely diagnosis.[33]

Image courtesy of NIH.

Go to Imaging of Alzheimer Disease for complete information on this topic.

Electroencephalography

Electroencephalography (EEG) is valuable when Creutzfeldt-Jakob disease or other prion-related disease is a likely diagnosis (see EEG in Dementia and Encephalopathy). Periodic high-amplitude sharp waves can eventually be detected in most cases of Creutzfeldt-Jakob disease.

EEG is also useful if pseudodementia is a realistic consideration when a normal EEG in a patient who appears profoundly demented would support that diagnosis. Multiple unwitnessed seizures rarely can present as dementia and an EEG would be valuable for evaluating that possibility.

Lumbar Puncture

Perform lumbar puncture in select cases to rule out conditions such as normal-pressure hydrocephalus, neurosyphilis, neuroborreliosis, and cryptococcosis.

Cerebrospinal fluid (CSF) levels of tau and phosphorylated tau are often elevated in AD, whereas amyloid levels are usually low. The reason for this is not known, but perhaps amyloid levels are low because the amyloid is deposited in the brain rather than the CSF. By measuring both proteins, sensitivity and specificity of at least 80% and more often 90% can be achieved.

At present, however, routine measurement of CSF tau and amyloid is not recommended except in research settings. Lumbar puncture for measurement of tau and amyloid may become part of the diagnostic workup when effective therapies that slow the rate of progression of AD are developed, particularly if the therapies are specific for AD and carry significant morbidity.

Genotyping

Genotyping for apolipoprotein E (APOE) alleles is a research tool that is helpful in determining the risk of AD in populations, but it is of little, if any, value in making a clinical diagnosis and developing a management plan in individual patients.

In a prospective, randomized, controlled trial of the effect of disclosing APOE genotyping results to 162 asymptomatic adults who had a parent with AD, Green et al found that follow-up testing over the course of a year showed no significant differences with disclosure versus nondisclosure on time-averaged measures of anxiety, depression, or test-related distress.

Test-related distress was reduced among those who learned that they did not carry the APOE epsilon 4 (APOE E4) allele. Persons who had high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure.[34]

Genetic Testing for APP and Presenilin Mutations

After appropriate counseling, genetic testing for APP and presenilin mutations is appropriate in early-onset cases.

Approach Considerations

Therapeutic approaches to Alzheimer disease (AD) will someday include both symptomatic therapy and disease-modifying therapies. To date, only symptomatic therapies are available. All drugs approved by the US Food and Drug Administration (FDA) for the treatment of AD modulate neurotransmitters, either acetylcholine or glutamate. The standard medical treatment for AD includes cholinesterase inhibitors (ChEIs) and partial N -methyl-D-aspartate (NMDA) antagonists.

Psychotropic medications are often used to treat secondary symptoms of AD, such as depression, agitation, and sleep disorders. These include antidepressants, anxiolytics, antiparkinsonian agents, beta-blockers, antiepileptic drugs used for their effects on behavior, and neuroleptics.[35]

Several studies have examined the efficacy of psychotropic drugs; most have demonstrated no or limited efficacy, but many issues make interpretation of data from these studies difficult.

Other medications that have been used to treat AD include antioxidants (vitamin E [α-tocopherol]), hormones (conjugated estrogens), nonsteroidal anti-inflammatory drugs (NSAIDs), and Ginkgo biloba.

Hospitalization should be considered for any unstable medical condition that may complicate the patient’s treatment. If a patient becomes a danger to him/herself or others, admission to a long-term care facility due to grave disability should be considered for everyone’s safety.

Treatment of Mild to Moderate Disease

ChEIs and mental exercises are used in an attempt to prevent or delay the deterioration of cognition in patients with AD.

Cholinesterase inhibition

Numerous lines of evidence suggest that cholinergic systems that modulate information processing in the hippocampus and neocortex are impaired early in the course of AD. These observations have suggested that some of the clinical manifestations of AD are due to loss of cholinergic innervation to the cerebral cortex.

Centrally acting ChEIs prevent the breakdown of acetylcholine. Four such agents have been approved by the FDA for the treatment of AD: tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne, formerly Reminyl).

All ChEIs have shown modest benefit compared with placebo on measures of cognitive function and activities of daily living. Patients on ChEIs decline more slowly on cognitive and functional measures than patients on placebo. In general, the benefits are temporary because ChEIs do not address the underlying cause of the degeneration of cholinergic neurons, which continues during the disease. The ChEIs may also alleviate the noncognitive manifestations of AD, such as agitation, wandering, and socially inappropriate behavior.

Although the ChEIs were originally expected to be efficacious in only the early and intermediate stages of AD (because the cholinergic deficit becomes more severe later in disease and fewer intact cholinergic synapses are present), they are also helpful in advanced disease.

ChEIs are also helpful in patients with AD with concomitant infarcts and in patients with dementia with Lewy bodies. (Frequently, AD and dementia with Lewy bodies occur in the same patient; this is sometimes called the Lewy body variant of AD.)

The ChEIs share a common profile of adverse effects, the most frequent of which are nausea, vomiting, diarrhea, and dizziness. These are typically dose related and can be mitigated with slow up-titration to the desired maintenance dose. As antimuscarinic drugs are used for the treatment of incontinence, logically, ChEIs might exacerbate incontinence. One brief report has supported this hypothesis.[36]

ChEIs prescribed to treat dementia can provoke symptomatic bradycardia and syncope and precipitate fall-related injuries, including hip fracture. A population-based cohort study that identified community-dwelling older adults with dementia who were taking cholinesterase inhibitors (n=19,803) and controls who were not (n=61,499) found hospital visits for syncope were more frequent in people receiving ChEIs than in controls (31.5 vs 18.6 events per 1000 person-years).

Other syncope-related events, including hospital visits for bradycardia, permanent pacemaker insertion, and hip fracture, were also more common among people receiving cholinesterase inhibitors compared with controls. ChEI use in older adults with dementia is associated with increased risk of syncope-related events; these risks must be weighed against the benefits of taking ChEIs.[37]

Anecdotal reports exist of acute cognitive and behavioral decline associated with the abrupt termination of ChEIs. In several of these cases, restarting the ChEI was not associated with substantial improvement. These reports have implications concerning the best practice when switching a patient from one ChEI to another in this class.

Reasons for switching might include undesirable side effects or seeming lack of efficacy. Nonetheless, no published data help clinicians know when switching to another ChEI would be helpful. The common practice of tapering a patient off one central nervous system (CNS)-active

medication before starting a new one should not be followed when changing ChEIs. For example, a patient who had been taking 10 mg of donepezil should be started the next day on galantamine, at least 8 mg/d and possibly 16 mg/d.

No current evidence supports the use of more than 1 ChEI at a time.

Of note, tacrine has potential liver toxicity, requires frequent blood monitoring, and has been rarely prescribed since the other agents have become available.

Centrally acting anticholinergic medications should be avoided. Patients not uncommonly receive both ChEIs and anticholinergic agents, which counteract each other. Medications with anticholinergic effects, such as diphenhydramine (Benadryl) and tricyclic antidepressants (eg, amitriptyline, nortriptyline) can cause cognitive dysfunction. Therefore, a careful listing of the patient’s medications is important so that the physician can reduce the doses of, or ideally eliminate, all centrally acting anticholinergic agents.

Mental activity to support cognition

Many patients with normal cognition or those with mild impairment are concerned that they may develop AD. Many experts believe that mentally challenging activities, such as doing crossword puzzles and brainteasers, may reduce the risk in such patients. Whether such activities might slow the rate of disease progression in patients who already have AD is not known. Clinical trials are underway to determine the effect these cognitive activities have on AD progression.

The mental activities should be kept within a reasonable level of difficulty for the patient. They should preferably be interactive, and they should be designed to allow the patient to recognize and correct mistakes. Most important, these activities should be administered in a manner that does not cause excessive frustration and that ideally motivates the patient to engage in them frequently. Unfortunately, little standardization or rigorous testing has been done to validate this treatment modality.

Some investigators have attempted various forms of cognitive retraining, also known as cognitive rehabilitation. The results of this approach remain controversial, and a substantial experimental study must still be performed to determine if it is useful in Alzheimer disease.

Treatment of Moderate to Severe Disease

The partial NMDA antagonist memantine (Namenda) is believed to work by improving the signal-to-noise ratio of glutamatergic transmission at the NMDA receptor. This agent is approved by the FDA for treating moderate and severe AD. Several studies have demonstrated that memantine can be safely used in combination with ChEIs. Studies suggest that the use of memantine with donepezil affects cognition in moderate to severe AD[38] but not in mild to moderate AD.[39]

Treatment of Secondary Symptoms

A variety of behavioral and pharmacologic interventions can temporarily alleviate clinical manifestations of AD, such as anxiety, agitation, depression, and psychotic behavior. The effectiveness of such interventions is often modest and temporary, and they do not prevent the eventual deterioration of the patient’s condition.

No specific agent or dose of individual agents is unanimously accepted for the wide array of clinical manifestations. At present, the FDA has not approved any psychotropic agent for the treatment of AD.

Go to Psychiatric Aspects of Alzheimer Disease for complete information on this topic.

Behavioral interventions

Behavioral interventions range from patient-centered approaches to caregiver training to help manage cognitive and behavioral manifestations of AD. These interventions are often combined with the more widely used pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for aberrant and/or socially disruptive behavior, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage).

Neuroleptic agents

In 2005, the FDA added a “black box warning” on the use of atypical neuroleptics in the treatment of secondary symptoms of AD such as agitation.[40] Analyses suggested that patients on atypical neuroleptics had increased risk of death or stroke compared with patients on placebo. In 2008, a black box warning was included on haloperidol, prochlorperazine, thioridazine, and chlorpromazine for the same reason.

The general recommendation is to use such agents as infrequently as possible and at the lowest doses possible to minimize adverse effects, particularly in frail, elderly patients. Particular concern has been raised about the potential for dopamine-depleting agents to aggravate the motor manifestations of dementia with Lewy bodies (DLB), because patients with DLB may be extremely sensitive to these agents.

Antidepressants and mood modulators

Antidepressants have an important role in the treatment of mood disorders in patients with AD. Depression is observed in more than 30% of patients with AD, and it frequently begins before AD is clinically diagnosed. Therefore, palliation of this frequent comorbid condition may improve cognitive and noncognitive performance.

Nyth found citalopram to be beneficial in mood and other neuropsychiatric symptoms in patients in the moderate stage of AD.[41] However, Weintraub et al[42] and Petracca[43] found sertraline and fluoxetine to have no short- or long-term benefit in mood over placebo.

Other mood modulators, such as valproic acid, can be helpful for the treatment of disruptive behaviors and outbursts of anger, which patients with moderately advanced or advanced stages of AD may have.

Results of several studies indicate that anticonvulsants (eg, gabapentin, valproic acid) may have a role in the treatment of behavioral problems in patients with Alzheimer disease.

Suppression of Brain Inflammation

Many studies have suggested that intense inflammation occurs in the brains of patients with AD. Epidemiologic studies suggest that some patients on long-term anti-inflammatory therapy have a decreased risk of developing AD. Nonetheless, no randomized clinical trial of greater than 6-months duration has demonstrated efficacy of anti-inflammatory drugs in slowing the rate of progression of AD.

Although previous reports reflect delayed onset of AD in individuals who used nonsteroidal anti-inflammatory drugs (NSAIDs), a study by Breitner et al showed that NSAIDs do not protect against AD, at least in very old people. Relying on computerized pharmacy dispensing records and biennial dementia screening, investigators found AD incidence was increased in heavy NSAID users. These findings may represent deferral of AD symptoms from earlier to later old age.[44]

Experimental Therapies

A variety of experimental therapies have been proposed for AD. These include antiamyloid therapy, reversal of excess tau phosphorylation, estrogen therapy, and vitamin E therapy free-radical scavenger therapy. Studies of these therapies have yielded mostly disappointing results.

Antiamyloid therapy

In the past 10 years, numerous studies have been conducted, and many are still ongoing, that test therapies designed to decrease toxic amyloid fragments in the brain. A wide variety of approaches have been tried, including the following:

Vaccination with amyloid species Administration of monoclonal antiamyloid antibodies

Administration of intravenous immune globulin that may contain amyloid-binding antibodies

Selective amyloid-lowering agents

Chelating agents to prevent amyloid polymerization

Brain shunting to improve removal of amyloid

Beta-secretase inhibitors to prevent generation of the A-beta amyloid fragment

To date, no phase III study of these approaches has shown an acceptable combination of efficacy and acceptable side effects.

Tau-directed therapies

Studies are also ongoing with agents that may prevent or reverse excess tau phosphorylation and thereby diminish formation of neurofibrillary tangles.

Free-radical scavenger therapy

Excess levels of free radicals in the brain are neurotoxic. Nonetheless, no study has demonstrated efficacy of free-radical scavengers in the treatment of the cognitive symptoms of AD.

Vitamin E therapy

A report by Sano et al in 1997 suggested that high-dose vitamin E (2000 units per day of alpha-tocopherol) might decrease the risk of death or the rate of conversion to severe dementia.[45] This benefit presumably resulted from the antioxidant effects of vitamin E. Nonetheless, subsequent studies suggested that vitamin E supplementation may increase risk of adverse cardiovascular outcomes. Therefore, use of these agents is not currently recommended, and most practitioners have abandoned their use.

Estrogen therapy

No data show that women with AD who are placed on estrogen therapy (ET) have fewer symptoms or progress more slowly than women treated with a placebo. Furthermore, a randomized clinical trial of estrogen in cognitively normal women aged 65 years and older with a first-degree relative with AD showed that ET might actually increase the risk of stroke and dementia.[12] Whether ET might decrease risk if started well before age 65 years is not known.

Presymptomatic disease-modifying therapy

Disease-modifying therapies would delay the onset of AD and/or slow the rate of progression. Since brain changes associated with AD probably start decades before dementia becomes clinically apparent, many investigators believe that disease-modifying therapies are much more likely to be effective if they are started in a presymptomatic stage.

Studies are identifying patients at increased risk with neuropsychological, neuroimaging, and genetic methods. Although phase III trials for several potential disease-modifying therapies have been completed, to date none of these agents have shown clear efficacy and hence none have been approved by the FDA.

Surgical Treatment

No accepted surgical treatments exist for AD. Potential surgical treatments in the future may include the use of devices to infuse neurotrophic factors, such as growth factors, to palliate AD.

Dietary Measures

No special dietary considerations exist for Alzheimer disease.

Caprylidene is a prescription medical food that is metabolized into ketone bodies. The brain can use these ketone bodies for energy when its ability to process glucose is impaired. Brain-imaging scans of older adults and persons with AD reveal dramatically decreased uptake of glucose.

The approval of caprylidene was based on a double-blind, randomized, placebo-controlled, 90-day study that enrolled 152 patients with mild-to-moderate AD.[46] At day 45, Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-Cog) scores stabilized in the caprylidene group, whereas these scores declined in the placebo group.

The ADAS-Cog change from baseline score was also analyzed based on APOE E4 genotype. The APOE E4(-) patients receiving caprylidene showed improved cognitive function when compared with APOE E4(-) patients receiving placebo. In APOE E4(+) patients, the mean change in ADAS-Cog total scores for the 2 groups was essentially identical at all time points, with more patients showing decline rather than improvement at days 45 and 90.

Go to Alzheimer Disease and APOE-4 for complete information on this topic.

Physical Activity

Routine physical activity and exercise may have an impact on AD progression, and perhaps has a protective effect on brain health.[47] Increased cardiorespiratory fitness levels are associated with higher hippocampal volumes in patients with mild AD, suggesting that cardiorespiratory fitness may modify AD-related brain atrophy.[48]

The activity of each patient should be individualized. The patient’s surroundings should be safe and familiar. If the patient’s activity is optimized too much, it can cause agitation, but too little can cause the patient to withdraw and maybe become depressed.

The patient needs contact with the outside environment. Television can be helpful for this task. Maintaining structured routines may be helpful to decrease patient stress in regard to meals, medication, and other therapeutic activities aimed at maintaining cognitive functioning.

Long Term Monitoring

Patients should receive regular follow-up care by their outpatient physician to closely monitor the illness and maximize the patient’s functioning as long as possible.