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Alzheimer Disease

Author: Heather S Anderson, MD; Chief Editor: Michael Hoffmann, MBBCh, MD, FCP(SA), FAAN, F

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 Alzheimers Disease: Slideshow.

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 neurons 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.

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 Alzheimers 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 earlyonset 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 -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 alleles 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-1) 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, 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] A study by Schrijvers et al notes that although plasma clusterin levels are significantly associated with baseline prevalence and severity of AD, they are not related to the risk of incidence of AD.[12]

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.[13]

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[14, 15, 16, 17] :

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[18, 19] and previous depression) and some protective factors (education,[20, 21] , antiinflammatory 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.[22]
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.[23] 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.[24] 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 21 19 APP APOE E4

Putative Mechanisms

Early Increased production of AB 42 Late Tau hyperphosphosphorylation Impaired production/

-polymerzation/ clearance of AB

14 1

PS-1 PS-2

Early Early increased production of AB 42 Early Early altered AB metabolism

Table 2. Other Locus or Susceptibility Genes Potentially Associated with Alzheimer Disease (Open Table in a new window)
Chromosome 12 6 Gene Unidentified HLA A2 Onset Late Unknown Late Possible relationship with immune system and inflammatory response Late AB aggregation Putative Mechanisms


a1-antichymotrypsin A allele 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.

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 Organizations review in 2000 on the Global Burden of Dementia[25] 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 womens higher life expectancy.[26]
Prevalence of Alzheimer disease by race

AD and other dementias are more common in African Americans than in whites. According to the Alzheimers Association, in the population aged 71 and older, African Americans are almost 2 times as likely to have AD and other dementias as 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]

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[27] ; however, AD as an underlying cause of death is frequently underreported.[28]

Patient Education
When counseling patients following a diagnosis of AD, it is essential to involve the patients 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 patients symptoms become more pronounced, a dialogue must be opened regarding the patients 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 patients decreasing ability to care for himself or herself.

Patients with Alzheimer disease (AD) most commonly present with insidiously progressive memory loss, to which other spheres of cognitive impairment are added over several years. This loss may be associated with slowly progressive behavioral changes. After memory loss occurs, patients may also experience language disorders (eg, anomia) and impairment in their visuospatial skills and executive functions. Patients with mild AD usually have somewhat less obvious executive, language, and/or visuospatial dysfunction. In atypical presentations, dysfunction in cognitive domains other than memory may be most apparent. In later stages, many patients develop extrapyramidal dysfunction. Substantially less common, but biopsy or autopsy-proven, presentations include right parietal lobe syndrome, progressive aphasia, spastic paraparesis, and impaired visuospatial skills, which is subsumed under the visual variant of AD. It is important to obtain a complete history not only from the patient but also from someone who knows the patient well.

Physical Examination
At the time of initial diagnosis, a complete physical examination, including a detailed neurologic examination and a Mental Status Examination (MSE,) should be performed to evaluate disease stage and rule out comorbid conditions. Initial mental status testing should include evaluation of attention and concentration, recent and remote memory, language, praxis, executive function, and visuospatial function. Brief standardized examinations such as the Mini-Mental Status Examination (MMSE) are less

sensitive and specific than longer batteries specifically tailored to individual patients. Nonetheless, screening exams have a role, particularly as a baseline. A complete neurologic examination is performed to look for signs of other diseases that could cause dementia, such as Parkinson disease or multiple strokes. A study by Chen et al suggests that using resting state functional MRI can also classify patients with AD, patients with amnestic mild cognitive impairment, and cognitively healthy patients.[29] Default mode network imaging appears to distinguish AD, MCI, and controls well and may complement PET scanning or prove to be more sensitive.[30] At all subsequent follow-up visits, a full MSE should be performed to evaluate disease progression and identify the development of any new neuropsychiatric symptoms. Go to Psychiatric Aspects of Alzheimer Disease for complete information on this topic.

Stages of Alzheimer Disease

Preclinical Alzheimer disease

AD begins in the entorhinal cortex, which is near the hippocampus and directly connected to it. AD then proceeds to the hippocampus, the structure that is essential to the formation of shortand long-term memories (see the images below). Affected regions begin to atrophy. These brain changes probably start 10-20 years before any visible signs or symptoms appear. Memory loss, the first visible sign, is the main feature of mild cognitive impairment (MCI). Many scientists think MCI is often an initial, transitional clinical phase between normal brain aging and AD.

Preclinical Alzheimer disease. Image courtesy of NIH.

Preclinical Alzheimer disease. Image courtesy of NIH.

A patient with preclinical AD may appear completely normal with regard on physical examination and MSE. At this stage, there is normally no alteration in judgment or the ability to perform activities of daily living.
Mild Alzheimer disease

As AD begins to affect the cerebral cortex, memory loss continues and changes as other cognitive abilities emerge. This stage is referred to as mild AD. The clinical diagnosis of AD is usually made during this stage. Signs of mild AD can include the following:

Memory loss Confusion about the location of familiar places (getting lost begins to occur) Taking longer to accomplish normal daily tasks Trouble handling money and paying bills Compromised judgment often leading to bad decisions Loss of spontaneity and sense of initiative Mood and personality changes; increased anxiety

The growing number of plaques and tangles first damage areas of the brain that control memory, language, and reasoning (see the images below). Later in the disease, physical abilities decline. This leads to a situation in mild AD in which a person seems to be healthy, but is actually having more and more trouble making sense of the world around him or her. The realization that something is wrong often comes gradually because the early signs can be confused with changes that can happen normally with aging.

Mild Alzheimer disease. The disease begins to affect the cerebral cortex, memory loss continues, and changes in other cognitive abilities emerge. The clinical diagnosis of

AD is usually made during this stage. Image courtesy of NIH. moderate Alzheimer disease. Image courtesy of NIH.


Accepting these signs of AD and deciding to seek diagnostic tests can be a huge hurdle for patients and their families to cross. Following initial diagnosis, patients should be carefully

monitored for depressed mood and specifically for suicidal ideation. A diagnosis of AD can be devastating, and many patients may perceive it as a death sentence.
Moderate Alzheimer disease

By the time AD reaches the moderate stage, damage has spread further to the areas of the cerebral cortex that control language, reasoning, sensory processing, and conscious thought. Affected regions continue to atrophy and signs and symptoms of the disease become more pronounced and widespread. Behavior problems, such as wandering and agitation, can occur. More intensive supervision and care become necessary, and this can be difficult for many spouses and families. The symptoms of this stage can include the following:

Increasing memory loss and confusion Shortened attention span Problems recognizing friends and family members Difficulty with language; problems with reading, writing, working with numbers Difficulty organizing thoughts and thinking logically Inability to learn new things or to cope with new or unexpected situations Restlessness, agitation, anxiety, tearfulness, wandering, especially in the late afternoon or at night Repetitive statements or movement, occasional muscle twitches Hallucinations, delusions, suspiciousness or paranoia, irritability Loss of impulse control (shown through sloppy table manners, undressing at inappropriate times or places, or vulgar language) Perceptual-motor problems (such as trouble getting out of a chair or setting the table)

Behavior is the result of complex brain processes, all of which take place in a fraction of a second in the healthy brain. In AD, many of these processes are disturbed, and this is the basis for many distressing or inappropriate behaviors. For example, patients may angrily refuse to take a bath or get dressed because they do not understand what the caregiver has asked them to do. If they do understand, they may not remember how to do what was asked. This anger is a mask for underlying confusion and anxiety. Consequently, the risk for violent and homicidal behavior is highest at this stage of disease progression. Patients should be carefully monitored for any behavior that may compromise the safety of those around them. For a person who cannot remember the past or anticipate the future, the world around them can be strange and frightening. Sticking close to a trusted and familiar caregiver may be the only thing that makes sense and provides security. A person with AD may constantly follow his or her caregiver and fret when the person is out of sight. Judgment and impulse control continue to decline at this stage. For example, taking off clothes may seem reasonable to a person with AD who feels hot and does not understand or remember that undressing in public is not acceptable.

Severe Alzheimer disease

In the last stage, severe AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further (see the images below). Patients cannot recognize family and loved ones or communicate in any way. They are completely dependent on others for care. All sense of self seems to vanish.

Severe Alzheimer disease. In the last stage of AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further. Patients cannot recognize family and loved ones or communicate in any way. They are completely dependent on others

for care. All sense of self seems to vanish. Image courtesy of NIH. Severe Alzheimer disease. Image courtesy of NIH.

Other symptoms can include the following:

Weight loss Seizures, skin infections, difficulty swallowing Groaning, moaning, or grunting Increased sleeping Lack of bladder and bowel control

At the end, patients may be in bed much or all of the time. Death is often the result of other illnesses, frequently aspiration pneumonia.

Diagnostic Considerations
Clinical guidelines for the diagnosis of Alzheimer disease (AD) have been formulated by the National Institutes of Health-Alzheimers Disease and Related Disorders Association (NIHADRDA); the American Psychiatric Association, in the Diagnostic and Statistical Manual of

Mental Disorders, Fourth Revision, Text Revision (DSM-IV-TR); and the Consortium to Establish a Registry in Alzheimers Disease (CERAD). In 2011, the National Institute on Aging (NIA) and the Alzheimers Association (AA) workgroup released new research and clinical diagnostic criteria for AD.[31] The NIH-ADRDA criteria for the diagnosis of AD require the finding of a slowly progressive memory loss of insidious onset in a fully conscious patient. AD cannot be diagnosed in patients with clouded consciousness or delirium. Toxic metabolic conditions and brain neoplasms must also be excluded as potential causes of the patients dementia. The focus of the 2011 NIA-AA criteria is the need to create a more accurate diagnosis of preclinical disease so that treatment can begin before neurons are significantly damaged, while they are more likely to respond. Therefore the report includes criteria for identification of asymptomatic, preclinical AD (for purposes of research, not clinical diagnosis)[32] ; for diagnosis of mild cognitive impairment (MCI), an early symptomatic but predementia phase of AD[33] ; and for diagnosis of AD dementia.[34] The DSM-IV-TR lists 6 diagnostic criteria, labeled A-F, for dementia of the Alzheimer type: A. The development of multiple cognitive deficits manifested by both of the following:

Memory impairment (impaired ability to learn new information or to recall previously learned information) One or more other cognitive disturbances

Other cognitive disturbances consist of the following:

Aphasia (language disturbance) Apraxia (impaired ability to carry out motor activities despite intact motor function) Agnosia (failure to recognize or identify objects despite intact sensory function) Disturbance of executive functioning

B. The cognitive deficits must each cause significant impairment in social or occupational function and represent a significant decline from a previous level of functioning. C. The course of disease is characterized by gradual onset and continuing decline. D. The cognitive deficits are not due to any of the following:

Other central nervous system conditions that cause progressive deficits in memory and cognition Systemic conditions that are known to cause dementia Substance-induced conditions

E. The deficits do not occur exclusively during the course of a delirium.

F. The disturbance is not better accounted for by another DSM-IV Axis I disorder (ie, a clinical disorder). These guidelines are widely believed to be 90-95% accurate (as histopathologically verified) when followed carefully. They are important not only for routine management but also for selecting and enrolling patients in therapeutic trials. Depression and AD and other dementias have an association that is likely to be complex and depression may be misdiagnosed in the realm of dementia. Recent Framingham data have helped bolster the epidemiological association. The study showed a 50% increase in AD and dementia in those who were depressed at baseline.[35] During a 17-year follow-up period, a total of 21.6% of participants who were depressed at baseline developed dementia compared with 16.6% of those who were not depressed. In another related study, recurrent depression was noted to be particularly pernicious. One episode of depression conferred an 8792% increase in dementia risk, while having 2 or more episodes nearly doubled the risk.[36] Other disorders to consider include the following:

Age-associated memory impairment Alcohol and drug abuse Chronic obstructive pulmonary disease Depression Fecal impaction Hearing or visual problems Hypernatremia Hypoglycemia Hypothyroidism Polypharmacy Volume depletion


Aphasia Carotid Artery, Stenosis Cortical Basal Ganglionic Degeneration Dementia in Motor Neuron Disease Dementia With Lewy Bodies Frontotemporal Lobe Dementia Huntington Disease Dementia Imaging in Normal Pressure Hydrocephalus Neurosyphilis Parkinson Disease Parkinson-Plus Syndromes Pediatric Lyme Disease Prion-Related Diseases

Thyroid Disease Vascular Dementia Wilson Disease

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 Alzheimers Association International Conference on Alzheimers 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) A42 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. However, the final version of the NIA-AA criteria, published in April (online) and May 2011, also includes core clinical criteria for diagnosis of mild cognitive impairment by health care providers without access to CSF testing or advanced imaging.[33] TheNIA-AA criteria for diagnosis of dementia due to AD are clinical, with biomarkers in an assisting, nonessential role.[34]

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.[37, 38] 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).[39] 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.[40]

Image courtesy of NIH.

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

Electroencephalography (EEG) is valuable when Creutzfeldt-Jakob disease or other prion-related disease is a likely diagnosis (see EEG in Dementia and Encephalopathy). Periodic highamplitude 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 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.[41]

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.[42]

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 [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 patients treatment. If a patient becomes a danger to him/herself or others, admission to a longterm care facility due to grave disability should be considered for everyones 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.[43] 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.[44] 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 patients 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[45] but not in mild to moderate AD.[46]

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 patients 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.
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.[47] 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.[48] However, Weintraub et al[49] and Petracca[50] 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 6months 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 antiinflammatory 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.[51]

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 freeradical 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 alphatocopherol) might decrease the risk of death or the rate of conversion to severe dementia.[52] 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.[13] 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, 90day study that enrolled 152 patients with mild-to-moderate AD.[53] At day 45, Alzheimers Disease Assessment Scalecognitive 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.[54] 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.[55] The activity of each patient should be individualized. The patients surroundings should be safe and familiar. If the patients 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 patients functioning as long as possible.

Medication Summary
The mainstay of therapy for patients with Alzheimer disease (AD) is the use of centrally acting cholinesterase inhibitors to attempt to compensate for the depletion of acetylcholine (ACh) in the cerebral cortex and hippocampus. A partial N -methyl-D-aspartate (NMDA) antagonist is approved for treatment of moderate and severe AD. Various medications are used for treatment of secondary symptoms of AD, including antidepressants, anti-anxiety agents, and antipsychotic agents.

Cholinesterase Inhibitors
Class Summary

Cholinesterase inhibitors (ChEIs) are used to palliate cholinergic deficiency. All 4 currently approved ChEIs (ie, tacrine, donepezil, rivastigmine, galantamine) inhibit acetylcholinesterase (AChE) at the synapse (specific cholinesterase). Tacrine and rivastigmine also inhibit butyrylcholinesterase (BuChE). Although BuChE levels may be increased in AD, it is not clear that rivastigmine or tacrine have greater clinical efficacy than donepezil and galantamine.

Galantamine has a different second mechanism of action; it is also a presynpatic nicotinic modulator. No data exist that this second mechanism is of clinical importance.
Donepezil (Aricept, Aricept ODT)

Donepezil is a centrally acting AChE inhibitor, but it does not inhibit BuChE.
Rivastigmine (Exelon)

Rivastigmine is a centrally acting inhibitor of both AChE and BuChE.

Rivastigmine transdermal patch (Exelon patch)

The rivastigmine transdermal patch is a competitive and reversible AChE inhibitor. While its mechanism of action is unknown, it may reversibly inhibit cholinesterase, which may, in turn, increase concentrations of ACh available for synaptic transmission in the central nervous system (CNS) and thereby enhance cholinergic function. The effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. It is available as a 5-cm2 patch containing 9 mg (releases 4.6 mg/24 h) and 10-cm2 patch containing 18 mg (releases 9.5 mg/24 h). It is indicated for the treatment of dementia associated with Alzheimer disease and for dementia associated with Parkinson disease.
Galantamine (Razadyne, Razadyne ER)

Galantamine is indicated for the treatment of mild-to-moderate dementia of the Alzheimer type. It enhances central cholinergic function and likely inhibits AChE.

N-Methyl-D-Aspartate (NMDA) Antagonists

Class Summary

NMDA antagonists are the newest class of agents indicated for the treatment of AD. The only FDA-approved drug in this class is memantine. This agent may be used alone or in combination with AChE inhibitors.
Memantine (Namenda, Axura)

Memantine is an NMDA antagonist indicated for all stages of AD. NMDA-receptor overstimulation in the CNS by glutamate (excitatory amino acid) may contribute to symptoms; no evidence confirms a glutamatergic deficit in AD.

Nutritional Supplement
Class Summary

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, which brainimaging scans suggest is the case in AD. Vitamin E has antioxidant properties.
Caprylidene (Axona)

Caprylidene is indicated for clinical dietary management of metabolic processes associated with mild-to-moderate AD. It is available in oral powder form (40 g/packet; contains 20 g mediumchain triglycerides).
Vitamin E (Aquasol E, Natural Vitamin E)

Vitamin E is a nutritional supplement with antioxidant properties. It is used to palliate postulated oxidative damage as a cause or contributing factor of AD.

Class Summary

The activity of anticonvulsants may be related to increased brain levels of gamma-aminobutyric acid (GABA) or enhanced GABA action. Results from several studies indicate that anticonvulsants (eg, gabapentin, valproic acid) may have a role in the treatment of behavioral problems in patients with Alzheimer disease (AD).
Carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Tegretol XR)

The anticonvulsant action of carbamazepine may involve depressing activity in the nucleus ventralis anterior of the thalamus, resulting in reduction of polysynaptic responses and blocking posttetanic potentiation. It reduces sustained high-frequency repetitive neural firing. Carbamazepine is a potent enzyme inducer that can induce its own metabolism. Due to potentially serious blood dyscrasias, undertake benefit-to-risk evaluation before carbamazepine is instituted. Therapeutic plasma levels are between 4-12 mcg/mL for analgesic and antiseizure response. Peak serum levels occur in 4-5 h. Half-life (serum) occurs in 12-17 h

with repeated doses. It is metabolized in liver to active metabolite (ie, epoxide derivative) with half-life of 5-8 h. Metabolites are excreted through feces and urine. Carbamazepine is effective in patients who have not responded to lithium therapy. It has been effective in treating patients who have rapid-cycling bipolar disorder or those who have not been responsive to lithium therapy.
Valproic acid (Depacon, Depakene, Depakote, Depakote ER, Depakote Sprinkles)

Although the mechanism of action of valproic acid is not established, its activity may be related to increased brain levels of GABA or enhanced GABA action. Valproate may also potentiate postsynaptic GABA responses, affect potassium channel, or have a direct membrane-stabilizing effect. Valproic acid has proven effectiveness in treating and preventing mania. It is classified as a mood stabilizer and can be used alone or in combination with lithium. It is useful in treating patients with rapid-cycling bipolar disorders and has been used to treat aggressive or behavioral disorders.
Gabapentin (Neurontin)

Gabapentin is a membrane stabilizer and structural analogue of inhibitory neurotransmitter GABA, which paradoxically is thought not to exert effect on GABA receptors. It appears to exert action via the alpha(2)delta1 and alpha(2)delta2 auxiliary subunits of voltage-gaited calcium channels

Antidepressants, Selective Serotonin Reuptake Inhibitors

Class Summary

This class of drug enhances serotonin activity due to selective reuptake inhibition at neuronal membrane. Antidepressants have an important role in the treatment of mood disorders in patients with Alzheimer disease (AD).
Sertraline (Zoloft)

Sertraline selectively inhibits presynaptic serotonin reuptake.

Citalopram (Celexa)

Citalopram enhances serotonin activity by selective reuptake inhibition at the neuronal membrane. It may be beneficial in mood and other neuropsychiatric symptoms in patients in the moderate stage of AD.

Antiparkinson Agents
Class Summary

Antiparkinson agents with activity against major depressive disorder may improve the behavioral aspects of AD.
Selegiline (Emsam, Eldepryl, Zelapar)

Selegiline is an irreversible monoamine oxidase inhibitor (MAOI). It has greater affinity for monoamine oxidase (MAO)-B than for MAO-A; however, at antidepressant doses, it inhibits both isoenzymes. MAO-A and MAO-B catabolize neurotransmitter amines in the CNS (eg, norepinephrine, dopamine, serotonin). It is indicated for treating major depressive disorder. At its lowest strength (ie, 6 mg delivered over 24 h), it may be used without the dietary restrictions required for oral MAOIs used to treat depression.

Antianxiety Agents
Class Summary

Anxiolytics can temporarily alleviate clinical manifestations of AD such as anxiety. Agents in this category may have effects in serotonergic neurotransmission and some dopaminergic effects in the CNS.
Lorazepam (Ativan)

Lorazepam is a benzodiazepine and sedative hypnotic with a short onset of effects and relatively long half-life. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, it may depress all levels of the CNS, including limbic and reticular formation. When the patient needs to be sedated for longer than a 24-hour period, this medication is excellent.
Buspirone (BuSpar)

Buspirone is an antianxiety agent that is not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative or anxiolytic drugs. It is a 5-HT1 agonist with serotonergic neurotransmission and some dopaminergic effects in the CNS. It has anxiolytic effects but may take up to 2-3 wk for full efficacy.

Antipsychotic Agents
Class Summary

The US Food and Drug Administration (FDA) has issued black box warnings regarding increased mortality with the use of both typical (first-generation) and all 3 classes of atypical (second-generation) antipsychotics as treatment for behavioral disturbances in elderly patients with dementia. 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.
Haloperidol (Haldol, Haldol Decanoate)

Haloperidol is the drug of choice for patients with acute psychosis when no contraindications exist. Haloperidol is a dopamine (D2) antagonist. It is a derivative of butyrophenone, which is noted for its high potency and low potential for causing orthostasis. The drawback is the high potential for extrapyramidal symptoms/dystonia. The parenteral dosage form may be mixed in same syringe with 2 mg of lorazepam for better anxiolytic effects.
Quetiapine (Seroquel, Seroquel XR)

Quetiapine may act by antagonizing dopamine and serotonin effects. It is a newer antipsychotic used for long-term management. Improvements over earlier antipsychotics include fewer anticholinergic effects and less dystonia, parkinsonism, and tardive dyskinesia. Immediate- and extended-release formulations are available.
Risperidone (Risperdal, Risperdal Consta, Risperdal M-Tab)

Risperidone has both D2 and serotonin 5-HT2 antagonism. It improves negative symptoms of psychoses and reduces the incidence of extrapyramidal adverse effects.

Alzheimer Disease Imaging

Author: Tarakad S Ramachandran, MBBS, FRCP(C), FACP; Chief Editor: L Gill Naul, MD

Alzheimer disease (Alzheimer's disease) was first described in 1907 by Alois Alzheimer. From its original status as a rare disease, Alzheimer disease has become one of the most common diseases in the aging population, ranking as the fourth most common cause of death. Alzheimer disease is a progressive neurodegenerative disorder characterized by the gradual onset of dementia. The pathologic hallmarks of the disease are beta-amyloid (A) plaques, neurofibrillary tangles (NFTs), and reactive gliosis (see the images and slideshows below).

Coronal T1-weighted magnetic resonance imaging (MRI) scan in a patient with moderate Alzheimer disease. Brain image reveals hippocampal atrophy, especially on the right side.

Axial T2-weighted MRI of the brain reveals atrophic changes in the temporal lobes.

Click here to view the Alzheimer Disease Radiograph slideshow. Click here to view a slideshow presentation on Alzheimer Disease. Current diagnosis of Alzheimer disease is made by clinical, neuropsychological, and neuroimaging assessments. Routine structural neuroimaging evaluation is based on nonspecific features, such as atrophy, which is a late feature in the progression of the disease. Therefore, developing new approaches for early and specific recognition of Alzheimer disease at the prodromal stages is of crucial importance.

Effective therapies to halt or slow disease progression and an appropriate cure are still lacking. A number of in vivo neuroimaging techniques, which can be used to reliably and noninvasively assess aspects of neuroanatomy, chemistry, physiology, and pathology, hold promise. With time and improvements in technology, these imaging techniques might yield acceptable neuroimaging biomarkers of Alzheimer disease. Although present therapy of Alzheimer disease involves enhancers of cholinergic function, disease-modifying agents may be available in the future. Emphasis is being placed on detecting the presymptomatic phase of the disease, which may be termed mild cognitive impairment (MCI). Neuroimaging is also used to exclude other causes of dementia, such as normal-pressure hydrocephalus, brain tumors, subdural hematoma, and multiple infarction.
Laboratory testing

Routine laboratory test results are normal in Alzheimer disease (Alzheimer's disease). Cerebrospinal fluid (CSF) is normal, although the protein count may be slightly increased. Ubiquitin and tau levels in the CSF have been reported to be raised in cases of Alzheimer disease. For sporadic or familial late-onset Alzheimer disease, the E4 polymorphism of the ApoE gene has been associated with a high risk of the disease; however, it does not provide sufficient sensitivity or specificity for diagnosis, and its use as a diagnostic marker is not recommended.
Neuroimaging studies

Magnetic resonance imaging (MRI) can be considered the preferred neuroimaging examination for Alzheimer disease because it allows for accurate measurement of the 3-dimensional (3D) volumes of brain structures, especially the size of the hippocampus and related regions. Neuroimaging is widely believed to be generally useful for excluding reversible causes of dementia syndrome, such as normal-pressure hydrocephalus, brain tumors, and subdural hematoma, and for excluding other likely causes of dementia, such as cerebrovascular disease. The most recent practice parameters for the diagnosis and evaluation of dementia, as published by the American Academy of Neurology (AAN), consider structural brain imaging optimal.[1] Nonenhanced computed tomography (CT) and MRI are the appropriate imaging methods.[2] The AAN suggests that neuroimaging may be most useful in patients with dementia characterized by an early onset or an unusual course. There have been several studies of neuroimaging findings in Alzheimer disease. Van de Pol et al found that medial temporal lobe atrophy seems to be a more important predictor of cognition than small-vessel disease in minimum cognitive impairment (MCI). Lacunes were associated with performance on the Digit Symbol Substitution Test, especially in subjects with milder median temporal lobe atrophy (MTA). There was no discernible association between white matter hyperintensities (WMHs) and the cognitive measures in this study after adjustment for age.[3]

Study of the dopamine transporter (DaTScan) is used to distinguish Lewy body dementia from Alzheimer disease. Numerous studies are under way to identify specific imaging markers for different types of dementia, including cerebral volumetric measurements, diffusion imaging, spectroscopy, very-high-field MRI scans of senile plaques, and positron emission tomography (PET) markers of senile plaques.[4] Blood-brain barrier (BBB) impairment is a stable characteristic over 1 year and is present in an important subgroup of patients with Alzheimer disease. Age, gender, ApoE status, vascular risk factors, and baseline Mini-Mental State Examination score did not explain the variability in BBB integrity. BBB impairment as a possible modifier of disease progression is suggested by correlations between the CSF-albumin index and measures of disease progression over 1 year.[5] The BBB is dysfunctional in a portion of all patients with Alzheimer disease, primarily in men. BBB dysfunction might influence the clearance of both harmful and beneficial substances across the barrier. Renal function might have an impact on the BBB.[6] Pittsburgh Compound B PET findings match histopathologic reports of A distribution in aging and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in the course of neurodegeneration and to determine if A deposition in nondemented subjects is preclinical Alzheimer disease are now feasible. Our findings also suggest that A may influence the development of dementia with Lewy bodies, and therefore, strategies to reduce A may benefit this condition.[7] De Leon et al concluded that the combined use of conventional imaging, such as MRI or fluorodeoxyglucose PET (FDG-PET) with selected CSF biomarkers incrementally contributes to the early and specific diagnosis of Alzheimer disease. Moreover, selected combinations of imaging and CSF biomarker measures are of importance in monitoring the course of Alzheimer disease and, therefore, relevant to evaluating clinical trials.[8]
Limitations of techniques

Routine laboratory test results are normal in Alzheimer disease (Alzheimer's disease). CSF results are normal, though a slight increase in protein count may be noted. Ubiquitin and tau protein levels in CSF are also reportedly raised in Alzheimer disease. For sporadic or familial late-onset Alzheimer disease, APOE*E4 polymorphism of the gene for ApoE has been associated with a high risk of the disease; however, it does not provide sufficient sensitivity or specificity for diagnosis, and its use as a diagnostic marker is not recommended. For more information, see the Medscape Reference topics Alzheimer Disease, Alzheimer's Disease and APOE-4, and Alzheimer Disease in Down Syndrome.

Computed Tomography
Overall atrophy

The initial criteria for CT diagnosis of Alzheimer disease (Alzheimer's disease) includes diffuse cerebral atrophy with enlargement of the cortical sulci and increased size of the ventricles. A multitude of studies have shown that cerebral atrophy is significantly greater in patients with Alzheimer disease than in patients who are aging without Alzheimer disease. This concept was soon challenged because cerebral atrophy can be present in elderly and healthy persons, and some patients with dementia may have no cerebral atrophy, at least in the early stages. The extent of cerebral atrophy was determined by using linear measurements, in particular bifrontal and bicaudate diameters and the diameters of the third and lateral ventricles. Various measurements were adjusted according to the diameter of the skull to account for normal variation. To complement this modification, volumetric studies of the ventricles were done. Despite these efforts, it is still difficult to distinguish between findings in a healthy elderly patient and those in a patient with dementia. In addition, a review of serial CT scans obtained over several months was not clinically useful in the primary diagnosis of the disease.
Rate of change of brain atrophy

Changes in the rate of atrophy progression can be useful for diagnosing Alzheimer disease.[9] Longitudinal changes in brain size are associated with longitudinal progression of cognitive loss,[10] and enlargement of the third and lateral ventricles is greater in patients with Alzheimer disease than in control subjects.[11]
Changes in brain structure

Diffuse cerebral atrophy with widened sulci and dilatation of the lateral ventricles can be observed. Disproportionate atrophy of the medial temporal lobe, particularly of the volume of the hippocampal formations (< 50%), can be seen. Dilatation of the perihippocampal fissure is a useful radiologic marker for the initial diagnosis of Alzheimer disease, with a predictive accuracy of 91%.[12] The hippocampal fissure is surrounded laterally by the hippocampus, superiorly by the dentate gyrus, and inferiorly by the subiculum. These structures are all involved in the early development of Alzheimer disease and explains the enlargement in the early stages. At the medial aspect, the fissure communicates with the ambient cistern, and its enlargement on CT scans is often seen as hippocampal lucency or hypoattenuation in the temporal area medial to the temporal horn. White-matter attenuation is not a feature of Alzheimer disease.

The temporal horns of the lateral ventricles may be enlarged. Prominence of the choroid and hippocampal fissures and enlargement of the sylvian fissure may be noted.
Degree of confidence

CT indices of hippocampal atrophy are highly associated with Alzheimer disease (Alzheimer's disease), but the specificity is not well established. Use of a nonquantitative rating scale showed a sensitivity of 81% and a specificity of 67% in differentiating 21 patients with Alzheimer disease with moderate dementia from 21 age-matched control subjects.[24] Hippocampal volumes in a sample of similar size permitted correct classification of 85% of control subjects.[25]

Magnetic Resonance Imaging

Many studies have shown that cerebral atrophy is significantly greater in patients with Alzheimer disease (Alzheimer's disease) than in persons without it. The variability of atrophy in the normal aging process makes it difficult to use MRI as a definitive diagnostic technique (see the images below).

Coronal T1-weighted magnetic resonance imaging (MRI) scan in a patient with moderate Alzheimer disease. Brain image reveals hippocampal atrophy, especially on the right side.

Axial T2-weighted MRI of the brain reveals atrophic changes in the temporal


Axial T2-weighted MRI shows dilated sylvian fissure resulting from

adjacent cortical atrophy, especially on the right side.

Axial T1-weighted

MRI shows a dilated sylvian fissure caused by adjacent cortical atrophy. Axial T1-weighted MRI shows bilateral cortical atrophy with accentuated cortical sulci, with decreased

involvement in the posterior aspect. Axial T1-weighted MRI shows bilateral cortical atrophy with accentuated cortical sulci, with decreased involvement in the posterior aspect.

Fox et al used an automated technique that is potentially applicable in the clinical setting to subtract MRIs obtained an average of 1 year apart. They observed that there was a significant difference between the rate of change in patients with Alzheimer disease and the rate in control subjects. With MRI, sensitivity and specificity were approximately 90% for predicting the decline in dementia.[13] Early MRI studies to evaluate the size of the hippocampus in patients with Alzheimer disease relative to control subjects showed large reductions in hippocampal volumes (approximately 50%) and high sensitivity and specificity for classification.[14] Over time, enlargement of the temporal horns, as well as the third and lateral ventricles, was noted in patients with Alzheimer disease compared with control subjects. On structural MRI, atrophy of the entorhinal cortex is already present in MCI. In the autosomal dominant forms of Alzheimer disease, the rate of atrophy of the medial temporal structures differentiates affected individuals from control subjects as early as 3 years before the clinical onset of cognitive impairment. The accelerated annual rate of brain atrophy is a surrogate tool for evaluating new therapies in small samples that saves time and resources. MRI measurements of the hippocampus, amygdala, cingulate gyrus, head of the caudate nucleus, temporal horn, lateral ventricles, third ventricle, and basal forebrain yield a prediction rate of 77% for conversion to Alzheimer disease from questionable Alzheimer disease.[15, 16] Functional MRI (fMRI) techniques can be used to measure cerebral perfusion. Dynamic susceptibility contrast (DSC) MRI consists of the passage of a concentrated bolus of a paramagnetic contrast agent that sufficiently distorts the local magnetic field to cause a transient loss of signal with pulse sequences, especially T2-weighted sequences. The passage of contrast material is imaged over time by sequential rapid imaging of the same section. In animal studies, the rate of change of signal intensity over time gives a measure directly proportional to cerebral blood volume. Studies in humans have shown a correlation between PET and DSC MRI results, as well as between cerebral blood volumes measured with DSC MRI and perfusion on singlephoton emission computed tomography (SPECT).

Studies have been performed by using MRI with echo-planar imaging and signal targeting with attenuation radiofrequency (EPISTAR) in patients with Alzheimer disease. Focal areas of hypoperfusion were in the posterior temporoparietooccipital regions. Ratios of signal intensity in the parietooccipital and temporo-occipital areas to signal intensity on whole section signal intensity were significantly lower in the patients with Alzheimer disease than in those without it. The parieto-occipital ratios were not correlated with the severity of dementia, as measured by using the Blessed Dementia Scale Information Memory Concentration subset. With fMRI, structural imaging can be done by using the same imaging plane, field of view, and section thickness. Activational fMRI studies have included blood oxygenation leveldependent (BOLD) imaging, which uses changes in the level of oxygenated hemoglobin in capillary beds to depict areas of regional brain activation. In Alzheimer disease, fMRI activation in the hippocampal and prefrontal regions is decreased. On fMRI, paradigms activate a larger area of parietotemporal association cortex in persons at high risk for Alzheimer disease than in others, whereas the entorhinal cortex activation is relatively low in MCI.[17] The techniques are reasonably sensitive and specific in differentiating Alzheimer disease from changes resulting from normal aging, and studies with pathologic confirmation show good sensitivity and specificity in differentiating Alzheimer disease from other dementias. These techniques can also be used to detect abnormalities in asymptomatic or presymptomatic individuals, and they may help in predicting the decline to dementia.
Degree of confidence

MRI findings of hippocampal atrophy are highly associated with Alzheimer disease (Alzheimer's disease), but the specificity is not well established.[18] Studies have shown that in patients with Alzheimer disease and moderate dementia, hippocampal volumes permitted correct classification in 85% of patients.[19] In patients with Alzheimer disease and mild dementia, sensitivity was 77% and specificity 80%.[20] Hippocampal volume was the best discriminator, though a number of medical temporal-lobe structures were studied, including the amygdala and the parahippocampal gyrus. Both hippocampal and entorhinal cortical atrophy are features of frontotemporal dementia, but they do not appear to be as profound as atrophy is in Alzheimer disease.[21]
False positives/negatives

Hippocampal atrophy appears to be a feature of vascular disease (multi-infarct dementia) and Parkinson disease, even in patients with Parkinson disease without dementia. Both hippocampal and entorhinal cortical atrophy are features of frontotemporal dementia, but they do not appear to be as profound as atrophy is in Alzheimer disease (Alzheimer's disease).

Nuclear Imaging
Single-photon emission CT

Single-photon emission computed tomography (SPECT) uses direct photon-emitting isotopes rather than radioisotopes. SPECT isotopes have an average half-life of 6-12 hours. SPECT instrumentation is highly variable; therefore, use of a SPECT scanner with poor resolution can result in poor clinical performance. Positron-emission tomography (PET) uses tracers that measure regional glucose metabolism (rCMRglc). SPECT imaging is most commonly used for blood-flow measurement. Early SPECT studies of blood flow replicated findings of functional reductions in the posterior temporal and parietal cortex. The severity of temporoparietal hypofunction has been correlated with the severity of dementia in a number of studies.[9, 22, 23] Reductions of blood flow and oxygen use can be found in the temporal and parietal neocortex in patients with Alzheimer disease and moderate-to-severe symptoms.[24] Early reductions of glucose metabolism are seen in the posterior cingulate cortex. SPECT is not commonly used to assess Alzheimer disease (Alzheimer's disease). SPECT is useful in the diagnostic assessment of Alzheimer disease if standardized and semiquantitative techniques are used. Trollor et al examined 18 patients with early Alzheimer disease and 10 healthy elderly control subjects with high-resolution SPECT during their performance of a simple word-discrimination task. SPECT images were coregistered with individual MRIs, allowing for the delineation of predetermined neuroanatomic regions of interest (ROI).They observed a gradation of regional cerebral blood flow (rCBF) values in both groups, with the lowest values in the hippocampus and the highest in the striatum, thalamus, and cerebellum.[25] Compared with healthy control subjects, patients with Alzheimer disease had low relative rCBF in parietal and prefrontal cortices. Analysis of individual ROI demonstrated bilateral reduction of rCBF in the prefrontal poles and posterior temporal and anterior parietal cortex, with unilateral reduction of rCBF in the left dorsolateral prefrontal cortex, right posterior parietal cortex, and left cingulate body. No significant differences in hippocampal, occipital, or basal ganglia rCBF were found. Discriminant function analysis indicated that rCBF in the prefrontal polar regions permitted the best classification.[25] In class II studies, the sensitivity of SPECT was lower than that of the clinical diagnosis.[26] Sensitivity increased as the severity of dementia worsened, but the pretest probability of Alzheimer disease increased as well.[27] The added value of SPECT was greatest for a positive test among patients with mild dementia in whom the diagnosis of Alzheimer disease was substantially doubted.[28] In this situation, a

positive SPECT result would have increased the posttest probability of Alzheimer disease by 30%, whereas a negative test result would have increased the likelihood of the absence of Alzheimer disease by only 10%.[29]
Positron emission tomography

PET is a powerful imaging technique that enables in vivo examination of brain functions. It allows for noninvasive quantification of cerebral blood flow, metabolism, and receptor binding. PET helps understand the disease pathogenesis, make the correct diagnosis, and monitor disease progression and response to treatment.[30] PET involves the introduction of a radioactive tracer into the human body, usually with an intravenous injection. A tracer is essentially a biologic compound of interest that is labeled with a positron-emitting isotope, such as carbon-11 (15 O). These isotopes are used because they have relatively short half-lives (from minutes to < 2 h), allowing the tracers to reach equilibrium in the body without exposing the subjects to prolonged radiation. The 2 most common physiologic process measurements performed by using PET scan include glucose with [18 F] fluorodeoxyglucose (FDG) and cerebral blood flow by using water.[18] FDG PET has been used extensively to study Alzheimer disease, and it is evolving into an effective tool for early diagnosis and for differentiation of Alzheimer disease from other types of dementia. FDG PET has been used to detect persons at risk for Alzheimer disease even before the onset of symptoms.[31] Patients with Alzheimer disease have characteristic temporoparietal glucose hypometabolism, the degree to which is correlated with the severity of dementia.[32] With disease progression frontal involvement may be evident. Glucose hypometabolism in Alzheimer disease is likely to be caused by a combination of neuronal cell loss and decreased synaptic activity.[33] In Alzheimer disease, FDG PET has a sensitivity of 94% and a specificity of 73%. It can also be used to correctly predict a progressive course of dementia with a 91% sensitivity and a nonprogressive course with a 75% specificity.[34] Individuals at high risk for Alzheimer disease (asymptomatic carriers of the APOE*E4 allele) exhibit a pattern of glucose hypometabolism similar to that of patients with Alzheimer disease. After a mean follow-up of 2 years, the cortical metabolic abnormality continues to decline despite preservation of cognitive performance.[35, 36] In control subjects, entorhinal cortex hypometabolism on FDG PET has predictive value in the progression of dementia to MCI or, even, to Alzheimer disease.[37, 36] The identification of asymptomatic individuals at risk will have an enormous role in the treatment strategy for Alzheimer disease.[38] On PET or SPECT, mild Alzheimer disease may be more difficult to detect than moderate or severe disease.

Temporal and parietal glucose hypometabolism is widely seen on PET images in patients with Alzheimer disease. Despite the technical differences, results from PET and SPECT are comparable, though data suggest that PET is more sensitive than SPECT.[39] In patients with Alzheimer disease, PET performed with ligand PK11195 labeled with carbon11, or (R)-[11 C] PK11195, showed increased binding in the entorhinal, temporoparietal, and cingulate cortices. This finding corresponded to the postmortem distribution of Alzheimer disease pathology.[40] Efforts to develop a specific ligand for A plaques may further enhance the sensitivity of PET for early diagnosis of Alzheimer disease and may provide a biologic marker of disease progression.[40] In their study, Boxer et al reported that different amyloid-binding PET agents (PIB and FDDNP) may have differential sensitivity to prion-related brain pathology and that a combination of amyloid imaging agents may be useful in the diagnosis of early-onset dementia.[41]
Degree of confidence

Without surprise, clinically validated SPECT studies showing differences between patients with Alzheimer disease (Alzheimer's disease) and control subjects reveal high sensitivities and specificities of 80-90%.[29] In one study, investigators compared patients from a dementia clinic with a community sample of control subjects using quantitative SPECT. Alzheimer disease was defined as temporal-lobe perfusion more than 2 standard deviations below control values. The authors reported 63% sensitivity and 87% specificity. Holman et al found that bilateral temporoparietal hypoperfusion had a positive predictive value of 82% for Alzheimer disease.[42] Using inhaled xenon-133 and injected technetium-99m hexamethylpropyleneamine oxime, researchers reported a sensitivity of 76% and a specificity of 73%, with a positive predictive value of 92% and a negative predictive value of 57%.[43] These studies may assist in the early and late diagnosis of Alzheimer disease and with the differential diagnosis of dementias.