Approximately 10% of all persons over the age of 70 years have significant memory loss, and in more than half, the cause is Alzheimer’s disease (AD). It is estimated that the median annual total cost of caring for a single patient with advanced AD is >$50,000, while the emotional toll for family members and caregivers is immeasurable. AD can manifest as young as the third decade, but it is the most common cause of dementia in the elderly. Patients most often present with an insidious loss of episodic memory followed by a slowly progressive dementia that evolves over years. In typical amnestic AD, brain imaging reveals atrophy that begins in the medial temporal lobes before spreading to lateral and medial parietal and temporal lobes and lateral frontal cortex. Microscopically, there are neuritic plaques containing amyloid beta (Aβ), neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau filaments, and Aβ accumulation of in blood vessel walls in cortex and leptomeninges (see “Pathology,” below). The identification of causative mutations and susceptibility genes for AD has provided a foundation for rapid progress in understanding the biological basis of the disorder. The major genetic risk for AD is apolipoprotein ε4 (Apo ε4). Carrying one Ε4 allele increases the risk for AD by 2- to 3-fold, whereas two alleles increase the risk 16-fold.
The cognitive changes of AD tend to follow a characteristic pattern, beginning with memory impairment and progressing to language and visuospatial deficits. Yet, approximately 20% of patients with AD present with nonmemory complaints such as word-finding, organizational, or navigational difficulty. In other patients, upstream visual processing dysfunction (referred to as posterior cortical atrophy syndrome) or a progressive “logopenic” aphasia are the primary manifestations of AD for years before progressing to involve memory and other cognitive domains. Still other patients may present with an asymmetric akinetic-rigid-dystonic (“corticobasal”) syndrome or a dysexecutive “frontal variant” of AD.
In the early stages of typical amnestic AD, the memory loss may go unrecognized or be ascribed to benign forgetfulness of aging. Once the memory loss becomes noticeable to the patient and spouse and falls 1.5 standard deviations below normal on standardized memory tests, the term mild cognitive impairment (MCI) is applied. This construct provides useful prognostic information, because approximately 50% of patients with MCI (roughly 12% per year) will progress to AD over 4 years. Increasingly, the MCI construct is being replaced by the notion of “early symptomatic AD” to signify that AD is considered the underlying disease (based on clinical or biomarker evidence) in a patient who remains functionally compensated. Even earlier in the course, “prodromal AD” refers to a person with biomarker evidence of AD (amyloid imaging positive with positron emission tomography or low cerebrospinal Aβ42 and mildly elevated tau) in the absence of symptoms. These refinements have been developed in anticipation of early-stage treatment and prevention trials that have already begun in humans. New evidence suggests that partial and sometimes generalized seizures herald AD and can occur even prior to dementia onset.
Eventually, with AD, the cognitive problems begin to interfere with daily activities, such as keeping track of finances, following instructions on the job, driving, shopping, and housekeeping. Some patients are unaware of these difficulties (anosognosia), but most remain acutely attuned to their deficits. Changes in environment (travel, relocation, hospitalization) tend to destabilize the patient. Over time patients become lost on walks or while driving. Social graces, routine behavior, and superficial conversation may be surprisingly intact, even into the later stages of the illness.
In the middle stages of AD, the patient is unable to work, is easily lost and confused, and requires daily supervision. Language becomes impaired—first naming, then comprehension, and finally fluency. Word-finding difficulties and circumlocution can be evident in the early stages, even when formal testing demonstrates intact naming and fluency. Apraxia emerges, and patients have trouble performing learned sequential motor tasks. Visuospatial deficits begin to interfere with dressing, eating, or even walking, and patients fail to solve simple puzzles or copy geometric figures. Simple calculations and clock reading become difficult in parallel.
In the late stages, some persons remain ambulatory, wandering aimlessly. Loss of judgment and reasoning is inevitable. Delusions are common, usually simple, with common themes of theft, infidelity, or misidentification. Approximately 10% of AD patients develop Capgras’ syndrome, believing that a caregiver has been replaced by an impostor. In contrast to dementia with Lewy bodies (DLB), where Capgras’ syndrome is an early feature, in AD this syndrome emerges late. Disinhibition and uncharacteristic belligerence may occur and alternate with passivity and withdrawal. Sleep-wake patterns are disrupted, and nighttime wandering becomes disturbing to the household. Some patients develop a shuffling gait with generalized muscle rigidity associated with slowness and awkwardness of movement. Patients often look parkinsonian (Chap. 449) but rarely have a high-amplitude, low-frequency tremor at rest. There is a strong overlap between Parkinson’s disease (PD) and AD, and some AD patients develop more classical PD features.
In the end stages, AD patients become rigid, mute, incontinent, and bedridden, and help is needed with eating, dressing, and toileting. Hyperactive tendon reflexes and myoclonic jerks (sudden brief contractions of various muscles or the whole body) may occur spontaneously or in response to physical or auditory stimulation. Often death results from malnutrition, secondary infections, pulmonary emboli, heart disease, or, most commonly, aspiration. The typical duration of AD is 8–10 years, but the course ranges from 1 to 25 years. For unknown reasons, some patients with AD show a steady decline in function while others have prolonged plateaus without major deterioration.
Early in the disease course, other etiologies of dementia should be excluded (see Tables 35-1, 35-3, and 35-4). Neuroimaging studies (computed tomography [CT] and magnetic resonance imaging [MRI]) do not show a single specific pattern with AD and may be normal early in the disease. As AD progresses, more distributed but usually posterior-predominant cortical atrophy becomes apparent, along with atrophy of the medial temporal memory structures (see Chap. 35, Fig. 35-1). The main purpose of imaging is to exclude other disorders, such as primary and secondary neoplasms, vascular dementia, diffuse white matter disease, and normal-pressure hydrocephalus (NPH). Imaging also helps to distinguish AD from other degenerative disorders, such as frontotemporal dementia (FTD) or Creutzfeldt-Jacob disease (CJD), which feature distinctive imaging patterns. Functional imaging studies, such as positron emission tomography (PET), reveal hypometabolism in the posterior temporal-parietal cortex in AD (see Fig. 35-1). PET can also be used to detect the presence of fibrillar amyloid in the brain (see Fig. 35-4), and amyloid PET positivity is becoming required for entry into treatment trials for AD. Barriers to interpretation continue, however, to limit the use of amyloid PET in routine clinical evaluation. Although amyloid binding with PET is typical for AD, many asymptomatic healthy older individuals show amyloid uptake, and the likelihood that these individuals will convert to clinical AD is still under study. Similarly, dementia due to a non-AD disorder can be the underlying etiology in a patient who is amyloid positive on imaging. Electroencephalogram (EEG) is normal or shows nonspecific slowing; prolonged EEG can be used to seek out intermittent nonconvulsive seizures. Routine spinal fluid examination is also normal. Cerebrospinal fluid (CSF) Aβ42 level is reduced, whereas the tau protein is elevated, but the test characteristics of these assays still make interpretation challenging in individual patients. Slowly progressive decline in memory and orientation, normal results on laboratory tests, and an MRI or CT scan showing only distributed or posteriorly predominant cortical and hippocampal atrophy are highly suggestive of AD. A clinical diagnosis of AD reached after careful evaluation is confirmed at autopsy about 90% of the time, with misdiagnosed cases usually representing one of the other dementing disorders described later in this chapter, a mixture of AD with vascular pathology, or DLB.
Simple clinical clues are useful in the differential diagnosis. Early prominent gait disturbance with only mild memory loss suggests vascular dementia or, rarely, NPH (see below). Resting tremor with stooped posture, bradykinesia, and masked facies suggest PD (Chap. 449). When dementia occurs after a well-established diagnosis of PD, PD dementia (PDD) is usually the correct diagnosis, but many patients with this diagnosis will show a mixture of AD and Lewy body disease at autopsy. The early appearance of parkinsonian features in association with fluctuating alertness, visual hallucinations, or delusional misidentification suggests DLB. Chronic alcoholism should prompt the search for vitamin deficiency. Loss of joint position and vibration sensibility accompanied by Babinski signs suggests vitamin B12 deficiency (Chap. 456). Early onset of a focal seizure suggests a metastatic or primary brain neoplasm (Chap. 118). Previous or ongoing depression raises suspicion for depression-related cognitive impairment, although AD can feature a depressive prodrome. A history of treatment for insomnia, anxiety, psychiatric disturbance, or epilepsy suggests chronic drug intoxication. Rapid progression over a few weeks or months associated with rigidity and myoclonus suggests CJD (Chap. 453e). Prominent behavioral changes with intact navigation and focal anterior-predominant atrophy on brain imaging are typical of FTD. A positive family history of dementia suggests either one of the familial forms of AD or one of the other genetic disorders associated with dementia, such as FTD (see below), HD (see below), prion disease (Chap. 453e), or rare hereditary ataxias (Chap. 450).
The most important risk factors for AD are old age and a positive family history. The prevalence of AD increases with each decade of adult life, reaching 20–40% of the population over the age of 85. A positive family history of dementia suggests a genetic contribution to AD, although autosomal dominant inheritance occurs in only 2% of patients. Female sex is a risk factor independent of the greater longevity of women, and women who carry an Apo ε4 allele are more susceptible than are male ε4 carriers. A history of head trauma with concussion increases the risk for AD. AD is more common in groups with low educational attainment, but education influences test-taking ability, and it is clear that AD can affect persons of all intellectual levels. One study found that the capacity to express complex written language in early adulthood correlated with a decreased risk for AD. Numerous environmental factors, including aluminum, mercury, and viruses, have been proposed as causes of AD, but rigorous studies have failed to demonstrate to a significant role for any of these exposures. Similarly, several studies suggest that the use of nonsteroidal anti-inflammatory agents is associated with a decreased risk of AD, but this risk has not been confirmed in large prospective studies. Vascular disease, and stroke in particular, seems to lower the threshold for the clinical expression of AD. Also, in many patients with AD, amyloid angiopathy can lead to microhemorrhages, large lobar hemorrhages, ischemic infarctions most often in the subcortical white matter, or in rare cases an inflammatory leukoencephalopathy. Diabetes increases the risk of AD threefold. Elevated homocysteine and cholesterol levels; hypertension; diminished serum levels of folic acid; low dietary intake of fruits, vegetables, and red wine; and low levels of exercise are all being explored as potential risk factors for AD.
At autopsy, the earliest and most severe degeneration is usually found in the medial temporal lobe (entorhinal/perirhinal cortex and hippocampus), lateral temporal cortex, and nucleus basalis of Meynert. The characteristic microscopic findings are neuritic plaques and NFTs (Fig. 448-1). These lesions may accumulate in small numbers during normal brain aging but dominate the picture in AD. Increasing evidence suggests that soluble amyloid species called oligomers may cause cellular dysfunction and represent the early toxic molecule in AD. Eventually, further amyloid polymerization and fibril formation lead to neuritic plaques, which contain a central core of amyloid, proteoglycans, Apo ε4, α-antichymotrypsin, and other proteins. Aβ is a protein of 39–42 amino acids that is derived proteolytically from a larger transmembrane protein, amyloid precursor protein (APP), when APP is cleaved by β and γ secretases (Fig. 448-2). The normal function of the Aβ peptides remains uncertain. APP has neurotrophic and neuroprotective properties. The plaque core is surrounded by a halo, which contains dystrophic, tau-immunoreactive neurites and activated microglia. The accumulation of Aβ in cerebral arterioles is termed amyloid angiopathy. NFTs are composed of silver-staining neuronal cytoplasmic fibrils composed of abnormally phosphorylated tau protein; they appear as paired helical filaments by electron microscopy. Tau binds to and stabilizes microtubules, supporting axonal transport of organelles, glycoproteins, neurotransmitters, and other important cargoes throughout the neuron. Once hyperphosphorylated, tau can no longer bind properly to microtubules and redistributes from the axon to throughout the neuronal cytoplasm and distal dendrites, compromising function. Finally, patients with AD often show comorbid DLB or vascular pathology. In animal models of AD, diminishing neuronal tau ameliorates the cognitive deficits and seizures, even though Aβ42 continues to accumulate, raising hope for tau-lowering therapies in humans. Biochemically, AD is associated with a decrease in the cortical levels of several proteins and neurotransmitters, especially acetylcholine, its synthetic enzyme choline acetyltransferase, and nicotinic cholinergic receptors. Reduction of acetylcholine reflects degeneration of cholinergic neurons in the nucleus basalis of Meynert that project throughout the cortex. There is also noradrenergic and serotonergic depletion due to degeneration of brainstem nuclei such as the locus coeruleus and dorsal raphe, where tau-immunoreactive neuronal cytoplasmic inclusions can be identified even in individuals lacking entorhinal cortex NFTs.
Neuropathology of Alzheimer’s disease. A. Early neurofibrillary degeneration, consisting of neurofibrillary tangles and neuropil threads, preferentially affects the medial temporal lobes, especially the stellate pyramidal neurons that compose the layer 2 islands of entorhinal cortex, as shown. B. Higher magnification view reveals the fibrillary nature of tangles (arrows) and the complex structure of neuritic plaques (arrowheads), whose major component is Aβ (inset shows immunohistochemistry for Aβ). Scale bars are 500 μM in A, 50 μM in B, and 20 μM in B inset.
Amyloid precursor protein (APP) is catabolized by α, β, and γ secretases. A key initial step is the digestion by either β secretase (BASE) or α secretase (ADAM10 or ADAM17 [TACE]), producing smaller nontoxic products. Cleavage of the β secretase product by γ secretase (Step 2) results in either the toxic Aβ42 or the nontoxic Aβ40 peptide; cleavage of the α secretase product by γ secretase produces the nontoxic P3 peptide. Excess production of Aβ42 is a key initiator of cellular damage in Alzheimer’s disease (AD). Therapeutics for AD have focused on attempts to reduce accumulation of Aβ42 by antagonizing β or γ secretases, promoting α secretase, or clearing Aβ42 that has already formed by use of specific antibodies.
Several genes play an important role in the pathogenesis of AD. One is the APP gene on chromosome 21. Adults with trisomy 21 (Down’s syndrome) consistently develop the typical neuropathologic hallmarks of AD if they survive beyond age 40 years, and many develop a progressive dementia superimposed on their baseline mental retardation. The extra dose of the APP gene on chromosome 21 is the initiating cause of AD in adult Down’s syndrome and results in excess cerebral amyloid production. Supporting this hypothesis, some families with early age-of-onset familial AD (FAD) have point mutations in APP. Although very rare, these families were the first examples of single-gene autosomal dominant transmission of AD.
Investigation of large families with multigenerational FAD led to the discovery of two additional AD-causing genes, the presenilins. Presenilin-1 (PS-1) is on chromosome 14 and encodes a protein called S182. Mutations in this gene cause an early-age-of-onset AD, with onset before the age of 60 and often before age 50, transmitted in an autosomal dominant, highly penetrant fashion. More than 100 different mutations have been found in the PS-1 gene in families from a wide range of ethnic backgrounds. Presenilin-2 (PS-2) is on chromosome 1 and encodes a protein called STM2. A mutation in the PS-2 gene was first found in a group of American families with Volga German ethnic background. Mutations in PS-1 are much more common than those in PS-2. The presenilins are highly homologous and encode similar proteins that at first appeared to have seven transmembrane domains (hence the designation STM), but subsequent studies have suggested eight such domains, with a ninth submembrane region. Both S182 and STM2 are cytoplasmic neuronal proteins that are widely expressed throughout the nervous system. They are homologous to a cell-trafficking protein, sel 12, found in the nematode Caenorhabditis elegans. Patients with mutations in the presenilin genes have elevated plasma levels of Aβ42, and PS-1 mutations produce increased Aβ42 in the media in cell culture. There is evidence that PS-1 is involved in the cleavage of APP at the γ secretase site and mutations in either gene (PS-1 or APP) may disturb γ secretase cleavage. Mutations in PS-1 are the most common cause of early-age-of-onset FAD, representing perhaps 40–70% of all cases. Mutations in PS-1 tend to produce AD with an earlier age of onset (mean onset 45 years) and a shorter, more rapidly progressive course (mean duration 6–7 years) than the disease caused by mutations in PS-2 (mean onset 53 years; duration 11 years). Although some carriers of PS-2 mutations have had onset of dementia after the age of 70, mutations in the presenilins rarely lead to late-age-of-onset AD. Clinical genetic testing for these uncommon mutations is available but likely to be revealing only in early-age-of-onset FAD and should be performed in association with formal genetic counseling.
The Apo ε gene on chromosome 19 is involved in the pathogenesis of AD. The protein, apolipoprotein E, participates in cholesterol transport (Chap. 421), and the gene has three alleles: ε2, ε3, and ε4. The Apo ε4 allele confers increased risk of AD in the general population, including sporadic and late-age-of-onset familial forms. Approximately 24–30% of the nondemented white population has at least one ε4 allele (12–15% allele frequency), and about 2% are ε4/ε4 homozygotes. Among patients with AD, 40–65% have at least one ε4 allele, a highly significant elevation compared with controls. Conversely, many AD patients have no ε4 allele, and ε4 carriers may never develop AD. Therefore, ε4 is neither necessary nor sufficient to cause AD. Nevertheless, the Apo ε4 allele represents the most important genetic risk factor for sporadic AD and acts as a dose-dependent disease modifier, with the earliest age of onset associated with the ε4 homozygosity. Precise mechanisms through which Apo ε4 confers AD risk or hastens onset remain unclear, but ε4 leads to less efficient amyloid clearance and to the production of toxic fragments from cleavage of the molecule. Apo ε can be identified in neuritic plaques and may also be involved in neurofibrillary tangle formation, because it binds to tau protein. Apo ε4 decreases neurite outgrowth in dorsal root ganglion neuronal cultures, perhaps indicating a deleterious role in the brain’s response to injury. Some evidence suggests that the ε2 allele may reduce AD risk. Use of Apo ε testing in AD diagnosis remains controversial. It is not indicated as a predictive test in normal persons because its precise predictive value is unclear, and many individuals with the ε4 allele never develop dementia. Many cognitively normal ε4 heterozygotes and homozygotes show decreased cerebral cortical metabolic function with PET, suggesting presymptomatic abnormalities due to AD or an inherited vulnerability of the AD-targeted network. In demented persons who meet clinical criteria for AD, finding an ε4 allele increases the reliability of diagnosis; however, the absence of an ε4 allele cannot be considered evidence against AD. Furthermore, all patients with dementia, including those with an ε4 allele, require a search for reversible causes of their cognitive impairment. Nevertheless, Apo ε4 remains the single most important biologic marker associated with AD risk, and studies of ε4’s functional role and diagnostic utility are progressing rapidly. The ε4 allele is not associated with risk for FTD, DLB, or CJD, although some evidence suggests that ε4 may exacerbate the phenotype of non-AD degenerative disorders, head trauma, and other brain injuries. Additional genes are also likely to be involved in AD, especially as minor risk alleles for sporadic forms of the disease. Genome-wide association studies have implicated the clusterin (CLU), phosphatidylinositol-binding clathrin assembly protein (PICALM), and complement component (3b/4b) receptor 1 (CR1) genes. CLU may play a role in synapse turnover, PICALM participates in clathrin-mediated endocytosis, and CR1 may be involved in amyloid clearance through the complement pathway. TREM2 is a gene involved with inflammation that increases the likelihood of dementia. Homozygous mutation carriers develop a frontal dementia with bone cysts (Nasu-Hakola disease), whereas heterozygotes are predisposed to the development of AD.
TREATMENT Alzheimer’s Disease
The management of AD is challenging and gratifying despite the absence of a cure or a robust pharmacologic treatment. The primary focus is on long-term amelioration of associated behavioral and neurologic problems, as well as providing caregiver support.
Building rapport with the patient, family members, and other caregivers is essential to successful management. In the early stages of AD, memory aids such as notebooks and posted daily reminders can be helpful. Family members should emphasize activities that are pleasant while curtailing those that increase stress on the patient. Kitchens, bathrooms, stairways, and bedrooms need to be made safe, and eventually patients will need to stop driving. Loss of independence and change of environment may worsen confusion, agitation, and anger. Communication and repeated calm reassurance are necessary. Caregiver “burnout” is common, often resulting in nursing home placement of the patient or new health problems for the caregiver. Respite breaks for the caregiver help to maintain a successful long-term therapeutic milieu. Use of adult day care centers can be helpful. Local and national support groups, such as the Alzheimer’s Association and the Family Caregiver Alliance, are valuable resources. Internet access to these resources has become available to clinicians and families in recent years.
Donepezil (target dose, 10 mg daily), rivastigmine (target dose, 6 mg twice daily or 9.5-mg patch daily), galantamine (target dose 24 mg daily, extended-release), and memantine (target dose, 10 mg twice daily) are approved by the Food and Drug Administration (FDA) for the treatment of AD. Due to hepatotoxicity, tacrine is no longer used. Dose escalations for each of these medications must be carried out over 4–6 weeks to minimize side effects. The pharmacologic action of donepezil, rivastigmine, and galantamine is inhibition of the cholinesterases, primarily acetylcholinesterase, with a resulting increase in cerebral acetylcholine levels. Memantine appears to act by blocking overexcited N-methyl-d-aspartate (NMDA) glutamate receptors. Double-blind, placebo-controlled, crossover studies with cholinesterase inhibitors and memantine in moderate to severe AD have shown them to be associated with improved caregiver ratings of patients’ functioning and with an apparent decreased rate of decline in cognitive test scores over periods of up to 3 years. The average patient on an anticholinesterase inhibitor maintains his or her mini-mental state examination (MMSE) score for close to a year, whereas a placebo-treated patient declines 2–3 points over the same time period. Memantine, used in conjunction with cholinesterase inhibitors or by itself, slows cognitive deterioration and decreases caregiver burden for patients with moderate to severe AD but is not approved for mild AD. Each of these compounds has only modest efficacy for AD. Cholinesterase inhibitors are relatively easy to administer, and their major side effects are gastrointestinal symptoms (nausea, diarrhea, cramps), altered sleep with unpleasant or vivid dreams, bradycardia (usually benign), and muscle cramps.
In a prospective observational study, the use of estrogen replacement therapy appeared to protect—by about 50%—against development of AD in women. This study seemed to confirm the results of two earlier case-controlled studies. Sadly, a prospective placebo-controlled study of a combined estrogen-progesterone therapy for asymptomatic postmenopausal women increased, rather than decreased, the prevalence of dementia. This study markedly dampened enthusiasm for hormonal treatments to prevent dementia. Additionally, no benefit has been found in the treatment of AD with estrogen alone.
A controlled trial of an extract of Ginkgo biloba found modest improvement in cognitive function in subjects with AD and vascular dementia. Unfortunately, a comprehensive 6-year multicenter prevention study using ginkgo found no slowing of progression to dementia in the treated group.
Vaccination against Aβ42 has proved highly efficacious in mouse models of AD, helping clear brain amyloid and preventing further amyloid accumulation. In human trials, this approach led to life-threatening complications, including meningoencephalitis, in a minority of patients. Another experimental approach to AD treatment has been the use of β and γ secretase inhibitors that diminish the production of Aβ42, but the first two placebo-controlled trials of γ secretase inhibitors, tarenflurbil and semagacestat, were negative, and semagacestat may have accelerated cognitive decline compared to placebo. Passive immunization with monoclonal antibodies against Aβ42 has been tried in mild to moderate AD. These studies were negative, leading some to suggest that the patients treated were too advanced to respond to amyloid-lowering therapies. Therefore, new trials have started in asymptomatic individuals with mild AD, in asymptomatic autosomal dominant forms of AD, and in cognitively normal elderly who are amyloid positive with PET. Medications that modify tau phosphorylation and aggregation, including tau antibodies, are beginning to be studied as possible treatments for both AD and non-AD tau-related disorders including FTD and progressive supranuclear palsy.
Several retrospective studies suggest that nonsteroidal anti-inflammatory agents and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) may have a protective effect on dementia if used prior to the onset of disease but do not influence clinically symptomatic AD. Finally, there is now a strong interest in the relationship between diabetes and AD, and insulin-regulating studies are being conducted.
Mild to moderate depression is common in the early stages of AD and may respond to antidepressants or cholinesterase inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are commonly used due to their low anticholinergic side effects (for example, escitalopram, target dose 5–10 mg daily). Seizures can be treated with levetiracetam unless the patient had a different regimen that was effective prior to the onset of AD. Agitation, insomnia, hallucinations, and belligerence are especially troublesome characteristics of some AD patients, and these behaviors can lead to nursing home placement. The newer generation of atypical antipsychotics, such as risperidone, quetiapine, and olanzapine, are being used in low doses to treat these neuropsychiatric symptoms. The few controlled studies comparing drugs against behavioral intervention in the treatment of agitation suggest mild efficacy with significant side effects related to sleep, gait, and cardiovascular complications, including an increased risk of death. All antipsychotics carry a black box FDA warning and should be used with caution in the demented elderly; however, careful, daily, nonpharmacologic behavior management is often not available, rendering medications necessary for some patients. Finally, medications with strong anticholinergic effects should be vigilantly avoided, including prescription and over-the-counter sleep aids (e.g., diphenhydramine) or incontinence therapies (e.g., oxybutynin).