Alzheimer disease (AD) …

Neurobehavioral & Cognitive Disorders

Updated 11.14.2023
Released 06.27.1994
Expires For CME 11.14.2026

Alzheimer disease

Authors: David S Geldmacher MD, D Luke Fischer MD PhD

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Editor: Howard S Kirshner MD

Alzheimer disease

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Introduction

Overview

Alzheimer disease is the most common cause of dementia (known as major neurocognitive disorder in the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders) among people over 65 years of age. In this article, the authors present an overview of the disease, including clinical manifestations, pathophysiology, etiology, and diagnostic workup. Information on results from clinical trials of diet and exercise are also included.

Historical note and terminology

Although cognitive decline in advanced age has been recognized throughout history, the understanding that it represents the result of specific disease states is more recent. In 1907 the German neurologist and pathologist Alois Alzheimer reported the case of a 56-year-old woman with progressive cognitive decline and behavior change associated with distinctive neuropathological features of senile plaques and neurofibrillary tangles (04). Although the term Alzheimer disease is often used synonymously with dementia, current theoretical frameworks distinguish the pathology of Alzheimer disease from the symptomatic expression, accounting for constructs like preclinical Alzheimer disease and mild cognitive impairment due to Alzheimer disease. For clarity and brevity in this article, Alzheimer dementia will be used to denote dementia due to Alzheimer disease.

Clinical manifestations

Presentation and course

	• Memory loss is the dominant feature in most patients and is often accompanied by anomia, visuospatial deficits, and executive dysfunctions.
	• Apathy, depression, and agitation are frequent noncognitive symptoms.
	• Approximately one in six patients with Alzheimer disease develop epilepsy.

Alzheimer disease is by far the most common pathology associated with dementia, especially among people over age 65, though mixed pathologies become increasingly frequent at older ages. The syndrome of dementia is characterized by persistent decline in two or more cognitive functions from a previously higher level. Memory loss is the predominant symptom at the onset of cognitive decline across all ages. Patients with younger age of onset are more likely to have problems with judgment, language, or visuospatial function as the presenting complaint (10). Indeed, one of these dysfunctions may be the primary presenting symptom for which there are the separate syndromes of executive variant Alzheimer disease (121), logopenic variant primary progressive aphasia (44), and posterior cortical atrophy (25), respectively. Memory dysfunction in Alzheimer disease involves impairment of learning new information, which is often described as short-term memory loss. In the early (mild) and moderate stages of Alzheimer dementia, recall of remote well-learned material may appear to be preserved, but new information cannot be adequately incorporated into memory. Recall of remote events often lacks details such as the dates and sequences of events. Closely associated with the breakdown of learning is progressive disorientation in time and place. Finally, in the later stages, frank failure of recall for previously well-remembered information (eg, names of the patient's own children) is observed. At least among those with the ability to participate in conversation, self-identity is retained among people with advanced dementia (12).

Language impairments are also a prominent feature of dementia due to Alzheimer disease. These often manifest first as difficulty in finding words in spontaneous speech, and result in reduced vocabulary, circumlocution, and word-finding pauses. The language of the mild Alzheimer disease patient is typically vague. It frequently lacks specifics, substituting generic words or broad categories in place of more explicit nouns. Pronouns (eg, he, she, they) often are used in place of proper nouns. Anomia on confrontational naming tests is most notable for parts of objects (eg, pocket), rather than the whole object (eg, lab coat). Conversational fluency is usually intact apart from word-finding pauses. Impaired comprehension of linguistic information becomes evident later in the course. Repetition is often preserved, even in more advanced cases.

Apraxia is a disorder of skilled movement, despite intact strength and coordination. Apraxia is evident on a detailed exam in over two-thirds of people within about two years after symptom onset (02). Nearly all patients with Alzheimer dementia will develop apraxia as the illness progresses, leading eventually to the inability to use eating utensils. The apraxia identified in most patients with Alzheimer dementia is an ideomotor disturbance, meaning they have difficulty in translating an idea into the proper action.

Deficits in complex visual function such as agnosia are present in many Alzheimer disease patients. Other focal cognitive deficits associated with temporoparietal lesions, such as spatial disorientation, acalculia, and left-right disorientation, are often present as well. Breakdowns of elemental visual processing may occur, leading to deficits in contrast and spatial frequency, motion detection, and figure ground discrimination, which may influence driving and other complex activities of daily living.

Difficulties with judgment, problem solving, planning, and abstract thinking are grouped together in the concept of executive dysfunction, which becomes apparent as socially inappropriate behavior, disinhibition, and poor task initiation or persistence. Executive dysfunction is present in a large majority of Alzheimer disease patients, even with relatively mild dementia (114). Detection of executive dysfunction is difficult in the presence of more severe cognitive deficits; therefore, difficulties in cognition and regulating behavior tend to be more obvious in the relatively earlier stages of cognitive decline. However, a dysexecutive profile (eg, difficulty with Trails B and phonemic fluency worse than semantic fluency) that predominates in the earliest stages of disease is more typical for vascular dementia than Alzheimer dementia.

Another common problem in Alzheimer dementia is unawareness of illness. Although this is often attributed to conscious denial of symptoms, it more often represents true anosognosia. It is characterized by a lack of recognition of the full extent and implications of cognitive or functional disability by the patient. Prevalence in mild to moderate Alzheimer dementia is about 40% (123). Unawareness of illness can be a major impediment to diagnosis and implementation of effective management strategies. Anosognosia is also associated with the risk for dangerous behaviors in patients with dementia (113).

Noncognitive or behavioral symptoms often account for a larger proportion of caregiver burden or stress than the cognitive dysfunction. Personality changes are common, with passivity and apathy appearing more frequently than agitation in the early phases of the illness. One retrospective review suggested that social withdrawal, mood changes, or depression were present in more than 70% of cases, initially occurring with a mean duration of more than two years prior to diagnosis of Alzheimer disease (59). Patients with amnestic mild cognitive impairment and apathy, including symptoms like decreased emotional expression, diminished initiative, and decreased expression of affection have a higher risk for progression to Alzheimer dementia (83). Apathy is the most common behavioral symptom in Alzheimer dementia, affecting 55% of patients in a large European sample (01).

Several schemes for classifying behavioral symptoms have emerged. These classifications may be useful for making treatment decisions that optimize efficacy and patient safety. A classification scheme suggests breaking behavioral changes into the following broad categories (17):

	• Psychopathological features
		- Disturbances in emotional experience - Delusions and abnormal thought content
	• Perceptual disturbances • Disturbances in motor function • Circadian rhythm disturbances • Appetite and eating behaviors

Emotional experience. A meta-analysis of 48 studies involving over 16,000 patients indicated depression and anxiety were each expressed in about 40% of patients with Alzheimer dementia (135). Frequency of depressive symptoms increases with disease severity. Patients with depression prior to the onset of cognitive decline are more likely to experience major depression during the course of their Alzheimer dementia (136). Catastrophic reactions (intense emotional outbursts of short duration characterized by tearfulness, aggressive behavior, and contrary behaviors) are associated with anxiety. They are typically provoked by stressful circumstances and resolve too quickly to be treated pharmacologically.

Thought content. Psychosis tends to occur later in the disease course and is associated with more rapid decline. Estimates of the prevalence of psychotic features in Alzheimer dementia vary widely and are prone to selection bias. A meta-analysis of studies using the neuropsychiatric inventory to measure symptoms indicates prevalence rates of approximately 30% for delusions and approximately 15% for hallucinations (135). In a more selective tertiary memory clinic sample (N=1227), the overall observed rate of hallucinations was substantially lower (4.5%) and increased in severity from 3% in people with mild dementia to 10% among severe cases (67). Visual hallucinations in Alzheimer dementia are 3-fold more common than in the auditory domain but sometimes have auditory components. Frequent themes include seeing deceased parents or siblings, unknown intruders, and animals.

Delusions are often paranoid in character and may lead to accusations of theft, infidelity, and persecution. The delusions that caregivers or family members are impostors or that ones home is not his or her real home are common triggers for wandering or aggression.

Motor function. Motor hyperactivity increases with disease progression (42). This often manifests as purposeless pacing from room to room and frequent rummaging in drawers or closets. Picking behaviors are another manifestation of hyperactivity. Alzheimer disease spares the elemental neurologic examination throughout most of its course. In later stages, extrapyramidal signs (eg, rigidity) and gait disturbances may become prominent, and loss of ambulation frequently accompanies the transition to terminal phase.

Epilepsy was identified in 17% of 64 pathologically proven cases of Alzheimer disease (92), which is consistent with frequently cited estimates of 10% to 20% seizure prevalence in patients with Alzheimer dementia. Younger patients and those with longer disease duration were more likely to have epilepsy. Myoclonus was recorded in 8.5% of patients diagnosed with Alzheimer dementia (13). Both seizures and myoclonus occurred most frequently in patients with younger age of onset, with seizures emerging about four years after diagnosis and myoclonus about one year later (13). Up to 25% of patients with Alzheimer dementia experience circadian rhythm disturbances (130). Sundowning, consisting of periods of agitated behaviors that begin in afternoon or evening, is perhaps the most common behavioral manifestation attributable to circadian disturbances (128). Patients may also unpredictably develop extended periods of insomnia or hypersomnia, which places significant burdens on caregivers.

Appetitive issues. Weight loss is a common event in Alzheimer dementia, affecting more than 40% of patients (41). Greater weight loss is associated with greater disease severity and increased mortality. Pathophysiologic events leading to Alzheimer-related weight loss may be active prior to the development of cognitive impairments (127), and weight loss in mild cognitive impairment is associated with a 3-fold increase in the risk of conversion to Alzheimer dementia (23).

Prognosis and complications

Survival estimates for patients with Alzheimer dementia vary widely. Study methods represent a major source of the variability. In a medical records-based study of over 59,000 patients, median survival after dementia diagnosis was 3 to 5 years and was notably shorter with older age of onset (71). In contrast, survival of over 12 years was observed in a sample of patients with Alzheimer disease (64). Overall life expectancy among patients with Alzheimer dementia is reduced by about 10 years (115). Younger patients have more cognitive dysfunction and more rapid cognitive decline, which may account for a greater reduction in life expectancy for those individuals (65).

In later stages, patients with Alzheimer disease most often succumb to complications of immobility, such as sepsis from pneumonia, urinary tract infection, and infected decubitus ulcers. They are at high risk for aspiration pneumonia and dehydration. Loss of ambulation is associated with a high rate of painful joint contractures. Delirium and acute confusion are common complications of dementia in the presence of even mild metabolic derangements.

Clinical vignette

A 74-year-old woman presented for evaluation of "short-term memory loss" at the behest of her family. The patient acknowledged memory difficulty but no more than her same age-peers. Believing she was well, the patient was unable to provide any detailed history of the present illness. Interestingly, she denied any health problems whatsoever, despite having brought her five daily medications with her to the visit.

History was, therefore, obtained from her daughter. Difficulties in cognition and daily function were first noted about three years earlier, shortly after she was widowed. Her problems were attributed to grieving and depression, so she was treated with sertraline. Her mood and activity returned to normal, but she continued to struggle with managing the finances and shopping. This was attributed to her unfamiliarity with these activities, as her husband had done them exclusively over the last five years. More recently, she had discontinued her regular church attendance, had been noted to wear dirty clothing, and had been losing weight; however, her housekeeping remained immaculate.

She had chronic atrial fibrillation and hypertension and had sustained a myocardial infarction seven years earlier. Current medications included digoxin, warfarin, lisinopril, metoprolol, and raloxifene. She lived at home. Her older sister had two strokes and progressive memory difficulties in the three years prior to her death at 72 years of age.

Her blood pressure was 180/102, and her pulse was 98, and irregularly irregular. She had 1+ pedal edema.

On cognitive examination, she was not oriented to date or month, but could identify the day of the week. She could repeat three words but recalled none after five minutes of distraction. She correctly named the president, but not the governor. She could not recount any recent major news events. She could name a watch, pencil, and jacket, but could not name the lapel, sleeve, or cuff. She correctly drew a clock, but could not set the hands to 8:20. General neurologic examination was unrevealing, apart from diminished large fiber sensation in the distal lower extremities, and a mildly unsteady gait.

Based on the history and findings, a clinical diagnosis of Alzheimer disease was made. Laboratory evaluation for reversible sources of dementia revealed normal Vitamin B12, thyroid function, and syphilis serology determinations. Her digoxin level was 0.1 and INR equaled 1.2. (Both were markedly subtherapeutic and suggested inconsistent medication adherence). CT scan of the brain revealed mild atrophy and ventricular enlargement. There were no areas of discrete infarction, and only mild periventricular hypodensity.

She was treated with donepezil 5 mg daily for six weeks, after which it was increased to 10 mg daily. Her three daughters agreed to a rotating schedule to monitor her adherence to medications to assist with meals and to monitor her weight. Her Mini-Mental State Examination score was 19/30 at treatment initiation, 21/30 at six months, and 20/30 after one year. She lost four additional pounds in the first six weeks of follow-up, gained two pounds back by six months of treatment, and lost no more weight by the end of one year of follow-up. Her family devoted progressively more time to supervision and caregiving activities over this year to "maintain Mothers independence." Due to the decline not captured by MMSE scores, memantine therapy was initiated and titrated to 10 mg twice daily after one year of donepezil treatment. Six months after memantine was begun, her family reported no clear improvement or decline in cognition or function. MMSE was 20/30. By two years after her first visit (4 to five years from the onset of a consistent symptom pattern), she had sustained a small kitchen fire, and she reluctantly moved in with her eldest daughter in order to be maintained with the 24-hour per day supervision recommended by her physician.

Biological basis

	• Alzheimer disease pathology is characterized by extracellular amyloid plaques and aggregated tau as a component of neurofibrillary tangles.
	• Symptoms and severity of illness are most correlated to degeneration of synapses and neuronal somata.

Etiology and pathogenesis

Pathophysiology. The exact etiopathologic mechanisms for premature cell death in Alzheimer disease have not been established. However, biomarker and imaging studies indicate that cerebral accumulation of amyloid beta is the first detectable abnormality, followed by metabolic failure of neurons, deposition of tau, and finally cognitive and functional losses (110).

Extensive neurotransmitter changes are associated with neuronal death in Alzheimer disease. Dementia severity and loss of cerebral cortical markers for acetylcholine metabolism are strongly correlated. The degree of cholinergic reduction in cortex is closely associated with the amount of cellular loss in the basal forebrain nuclei, where the neurons that produce much of the cortical acetylcholine are located. However, Alzheimer disease is not simply the result of cholinergic depletion. Other ascending pathways, such as those for dopamine, norepinephrine, and serotonin also are affected, and their dysfunction may underlie many of the noncognitive symptoms of Alzheimer disease, including executive function, mood, and motivation. Intrinsic classical neurotransmitters (ie, gamma amino butyric acid and glutamate) are disordered, as are many cortically localized neuropeptides (ie, somatostatin and corticotropin releasing factor).

Genetics. Family history of dementia is the strongest known risk factor. Although autosomal dominant early onset familial Alzheimer disease kindreds have been linked to chromosomes 21, 14, or 1, fewer than 2% of Alzheimer dementia cases can be tied to specific genes. Individuals with an affected first-degree relative, but not an autosomal dominant family history, have a 2-fold to 4-fold increase in their age-adjusted risk for developing Alzheimer disease. Risk appears to increase with larger numbers of affected relatives. Rates as high as 40 times normal have been suggested for individuals with two or more first-degree relatives with dementia. The risk imparted by family history is greatest when ages of both the affected family member and the person at risk were less than 70 years (106).

The E4 allele for apolipoprotein E, a chromosome 19 gene, confers increased risk for the development of late-onset familial and sporadic Alzheimer disease but does not appear to be the proximate cause of Alzheimer disease-related neuronal death. The critical role of apolipoprotein E in the genesis of Alzheimer disease is reinforced by the discovery of an E3 allelic mutation that appears to be protective against Alzheimer pathology in a person with a presenilin 1 gene mutation deterministic for Alzheimer disease (08). Genome-wide association studies have identified more than 30 loci associated with Alzheimer dementia; newer technologies, including next-generation sequencing, continue to identify more mutations. Apart from APOE4, the net contribution of each of these genetic variations to overall populational risk is small. However, a polygenic risk score derived from genome-wide association studies data may be useful in predicting progression to Alzheimer dementia (18).

Nearly 100% of people with Down syndrome surviving into their fifth decade develop neuropathologic findings of Alzheimer disease. Concomitant dementia occurs in most. A family history of Down syndrome may also be a risk factor for the development of Alzheimer disease.

Pathology. Prior to the development of transgenic mouse models in the 1990s, the understanding of Alzheimer pathophysiology was primarily derived from knowledge of its pathological expression in autopsy samples. On gross examination, the brain often appears atrophic with enlarged ventricles and sulci. Overall brain weight is invariably reduced, but there is significant overlap with the normal range of brain weights corrected for age.

Normal brain (coronal section)

Coronal section of cerebral hemispheres in a 64-year-old nondemented male. Notice size of ventricular system and hippocampal gyrus. (Contributed by Dr. David Geldmacher.)
Gross brain atrophy in Alzheimer disease

Coronal section of cerebral hemispheres in a 65-year-old male with Alzheimer disease. Notice diffuse cerebral atrophy evidenced by widened subarachnoid spaces and dilatation of lateral ventricles and temporal horns. Notice atrophy...

Senile or neuritic plaques and neurofibrillary tangles are the distinguishing microscopic features used in the pathological diagnosis of Alzheimer disease, it is important to remember that neuronal loss and synaptic loss are the pathological features most closely associated with dementia symptoms. Therefore, treatments that reverse or remove plaque and tangle pathology in animal models are not likely to reverse symptoms of the human disease. Other pathologic findings include intracerebral and intravascular deposition of amyloid peptide, Hirano bodies, and granulovacuolar degeneration.

Neuritic plaques (photomicrograph) (1)

Section of cerebral cortex stained with modified Bielschowsky silver method illustrating numerous neuritic plaques. Scattered among the plaques are also neurofibrillary tangles. (Contributed by Dr. David Geldmacher.)
Neuritic plaques (photomicrograph) (2)

Section of cerebral cortex stained with anti-A antibody illustrating numerous neuritic plaques. Scattered among the plaques are also neurofibrillary tangles. (ABC method, 1:5000; x31.25; Anti-A antibody (10D5) was provided by Athe...
Amyloid deposition (photomicrograph)

Thioflavine-S stained section viewed under ultraviolet light illustrating yellow-green fluorescence of meningeal and cortical vessels, indicating amyloid deposition. (x12.5) (Contributed by Dr. David Geldmacher.)

Senile or neuritic plaques are composed of neuronal and glial processes as well as extracellular amyloid. They range in diameter from 15µ to 100µ and are distributed throughout the cortex and limbic nuclei, such as the amygdala and hippocampus.

Neuritic plaques, two types (photomicrograph) (1)

Section stained with modified Bielschowsky silver method to illustrate primitive plaques. Conglomerate of dystrophic neuritic processes without a central amyloid core. (Contributed by Dr. David Geldmacher.)
Neuritic plaques, two types (photomicrograph) (2)

Section stained with modified Bielschowsky silver method to illustrate classic plaques. Central amyloid core (yellow star-shaped structure) surrounded by dystrophic neuritic processes (center and right upper corner). (Contributed ...
Neurofibrillary tangles in the CA1 region (photomicrograph) (1)

Section of hippocampus stained with modified Bielschowsky silver method illustrating large numbers of neurofibrillary tangles in the CA1 region. (Contributed by Dr. David Geldmacher.)
Neurofibrillary tangles in the CA1 region (photomicrograph) (2)

Section of hippocampus stained with modified Bielschowsky silver method illustrating large numbers of neurofibrillary tangles in the CA1 region. (Contributed by Dr. David Geldmacher.)

Senile (amyloid) plaques, tangles, and the amount of synaptic loss are all associated with the severity of cognitive impairment, but other factors, such as age and the amount of cerebrovascular disease burden, also have strong influences on symptom severity (78).

The primary component of plaques is a 39 to 43 amino acid peptide known as amyloid beta, which is derived from a larger protein known as amyloid precursor protein encoded on chromosome 21. The precursor protein undergoes proteolysis by normal, constitutively expressed enzymes known as secretases. The protein encoded by the presenilin-1 gene is a major component of the complex of proteins that functions as gamma secretase. Presenilin-1 mutations account for the largest proportion of autosomal dominant cases of Alzheimer disease that have been associated with a specific mutation. The combined effects of beta-secretase and gamma-secretase on amyloid precursor protein result in the formation of the beta amyloid peptide. The amyloid beta peptide forms soluble oligomers, which aggregate into insoluble fibrils. Fibrils accumulate into an insoluble extracellular beta-pleated sheet that forms the basis of the senile plaque. Longer forms, especially the 42 amino acid variant, are particularly prone to fibril formation. Growing evidence suggests that the oligomeric forms of amyloid beta that target specific synaptic proteins may be more responsible for synaptic dysfunction than the senile plaques (30). Secretase inhibition (beta or gamma), inhibition of beta-sheet formation, or immunomodulation of serum amyloid-beta concentrations are, therefore, all potential amyloid related mechanisms for therapies to prevent or slow Alzheimer pathology but are unproven as effective in large-scale human clinical trials to date.

Brain amyloid accumulation can be imaged with PET scans using ligands that bind to amyloid beta. Three ligands (florbetaben, florbetapir, and flutemetamol) are available for clinical use in the United States to identify whether amyloid plaques composed of amyloid beta are present. In October 2023, the U.S. Centers for Medicare and Medicaid Services (CMS) changed their policies to allow payment for amyloid PET scans. A negative amyloid scan largely excludes the diagnosis of Alzheimer disease in a patient with cognitive symptoms. The accumulations correlate with cerebral atrophy in prodromal Alzheimer disease, but that relationship breaks down with increasing severity (19). Monoclonal antibody treatment directed at aggregated amyloid beta is associated with reduced cortical amyloid burden in Alzheimer disease patients, but the relationship with clinical improvement is inconsistent across studies (103). Anti-amyloid therapies are discussed in the Management section.

Neurofibrillary tangles are intracellular collections of abnormal hyperphosphorylated filaments that form a distinctive paired helical structure in Alzheimer disease.

Neurofibrillary tangles - paired helical structure (electron micrograph)

Note periodic constrictions. (approximately x100,000) (Contributed by Dr. David Geldmacher.)

Other illnesses, such as progressive supranuclear palsy and chronic traumatic encephalopathy, are also characterized by the presence of neurofibrillary tangles, but do not have the paired helical structure characteristic of Alzheimer pathology. Neurofibrillary tangles also appear in the brain in small numbers among nondemented older adults, and may represent a nonspecific end-stage neuronal finding. The protein components of neurofibrillary tangles have been identified as microtubules, tau (microtubular associated protein), and ubiquitin. Neurofibrillary tangles are found throughout the neocortex and limbic nuclei. They are also strongly represented in the basal forebrain, substantia nigra, raphe nuclei, and locus ceruleus.

Hippocampus from nondemented male (photomicrograph)

Section of hippocampus stained with modified Bielschowsky silver method from a nondemented 71-year-old male for comparison. Notice pale yellow-brown staining of the cytoplasm and darker staining of nuclei and nucleoli. (x12.5) (Co...
Hippocampus from patient with Alzheimer disease (photomicrograph)

Section of hippocampus stained with anti-tau-2 antibody. Only intracellular tangles (flame-shaped structures surrounding the clear nucleus) are demonstrated. Also notice clusters of brown reactive product (two left, two in the ...

Widespread cortical neuronal loss is observed in autopsy cases and is more obvious in cases with younger onset or greater disease severity at the time of death. The deep layers of the temporal cortex and the hippocampus appear to be most affected. Substantial neuronal dropout is more prominent in the basal forebrain cholinergic cells, as well as in the monoaminergic cells of the locus coeruleus and the raphe nuclei. The substantia nigra can also be affected, which may contribute to parkinsonian changes late in the course of the illness and symptomatic overlap with dementia with Lewy bodies.

Intense granulovacuolar degeneration is seen in Alzheimer disease but also occurs, to a lesser degree, in normal aging. In demented patients, the pyramidal area of the hippocampus seems to be particularly prone to the development of these clear 5 µm diameter zones with an argyrophilic core. Hirano bodies are eosinophilic cellular inclusions that are also in the hippocampal pyramidal layer.

Hirano body (photomicrograph)

Oil immersion photomicrograph of CA1 region of hippocampus illustrating Hirano body (eosinophilic rod) between two neurons and granulovacuolar degeneration of two neurons (right upper and left lower corners). (x312.5) (Contribu...

Epidemiology

	• Alzheimer disease is the most common cause of dementia.
	• The prevalence of Alzheimer disease is rapidly increasing and is projected to continue to rise through the 2050s. This increase reflects an aging population as well as higher rates of diagnosis among affected individuals.

One useful model for understanding the prevalence of dementia is to assume a doubling every five years, beginning with 1% at 60 years of age, and increasing to 2% at 65 years of age, 4% at 70 years of age, 8% at 75 years of age, 16% at 80 years of age, and 32% at 85 years of age (131). Incidence rates also increase with age from 0.6% for persons 65 to 69 years of age, to 1% for 70 to 74 years of age, 2% for 75 to 79 years of age, 3.3% for 80 to 84 years of age, and 8.4% for those over 85 years of age (47). Clinically diagnosed Alzheimer disease, alone or in combination with other illnesses, accounts for up to 90% of dementia in the United States (66), although many of these cases are of mixed etiologies. The number of cases is expected to exceed 12 million in the United States by 2050 (90). However, analyses indicate that the age-adjusted incidence of dementia may be dropping, rendering past epidemiologic projections of the future prevalence of Alzheimer disease less reliable (100).

The frequency of concomitant degenerative pathologies seen with Alzheimer disease ranges from one-third to two-thirds, depending on the series (66). The most common concurrent pathologies are stroke and Lewy bodies. Of note, a history of stroke may lower the threshold to develop dementia (109).

The death rate associated with Alzheimer disease increased more than 50% between 1999 and 2014, from 16.5 deaths per 100,000 population to 25.4; the proportion of patients with Alzheimer disease dying at home nearly doubled over the same interval, from 13.9% to 24.9% (119). Several factors probably contribute to this increase, including the aging of the population and increased willingness of physicians to diagnose Alzheimer dementia and attribute death to the condition.

The direct health care costs for patients with dementia is reported to be about $350 billion annually in the United States in 2023, exceeding the costs of more common illnesses like diabetes and arthritis. Almost half of nursing home residents are diagnosed with Alzheimer disease or other forms of dementia. In addition, the number of cases is expected to exceed 13 million in the United States by 2050, with much of the growth being attributable to the aging of the population (48).

Potential risk factors for cognitive decline include the following: depression, female sex, APOE4 genotype, hypertension, heart disease, diabetes, elevated low-density lipoprotein cholesterol level, elevated homocysteine level, transient ischemic attacks or strokes, head trauma, environmental exposure to toxins (particularly lead), smoking, alcoholism, substance abuse, low educational achievement, lack of intellectual activity, lack of physical activity, lack of social interaction, lack of leisure activities, and excessive response to stress (elevated cortisol levels). Given the large number of reported risks, the relative contribution of any one risk is difficult to calculate and may vary from one person to another. In large prospective trials, evidence suggested that hormone replacement therapy may also exacerbate cognitive decline and dementia risk in women (105; 104; 35).

Prevention

A 2010 United States National Institutes of Health State of the Science conference concluded that there is insufficient evidence to support any interventions to reduce the risk for Alzheimer disease or delay its onset (28). However, epidemiologic studies suggest potential protective effects for anti-inflammatory agents (54), statin-type cholesterol-lowering drugs (133), exercise (29), Mediterranean and DASH diets (80), and dietary fish intake (79), but conflicting evidence also has been reported; for example, a randomized controlled clinical trial showed the MIND diet was no better than mild caloric restriction (11). Because amyloid deposition and neuronal loss begins years, possibly decades, prior to the first symptoms, the role of late-life risk management is unclear. However, a practice parameter from the American Academy of Neurology indicates that evidence-supported twice weekly exercise may improve cognition in people with mild cognitive impairment (85).

Educational achievement and mental activity have also been suggested as protective factors, perhaps through their enhancement of synaptic density or cognitive reserve. It is possible, however, that the underlying disease process is not affected by these factors, and the onset of symptoms is delayed. Increased morbidity from non-Alzheimer disease causes in groups with lower socioeconomic status may also be responsible for an apparent protective factor of education (21). The evidence that inorganic aluminum from dietary sources, or other environmental exposures contributes to the risk of Alzheimer disease is largely inferential, and these hypotheses generally have not been accepted.

In light of the above considerations, a 2020 report on dementia prevention from The Lancet Commission listed 12 factors (three new since its 2017 report) on which to focus dementia prevention and policy efforts: (1) excessive alcohol consumption, (2) head injury, (3) air pollution, (4) less education, (5) hypertension, (6) hearing impairment, (7) smoking, (8) obesity, (9) depression, (10) physical inactivity, (11) diabetes, and (12) infrequent social contact (68).

Differential diagnosis

Confusing conditions

Nondementia states, such as delirium and depression, must be excluded as the cause of the functional disability. Delirium is defined by diminished attention, which is often characterized as "clouding of consciousness." Many neurologists use the term "metabolic encephalopathy" to describe this state. In contrast, dementia is characterized by a clear sensorium. Delirium symptoms fluctuate often throughout the day to a far greater extent than in dementia. Delirium itself may be a sign of previously undiagnosed dementia (89). Indeed, reduced cognitive scores are associated with delirium incidence, and delirium may accelerate ongoing cognitive decline (39).

Depression has long been held as a cause of "pseudo-dementia." A significant overlap occurs between the behavioral symptoms of Alzheimer dementia and of depression. In general, the depressed individual will demonstrate poor effort on testing and otherwise slow, but intact performance on cognitively demanding tasks. Negative self-perceptions like guilt or worthlessness can help distinguish depression from apathy. A history of depression, even when responsive to medications, is associated with increased risk for dementia. The association between depression and Alzheimer disease risk may be stronger for men than women (49).

Clinicians also must consider alcohol and other drug use as potential contributors to late life cognitive decline, especially unintended polypharmacy from multiple providers. Anticholinergic drugs for gastrointestinal or genitourinary complaints contribute significantly to cognitive dysfunction in older adults (07). The potential role of anxiolytics, sedatives, hypnotics (including over the counter products), H2-blocking GI agents, and opioid CNS-acting analgesics (eg, opiates, gabapentin, tricyclics) must also be evaluated.

Potentially treatable causes of cognitive dysfunction that may mimic Alzheimer dementia include chronic pain, depression, hypothyroidism, vitamin B12 deficiency, sleep disorders, cerebral vasculitis, neurosyphilis, AIDS and its complications, and strokes, among others. It would be unusual for any of these to present with the characteristic pattern of multiple deficits in higher cortical function (ie, the subtle aphasia, apraxia, acalculia, and visuospatial dysfunction) seen early in typical Alzheimer dementia. The memory dysfunction in such conditions may, however, be indistinguishable on bedside evaluation. Overall, potentially reversible causes of dementia are seen in fewer than 10% of cases, and only 0.6% of cases appear to reverse completely (20).

A more difficult differential diagnosis involves distinguishing Alzheimer dementia from frontotemporal degeneration, in which behavior or behavioral language disturbances appear early in the course and remain the most prominent problem. Behavioral abnormalities typically include abnormal social and interpersonal conduct (out of character for the affected individual) and may be accompanied by language disturbances, disinhibition, impulsivity, and apathy. The degree of disordered behavior (or language) is out of proportion to memory and visuospatial impairments. Many cases of Alzheimer disease also have prominent frontal-type symptoms, but in contrast to patients with frontotemporal degeneration, these individuals usually have significant problems in memory, orientation, praxis, or visuospatial performance. In addition, the median age of diagnosis for frontotemporal dementias was 63, significantly lower than typically reported for Alzheimer dementia (24). CMS guidelines allow payment for FDG-PET scanning to distinguish Alzheimer disease from frontotemporal degeneration using specific criteria.

Dementia with Lewy bodies should be considered strongly when dementia develops along with prominent psychosis, parkinsonian motor signs, or marked fluctuations in awareness. The development of visual hallucinations with otherwise mild cognitive disturbances characterizes many cases of dementia with Lewy bodies. These tend to be benign, nondirective, and purely visual. They are frequently microptic in character, such that the patient will describe "little people" or "little animals" as their visual experience. Delusions are less frequent. A history of hyperkinetic sleep syndromes like REM behavioral disorder or periodic limb movements of sleep is often associated with dementia with Lewy bodies (16). Abnormalities on visuospatial testing are frequent in dementia with Lewy bodies patients with hallucinosis. Other typical cognitive changes in dementia with Lewy bodies include general slowness of thought and action (ie, bradyphrenia or psychomotor slowing) and disorders of executive function (ie, planning and initiation of appropriate behaviors). Tremor is not often a major feature of the parkinsonism. Rigidity, bradykinesia, and postural changes more commonly appear. Transient and otherwise unexplained lapses of consciousness may occur and easily can be mistaken for seizures or orthostatic syncope. Delusions and hallucinations may be exacerbated by treatment of the parkinsonism. Alzheimer disease pathological features are present in a majority of dementia with Lewy bodies cases. Even if the clinical criteria for dementia with Lewy bodies are not met, parkinsonian symptoms can appear as part of Alzheimer disease, typically in the later stages.

Cerebral ischemia has long been considered a primary cause of dementia, under the names of Binswanger disease, multi-infarct dementia, and vascular dementia. In a community-based autopsy series of dementia patients, cerebrovascular disease complicating Alzheimer disease was as common as cerebrovascular disease alone. Each occurred at about one fifth the rate of uncomplicated Alzheimer disease (63). The typical cognitive pattern in vascular dementia includes prominent frontal and executive dysfunction, generally with better preservation of language and insight than seen in Alzheimer dementia. Psychomotor slowing may be prominent. Focal cortical signs (ie, visuospatial dysfunction and apraxia) are seen only when relevant areas of the brain have sustained cerebrovascular lesions. Early emergence of urinary dysfunction and gait disturbances have been suggested as markers of vascular dementia that can help differentiate it from Alzheimer disease. Facial masking, rigidity, and Babinski sign are also common earlier in vascular dementia than Alzheimer disease.

Normal pressure hydrocephalus, corticobasal degeneration, and progressive supranuclear palsy all can manifest with parkinsonian motor signs and dementia, but the cognitive dysfunction tends not to have the amnestic and multifocal cortical pattern of typical Alzheimer dementia. In idiopathic Parkinson disease, motor signs usually predate clinically evident dementia by several years.

In its earliest stages, Creutzfeldt-Jakob disease can also mimic Alzheimer disease, especially the posterior cortical atrophy variant. However, as a prion disorder, Creutzfeldt-Jakob disease usually progresses much more rapidly, leading to debility within months and death within months to a few years. As with Alzheimer dementia, familial forms do occur. Rare antineuronal antibody syndromes may include prominent behavioral disturbances and some cognitive impairment. These can be the presenting sign in some cases of cancer, especially small cell tumors and teratomas, or complicate primary autoimmune disorders such as Hashimoto encephalopathy.

Lastly, there are three neuropathological entities that mimic prototypical Alzheimer disease. First, primary age-related tauopathy (PART) shows Alzheimer disease-appearing tauopathy without the presence of amyloid and generally has a slower decline (50). Second, the new pathologic entity limbic-predominant age-related TDP-43 encephalopathy-neuropathological change (LATE-NC) is associated with a late-onset cognitive profile that parallels Alzheimer dementia and is identified postmortem, often as a comorbid neuropathologic finding (96). Similarly, argyrophilic grain disease (AGD) results in slowly progressive, amnestic symptoms and is observed frequently postmortem (97). These entities deserve further investigation, but there is currently no clear clinical use to distinguish them. Determining the relative contributions to symptom burden of LATE-NC and/or argyrophilic grain disease with Alzheimer disease in a given patient may be useful in the future when considering the potential benefit of anti-amyloid therapies; however, treatment decisions at present are based simply on whether amyloid is present (see further discussion below).

Associated or underlying disorders

Down syndrome

Diagnostic workup

	• Clinical screening tests should include assessment for depression.
	• Laboratory testing should include measurement of thyroid function and vitamin B12 levels.
	• Head imaging (CT or MRI) is often valuable in excluding other causes and can aid in identification and grading of temporal (especially hippocampal) or parietal atrophy.
	• Biomarker testing through analysis of cerebrospinal fluid or PET offer greatly increased diagnostic confidence when clinically necessary. FDA-approved proprietary blood-based biomarker assays for A-beta ratios and phosphorylated tau will be increasingly used in place of more invasive or expensive tests.

The clinical approach to diagnosis of Alzheimer disease in a patient presenting with memory problems is based on identification of patterns of cognitive changes that result from Alzheimer pathology. Careful physical and neurologic examinations, accompanied by mental status testing to identify the characteristic memory, language, and visuospatial deficits, as well as other cognitive and noncognitive symptoms are the key components in evaluation of the individual with suspected dementia.

The American Academy of Neurology has published evidence-based guidelines for the diagnosis of dementia (61). As of 2023, no newer evidence-based guidelines have been issued by this body. These guidelines recommend the use of clinical criteria to establish the diagnosis of Alzheimer disease. Either of two criterion sets may be used: (1) The National Institute of Aging and the Alzheimers Association (NIA-AA) criteria, which was updated in 2018 for research purposes (Table 1) (74) and is currently under revision, or (2) major neurocognitive disorder due to Alzheimers disease criteria in the Diagnostic and Statistical Manual for Mental Disorders, fifth edition, (DSM-V), which require impairment in two or more cognitive domains that include complex attention, executive function, learning and memory, language, or perceptual-motor or social cognition (05). Importantly, the decline should be gradual, progressive, and of sufficient severity to interfere with usual levels of social or occupational function, ie, independent activities of daily living.

Of patients diagnosed with possible or probable Alzheimer disease using the older NINCDS-ADRDA or similar criteria, the diagnosis is confirmed at autopsy in over 85%, but many cases also have other concomitant pathology, typically strokes (66). The research criteria for probable Alzheimer disease are highly specific (around 100%), but relatively insensitive (49%); if the criteria for probable or possible Alzheimer disease are combined, their specificity drops to 61%, but sensitivity reaches 85% (58).

Although these criteria define the illnesss clinical syndrome for research purposes, one consensus process called for physicians to consider Alzheimer disease a diagnosis of inclusion, recognized by its characteristic pattern of insidious onset and progressive course dominated by memory loss and accompanied by other cognitive and behavioral change (108). This does not mean that physicians should not evaluate for other causes, rather Alzheimer disease should be considered likely in people with a progressive amnestic disorder, even though other illnesses may be present. This more inclusive approach to diagnosis is supported by the observation that less than 10% of dementia cases are associated with "reversible" causes and less than 1% actually resolve with treatment (20).

Revised diagnostic criteria for Alzheimer disease in research studies call for the consideration of imaging and biomarkers rather than reliance on the full clinical syndrome alone (56). Their utility for clinical purposes generally was limited to defining Alzheimer disease for most clinical research, but this changed dramatically with the advent of drug amyloid-lowering therapies (discussed below). Three broad clinical syndromes are included: cognitively unimpaired, mild cognitive impairment, and dementia; these are summarized in Table 1. The biomarker and clinical profiles can be mapped to each other to predict the short-term rate of progression. Confusingly, an alternative diagnostic scheme, the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) has eliminated the word dementia from its lexicon, substituting the term major neurocognitive disorder in its place, thus, rendering the equivalent diagnosis in that schema as major neurocognitive disorder due to Alzheimer disease (05). Despite the changes in research nomenclature and categorization, most neurologists continue to use the terms Alzheimer(s) disease, Alzheimer(s) dementia, and dementia due to Alzheimer(s) disease interchangeably.

Table 1. Key Features of the 2018 Revised Criteria for Syndromal Staging of Cognitive Impairment

Cognitively unimpaired. Characterized by cognitive performance in the expected range (some will report subjective cognitive complaints or show decline on sequential testing)
Mild cognitive impairment
	• Cognitive performance is below the expected range
	• Impaired cognition represents a decline from baseline
	• Performs activities of daily living independently (but the cognitive impairment may make complex activities more difficult)
Dementia
	• Substantial progressive cognitive impairment affects several domains or neurobehavioral symptoms
	• Cognitive impairment or behavioral symptoms result in clearly evident loss of daily function
	• No longer fully independent (ie, requires assistance) in activities of daily living
	• May be divided into mild, moderate, and severe stages, though these are not precisely defined
Adapted from (56)

Dementia criteria identify losses of intellectual ability and personal interaction that represent a decline from a previously higher level and are sufficiently severe to interfere with daily functioning. The early symptoms of dementia are subtle and are frequently present for years before coming to medical attention. The concept of "mild cognitive impairment" has evolved in recognition of the fact that measurable memory and other cognitive deficits, more severe than can be accounted for by the aging process alone, can be identified in people without enough functional decline to qualify for a diagnosis of dementia. Most mild cognitive impairment patients with prominent amnesia eventually will develop dementia, but the interval between onset of memory loss and functional decline may be several years. A previous Agency for Health Care Policy and Research guideline suggested several findings that should "trigger" a clinician to evaluate for the presence of dementia or mild cognitive impairment. These are illustrated in Table 2. Questions to elicit these aspects of functional ability can be asked in a nonthreatening manner when obtaining the social history.

Table 2. Triggers for Evaluation of Possible Dementia

Difficulties in these areas:
• Learning and retaining information
	- repetitiveness - trouble remembering conversations - frequently misplaces items
• Handling complex tasks
	- eg, meal preparation and finances
• Reasoning ability
	- planning and problem solving (eg, response to flooding a bathroom) - following rules of social conduct
• Spatial ability and orientation
	- driving - household organization - finding ones way around familiar settings
• Language
	- word finding - following conversation
• Behavior
	- passive or less responsive - irritable - suspicious - misinterprets visual or auditory stimuli

Screening tests should include assessment for depression and laboratory testing with particular emphasis on thyroid function and vitamin B12 levels (61). EEG is not recommended for routine use; it is often normal in early stages with evolution toward generalized, nonspecific slowing as the disease progresses.

CT or MRI has historically been used to exclude structural lesions that may contribute to the dementia, such as cerebral infarctions, neoplasm, extracerebral fluid collections, and hydrocephalus. Consistent with new diagnostic criteria, mesial temporal atrophy on MRI strongly supports the likelihood of Alzheimer disease when appropriate clinical features are present (129). An easy-to-use visual rating scale for hippocampal and mesial temporal cortex atrophy can be useful for identifying Alzheimer patterns on routine clinical MRI sequences in the coronal plane (32).

In addition, inspection of the parietal lobes and, in particular, the precuneus may reveal early atrophic changes associated with Alzheimer disease. FDG-PET scanning to distinguish Alzheimer disease from frontotemporal degeneration. Despite approval for payment by Medicare in the United States, many private insurers remain unwilling to pay for FDG-PET scans with this indication.

The [18]F PET imaging ligands that bind to fibrillar amyloid in brain tissue are approved by the Food and Drug Administration but have not been widely used in the United States because they were not covered by Medicare and most other health insurance. However, the role of amyloid imaging in guiding treatment decisions and more favorable payment policies will likely result in increased use. Even before the availability of amyloid-lowering therapies, the IDEAS study indicated that results of amyloid scans altered clinical decision making in more than 60% of 11,409 participants, but the influence on clinical outcomes was established (88). Cerebrospinal fluid (CSF) examination by lumbar puncture is not a routine part of the dementia evaluation. The diagnostic yield of standard CSF tests is relatively low. CSF examination can have an important role in cases with serologic evidence of past syphilis, as well as in patients with immunosuppression or atypical dementia symptom patterns. For instance, cryptococcal meningitis can cause dementia in patients with immune compromise. CSF assays for soluble beta amyloid and tau are commercially available. These are useful for confirming or excluding the presence of Alzheimer disease pathophysiology in symptomatic patients; however, sometimes the results are borderline and difficult to interpret, and they are not directly comparable between testing platforms.

Similarly, apolipoprotein E assessment has been suggested to reduce the rate of false-positive diagnosis when used with clinical criteria (72), but its cost-effectiveness in clinical settings is not well supported for diagnostic certainty. That said, the accuracy of Alzheimer disease diagnosis based on accepted clinical criteria is superior to common medical diseases like lupus (77; 82). Further, blood-based tests for Alzheimer disease are improving in their accuracy and have entered the U.S. marketplace; however, caution is advised in their clinical use, as many tests currently available are not the same platforms used in clinical trials, so their performance characteristics are uncertain (43). All the same, it is increasingly likely that blood-based biomarkers with high diagnostic accuracy will be available clinically in the near future.

Historically, the presence of Alzheimer disease pathophysiology could only be proven by neuropathological examination; the emergence of CSF and plasma biomarkers, as well as PET imaging for amyloid and tau, has changed this but opened a new problem of understanding the clinical significance of the pathology in mildly symptomatic people. Biopsy remains not recommended for diagnosis. A negative biopsy will not exclude Alzheimer disease, and biopsy results are not likely to alter treatment plans. The new diagnostic criteria published in 2018 separate neuropathological diagnosis of Alzheimer disease (by biomarkers) from the clinical syndromes of cognitive impairment and dementia, rating each separately. The most important change associated with the revision is the classification of biomarker support for identifying Alzheimer disease pathophysiology into three categories: amyloid, tau, and neurodegeneration (or A-T-N), respectively (56). The measurement in serum of phosphorylated tau at different amino acids has been under investigation and shows great promise for increasing diagnostic certainty (120; 125); however, these tests require further validation across clinical cohorts and with each other to allow for comparisons across testing platforms (57).

Management

	• Current drugs for Alzheimer disease fall into two categories: symptomatic benefit and putative disease modification.
	• The usefulness of antipsychotic drugs for the treatment of agitation is modest and is limited by increased mortality risks. SSRIs may offer a better safety and efficacy profile than antipsychotics for agitation without psychosis.

Treatment strategies. The management of dementia is complex; ideally, it involves an interdisciplinary approach to assessment, treatment, and education. The roles of nursing, social work, psychology, legal representation, and case management can be vital to the effective longitudinal care of the patient with Alzheimer disease. The impact of an interdisciplinary treatment approach can be much greater than any medical or pharmacologic intervention in isolation. Other resources to draw on include community support groups as well as educational programs sponsored by the Alzheimers Association. This national support and advocacy group has many local chapters and provides both a telephone help line 1-800-272-3900 and a website The Alzheimers Association.

The American Academy of Neurology guidelines for management of dementia emphasize the role of nonpharmacologic approaches to care (31). Increased socialization (such as through daycare programs) and improved sleep hygiene may reduce the need for pharmacologic intervention for many difficult behaviors. The guidelines encourage education of family and paid caregivers on methods of minimizing agitation.

A major goal of the overall treatment plan should be the prevention of excess disability, achieved by minimizing adverse drug effects and by maximizing caregiver skills and knowledge. Acute behavioral or cognitive changes mandate evaluation for a complicating factor such as infection or metabolic disturbance. Preparing for the future also should be incorporated into the plan of care. Financial planning and legal advice should be accomplished early in the course of the illness to minimize stressors at the more advanced stages. Advance directives for care should also be explored early, and with the patient's input when appropriate, so that the patients wishes might be carried through should he/she become unable to express them later. Participation in research programs is also of great value to caregivers, as it can convey a sense of hope and positive outcomes from an otherwise devastating illness.

One particularly troublesome aspect of management is promoting personal safety. Visiting nurses or occupational therapy specialists can help families with home safety evaluations. The Alzheimers Association administers the "Safe Return" program to help manage the risk of wandering. The issue of driving cessation, however, often falls squarely on the physicians shoulders. Laws regarding physician reporting of potential driving impairment vary from state to state. The American Academy of Neurology has produced a practice parameter regarding driving with dementia (55). There is good evidence that patients diagnosed with Alzheimer disease who meet criteria for "mild" Alzheimer disease on the Clinical Dementia Rating should be advised to discontinue driving. Mini-Mental State Exam scores less than 24/30, reports of recent crashes, self-restricted driving activities, impulsive or aggressive behaviors, or caregiver-stated concerns about driving also have been linked to increased risk for crashes involving patients with dementia. No neuropsychological instrument is strongly supported as a predictor of driving performance.

Quality management. The American Academy of Neurology proposed a series of quality measures under the Physician Quality Reporting System process to guide appropriate care of the patient with dementia (98). Recommended elements for documentation on an annual basis are included in Table 3.

Table 3. Recommended Elements for Documentation

1. Disclosure of dementia diagnosis
2. Education and support of caregivers
3. Functional status assessment
4. Screening and management of behavioral and psychiatric symptoms
5. Safety concerns
6. Driving screening and follow-up
7. Advance care planning and palliative care counseling
8. Pain assessment
9. Pharmacologic treatment

Drug treatment. The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine are approved for use in the treatment of mild to moderate Alzheimer disease. Donepezil and rivastigmine are also approved for use in the severe stage of Alzheimer disease, and the three agents are similar in overall efficacy (95). Memantine is an NMDA-receptor antagonist unrelated to the cholinesterase inhibitor class and has been approved for use in the treatment of moderate to severe Alzheimer disease. A combination product that includes 10 mg donepezil and 28 mg extended release memantine is also available. Brexpiprazole received U.S. FDA approval for treatment of agitation associated with Alzheimer disease in 2023. Its use is described in the Behavioral Symptoms section, below.

Donepezil has been the most commonly prescribed anti-dementia therapy in the United States. Meta-analysis indicates a slight superiority of 10 mg daily dosing over the 5 mg dose, perhaps offset somewhat by a higher rate of GI intolerance (95). A 23 mg formulation is approved for use in moderate and severe Alzheimer disease. The 23 mg dose was superior to 10 mg daily on cognitive, but not global, outcomes; as with other dose forms of donepezil, higher doses were also associated with higher rates of adverse effects (36). Evidence suggests that donepezil treatment maintains cognitive test scores at or above baseline for a period of 9 months to 12 months and is superior to placebo for two years (22). Donepezil is associated with better maintenance of activities of daily living for up to two years (76; 22). Reductions in dementia-related behavioral disturbances and caregiver distress have been identified in a double-blind, placebo-controlled trial of donepezil (51), but treatment was not effective in reducing agitation in another trial (53). Donepezil treatment for more than nine months was associated with delayed nursing home admission in one nonrandomized study (40), but this was not supported in the AD2000 community-based placebo-controlled study in the U.K. (22).

Rivastigmine has shown efficacy for improving cognition, behavior, and function relative to a projected natural course, for periods as long as two years (38; 45). The transdermal formulation of rivastigmine is associated with significantly better GI tolerability than the oral form, with comparable efficacy on cognitive and global outcomes (132). A 13.3 mg/day transdermal dosage form was approved in 2012, after showing benefit in activities in daily living compared to the prior maximum dose of 9.5mg/day (27). Rivastigmine also has been shown to be associated with reduced risk for nursing home placement (14).

Galantamine has acetylcholinesterase inhibitory activity and may also have a direct facilitative effect on nicotinic ACh receptors. Clinical trials experience suggests cognitive, behavioral, and functional effects similar in magnitude to other cholinesterase inhibitors (91; 118). It is available in a once-daily extended-release formulation. Unlike donepezil and rivastigmine, greater efficacy with higher doses was not observed (95). The expected cholinergic side effects of nausea and vomiting were the most common adverse experiences in the clinical trials, at rates between those of donepezil and oral rivastigmine.

Memantine is an NMDA-receptor antagonist for which benefit relative to placebo for six months was observed in patients with moderate to severe Alzheimer disease (93). In an open label-extension, patients previously exposed to placebo benefited from memantine treatment, but there were no apparent differences between the group with one year of treatment and those who began later when assessed at the 12-month time point (94). Evidence also suggests better efficacy of memantine combined with donepezil in moderate to severe Alzheimer disease than chronic donepezil alone over six months (117). However, over the course of 12 months, donepezil may have more persistent benefit in patients with moderate to severe dementia due to Alzheimer disease than memantine (94; 52).

Meta-analytic approaches have not identified benefits for memantine in patients with mild dementia severity (101). Memantine tends to be well tolerated, but some patients develop confusion in response to the activating effects of the drug. There is no clear guidance from placebo-controlled trials regarding the duration of benefit from these medications.

Disease modification. Other agents have been studied for their ability to slow the progression of Alzheimer disease by altering the rate of neuronal death. The antioxidant compounds vitamin E (alpha-tocopherol) and selegiline have been reported to slow the progress of moderately severe Alzheimer disease without improving cognitive ability (99), but the effect was not replicated in patients with mild cognitive impairment (84). A study suggested a role for vitamin E dosed at 2000 IU/day in slowing functional decline in mild and moderate Alzheimer disease dementia, either alone or in conjunction with memantine (33). Caution is warranted, however, because evidence from cardiovascular studies suggests significant safety concerns at vitamin E doses over 400 International Units daily (75).

Despite epidemiologic support for a possible role in risk reduction, no large-scale clinical trials have supported a role for anti-inflammatory drugs, including prednisone, in affecting the symptoms or progression of Alzheimer disease. Similarly, a double-blind, placebo-controlled trial found no effect of estrogen on Alzheimer disease progression (81). Gingko biloba has not demonstrated consistent efficacy in reducing Alzheimer disease risk or altering progression (15).

Protein aggregation-targeting clinical trials for amyloid-beta have been more fruitful. Earlier treatments with BACE (β-site amyloid precursor protein cleaving enzyme) inhibitors that clearly lower production of amyloid-beta have been suggested to worsen, rather than improve, cognition and daily function (34). In contrast, amyloid removal through immunotherapy has been more successful. Initially, a preliminary study of the anti-amyloid antibody aducanumab showed significant dose-related effects on reducing dementia progression (103), and subsequent studies indicated the potential for clinical benefit, resulting in the U.S. Food and Drug Administrations approval of aducanumab via the accelerated approval pathway, despite advisory panel recommendations that the application be denied due to inconsistent results from two identical studies (62). CMS has not approved payment for treatment with aducanumab in the United States. Although remaining controversy has limited its use, other anti-amyloid antibodies have demonstrated greater clinical success. Lecanemab was granted traditional FDA approval in July of 2023, based on an approximately 28% reduction in the rate of decline on the Clinical Dementia Rating scale Sum of Boxes score in the CLARITY-AD Phase III trial (126). Donanemab showed a similar clinical effect in the TRAILBLAZER-ALZ 2 trial that was driven by the subgroup of participants with a low-to-medium measures of tau accumulation (107). As of November 2023, donanemab is under review for approval by the FDA. These and other data suggest that reducing plaque burden results in greater clinical efficacy in earlier stages of disease, but this effect may depend on targeting specific forms of amyloid, as therapy targeting monomers, but without plaque-reducing effect, was ineffective (111).

Importantly, plaque-reducing antibodies like lecanemab and donanemab are associated with potentially serious adverse effects collectively called amyloid relative imaging abnormalities (ARIA), including cerebral edema/effusion (ARIA-E) and hemorrhage (ARIA-H). ARIA was most frequently detected by routine surveillance MRIs rather than the as the result of newly expressed neurologic symptoms. In either case, its emergence may dictate altering the dosage plan, waiting for resolution of findings, or discontinuing treatment altogether (26). Only rare cases require escalation of therapy with interventions like intravenous steroids (124). The risk for ARIA may be predicted by a patients APOE E4 genotype, as the incidence is correlated with the number of copies of the E4 allele (107; 126). Clinical use overall has been tempered by the CMS requirement that patients must be included in a registry to allow payment under a Coverage with Evidence Development approval.

Treatment of behavioral symptoms. The American Academy of Neurology guidelines for management of dementia emphasize the role of nonpharmacologic approaches to care (31). Increased socialization (such as through daycare programs) and improved sleep hygiene may reduce the need for pharmacologic intervention for many difficult behaviors. The guidelines encourage education of family and paid caregivers on methods of minimizing agitation.

When pharmacotherapy is required, noncognitive symptoms are usually treated with conventional psychotropic agents, such as antipsychotics, antidepressants, and anxiolytics. Cholinesterase inhibitors can also alleviate noncognitive symptoms (122; 51). Larger cholinesterase inhibitor effects are seen in moderately affected individuals who also do not take psychotropic agents (118; 37). Consensus approaches generally favor selective serotonin reuptake inhibitors as the treatment of choice for agitated symptoms without psychotic features because of their favorable side effect profile (06; 03). Citalopram has demonstrated efficacy similar to risperidone for treating behavioral and psychotic symptoms in controlled trials (86). Citalopram also demonstrated efficacy on global function in patients with agitation (87). Doses above 20 mg daily were associated with increased risk for adverse cognitive effects and cardiac rhythm disturbances. The atypical serotonergic antidepressant trazodone has also been suggested as useful as a sedative treatment for agitation. Strongly anticholinergic agents, such as amitriptyline, are best avoided. Further, bupropion was ineffective compared to placebo in a randomized trial for the treatment of apathy in the absence of depressed mood (70).

Antipsychotic drugs have been the treatment of choice when delusions or hallucinations are disabling, or when other treatment approaches fail. Atypical antipsychotics like risperidone, olanzapine, and quetiapine may offer a more favorable side effect profile than haloperidol, at the low doses most commonly used in dementia, but this benefit is potentially offset by a higher risk for diabetes, stroke, and overall mortality. None of these agents performed better than the others or placebo in a large comparative trial (102). Pimavanserin is a released 5-HT2A receptor inverse agonist that has shown promise in treating more severe psychosis in patients with Alzheimer dementia (09). However, as of 2023, pimavanserin was not FDA-approved for use in the treatment of persons with Alzheimer disease, despite promising results for dementia-related psychosis (116). In contrast, based on results two 12-week studies, brexprirazole was approved by the FDA in 2023 as the first agent labeled specifically for treatment of agitation associated with dementia due to Alzheimers disease (46). Brexpiprazole is an atypical antipsychotic, which acts as a D2 dopamine and serotonin 1A partial agonist. Like other atypical antipsychotics, it carries a Black Box warning for increased mortality for patients with dementia. Somewhat paradoxically, the prescribing information warns, that brexpiprazole is not approved for the treatment of patients with dementia-related psychosis. Dosing should start at 0.25 mg daily and can be increased by 0.25 mg/day every 3 to 5 days until benefit is achieved. The maximum recommended daily dose is 3 mg daily dose. The most commonly reported adverse effects (relative to placebo) were sedation, dizziness, and urinary tract infections.

Benzodiazepine anxiolytics are not recommended for chronic use. They can cause increased cognitive impairments, paradoxical agitation, and increased risk for falls. Poor nocturnal sleep and reversal of day-night cycles are best treated by increased daytime activity and strict avoidance of naps, but these may be augmented with trazodone or zolpidem if sleep initiation, rather than sleep maintenance, is the major problem. Melatonin has provided mixed results in studies to date but may be useful for regulating sleep in some individuals (69). With this in mind, there is an overall lack of quality evidence for pharmacologic sleep interventions, as noted in a 2020 Cochrane review, though some benefit from trazodone or zolpidem was noted (73).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

David S Geldmacher MD

Dr. Geldmacher of the University of Alabama at Birmingham received research grants from Athira, Biogen, Eisai, and Janssen and consultation fees from Genentech and Lilly.
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D Luke Fischer MD PhD

Dr. Fischer of the University of California San Francisco has no relevant financial relationships to disclose.
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Editor

Howard S Kirshner MD

Dr. Kirshner of Vanderbilt University School of Medicine has no relevant financial relationships to disclose.
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Former Authors

Martin R Farlow MD

Patient Profile

Age range of presentation: 19 to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Alzheimer disease: 331.0

Presenile dementia: 290.1
ICD-10: Alzheimer disease: G30

Dementia in Alzheimer disease: F00
OMIM: Alzheimer disease: #104300

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Alzheimer disease

Associated Disorders

Down syndrome

Differential Diagnosis

Delirium
Pseudo-dementia of depression
Dementia with Lewy bodies
Drug-induced dementia
Frontotemporal dementia
- Hypothyroidism
- Korsakoff syndrome
- Paraneoplastic limbic encephalitis
- Metabolic encephalopathy
- Metal neurotoxicity
- Mixed dementia
- Neurosyphilis
- Normal pressure hydrocephalus
- Polypharmacy
- Antineuronal antibody syndromes
- Cerebral vasculitis presenting with dementia
- Chronic traumatic encephalopathy
- Progressive subcortical gliosis
- Subcortical vascular cognitive impairment
- Vascular cognitive impairment
- Vitamin B12 deficiency
- Limbic-predominant age-related TDP-43 encephalopathy (LATE)

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Familial Alzheimer disease
Memory loss
Mental status examination
Neurologic disorders of aging
Pre-mild cognitive impairment
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- Vitamin E in neurologic disorders
- Executive dysfunction
- Sleep and dementia
- Irregular sleep-wake rhythm disorder

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Alzheimer disease

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Overview

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Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Table 1. Key Features of the 2018 Revised Criteria for Syndromal Staging of Cognitive Impairment

Table 2. Triggers for Evaluation of Possible Dementia

Management

Table 3. Recommended Elements for Documentation

Special considerations

Anesthesia

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ICD & OMIM codes

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Wilson disease

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Hyperventilation syndrome

Apraxia

Neurologic disorders associated with behavioral symptoms

Cortical blindness

Leukodystrophies

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