3372 PART 13 Neurologic Disorders

■ EPIDEMIOLOGY

The most important risk factors for AD are increasing age and a positive family history. In the United States, approximately 10% of people

over age 65 years have AD, including 3% of people age 65–74 years, 17%

of people age 75–84 years, and 32% of people age 85 years and older. A

positive family history of dementia suggests a genetic contribution to

AD, which is usually attributable to the ApoE ε4 risk allele. Autosomal

dominant inheritance occurs in only 1–2% of patients and is typically

accompanied by a multigenerational history of early-onset dementia.

Female sex is a risk factor independent of the greater longevity of

females, and women who carry a single ApoE ε4 allele are more susceptible than are male ε4 carriers. A history of mild-to-severe traumatic

brain injury 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. Similarly,

illiteracy and low educational attainment are risk factors for dementia.

Numerous environmental factors, including aluminum, mercury, and

viruses, have been proposed as causes of AD, but rigorous studies have

failed to demonstrate 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; obesity; hearing loss; tobacco use; diminished serum levels of folic acid; low dietary

intake of fruits, vegetables, and red wine; sleep disorders; low levels of

exercise; and air pollution exposure are all being explored as potential

risk factors for dementia in general and AD in particular.

■ PATHOLOGY

At autopsy, the earliest and most severe degeneration is usually

found in the medial temporal lobe (entorhinal/perirhinal cortex and

hippocampus), inferolateral temporal cortex, and nucleus basalis of

Meynert. The characteristic microscopic findings are neuritic plaques

and NFTs (Fig. 431-2). These lesions accumulate in small numbers

during normal brain aging but dominate the picture in AD. The

overall burden of AD neuropathologic changes can be graded based

on the topography of Aβ plaques, the density of neuritic plaques, and

the spatial extent of NFTs present. 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, ApoE, αantichymotrypsin, 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. 431-3). 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. Other theories emphasize that abnormal conformations of tau induce misfolding of native

(unfolded) tau into pathologic conformations and that this prionlike templating process is responsible for tau spreading (Chap. 424).

Finally, patients with AD often show comorbid DLB, TDP-43, or vascular pathology. Most prevailing rodent models of AD involve expression

of mutant transgenes that leads to Aβ42 accumulation in the absence of

tauopathy. Even in these models, diminishing neuronal tau ameliorates

cognitive deficits and nonconvulsive seizures while 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

A B

FIGURE 431-2 Neuropathology of Alzheimer’s disease. A. Early neurofibrillary degeneration, consisting of NFTs 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 using Gallyas silver staining. B. Higher

magnification view reveals the fibrillar 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.

3373Alzheimer’s Disease CHAPTER 431

synthetic enzyme choline acetyltransferase, and nicotinic cholinergic

receptors. Reduction of acetylcholine reflects degeneration of cholinergic neurons in the nucleus basalis of Meynert, located just below the

thalamus and adjacent to the third ventricle, that project throughout

the cortex. There is also noradrenergic and serotonergic depletion due

to degeneration of upper brainstem nuclei such as the locus coeruleus

(norepinephrine) and dorsal raphe (serotonin), where tau-immunoreactive neuronal cytoplasmic inclusions can be identified in early adult

life, even in individuals lacking entorhinal cortex NFTs.

■ GENETIC CONSIDERATIONS

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 deficits. 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

(PSEN-1) is on chromosome 14 and encodes presenilin-1 protein (also

known as S182). Mutations in this gene cause an early-age-of-onset

AD, with onset typically before age 60 and often before age 50, transmitted in an autosomal dominant, highly penetrant fashion. More than

100 different mutations have been found in the PSEN-1 gene in families

from a wide range of ethnic backgrounds. Presenilin-2 (PSEN-2) is

on chromosome 1 and encodes the presenilin-2 protein (also known

as STM2). A mutation in the PSEN-2 gene was first found in a group

of American families with Volga German ethnic background. Mutations in PSEN-1 are much more common than those in PSEN-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 presenilins 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. Prior to symptom

Nontoxic

Cell

membrane

Step 1: Cleavage by either α or β secretase

Step 2: Cleavage by γ secretase

β Secretase product α Secretase product

APP β α

γ

Toxic Nontoxic

Amyloidogenic

Aβ42 Aβ40 P3

FIGURE 431-3 Amyloid precursor protein (APP) is catabolized by α, β, and γ

secretases. A key initial step is the digestion by either β secretase (BACE) 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.

onset, patients with mutations in the presenilin genes have elevated

CSF levels of Aβ42, and PSEN-1 mutations produce increased Aβ42 in

the media in cell culture. PSEN-1 is involved in the cleavage of APP at

the γ secretase site and mutations in either gene (PSEN-1 or APP) may

disturb γ secretase cleavage. Mutations in PSEN-1 are the most common cause of early-age-of-onset FAD, representing 40–70% of all cases.

Mutations in PSEN-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 mutations in PSEN-2 (mean onset 53

years; duration 11 years). Although some carriers of PSEN-2 mutations

have had onset of dementia after the age of 70 years, 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 APOE gene on chromosome 19 is involved in the pathogenesis

of AD. The protein product, ApoE, participates in cholesterol transport (Chap. 407), and the gene has three alleles: ε2, ε3, and ε4. The

ApoE 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. The increased risk associated with a single ε4 allele is especially prominent in women. The risk

of AD in ApoE ε4 carriers also varies by racial and ethnic background,

with increased risk in East Asians and decreased risk in blacks and

Hispanics compared with whites. Additionally, many patients with

AD have no ε4 allele, and ε4 carriers may never develop AD. Therefore, ε4 is neither necessary nor sufficient to cause AD. Nevertheless,

the ApoE ε4 allele represents the most important genetic risk factor

for sporadic AD and acts as a dose-dependent disease modifier, with

each ApoE ε4 allele associated with an approximately 10-year earlier

age of onset. The association between ApoE ε4 and AD is strongest in

patients 60–85 years of age and is weaker in younger patients and in

the very old. The precise mechanisms through which ApoE ε4 confers

AD risk or hastens onset remain unclear, but ε4 leads to less efficient

amyloid clearance and production of toxic fragments from cleavage

of the molecule. ApoE can be identified in neuritic plaques and may

also be involved in NFT formation, because it binds to tau protein.

ApoE ε4 decreases neurite outgrowth in dorsal root ganglion neuronal

cultures, perhaps indicating a deleterious role in the brain’s response

to injury. Increasing evidence suggests that the ε2 allele may reduce

AD risk. Use of ApoE testing in AD diagnosis remains controversial

because its predictive value remains unclear and many individuals

with the ε4 allele will never develop dementia. Cognitively normal ε4

heterozygotes and homozygotes may show decreased posterior cerebral

cortical metabolic function by PET imaging, 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. Nevertheless, ApoE 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. ApoE genotyping is available

in some straight-to-consumer genetic testing platforms. The ε4 allele

is associated with increased risk for cerebral amyloid angiopathy

(CAA), DLB, and vascular dementia, while its association with FTD is

uncertain. Some evidence suggests that ε4 may worsen the expression

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 identified more than 20 additional common

genetic variants that, individually, have small (i.e., odds ratios ~1.1–1.2

or 0.8–0.9) impacts on the risk of AD. Implicated genes converge in

biologic pathways related to innate immunity, lipid metabolism, and

synaptic function. Examples include the clusterin (CLU), phosphatidylinositol-binding clathrin assembly protein (PICALM), and complement component (3b/4b) receptor 1 (CR1) genes, among others. CLU

3374 PART 13 Neurologic Disorders

may play a role in synapse turnover, PICALM participates in clathrinmediated endocytosis, and CR1 may be involved in amyloid clearance

or synapse loss 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. TREM2 risk alleles are rare but have strong

effects, with odds ratios estimated at 3–4 for developing clinical AD.

Polygenic hazard scores that integrate the presence of multiple risk and

protective alleles may be useful in predicting an individual’s lifetime

risk of developing AD. The vast majority of AD genetic studies have

focused on white populations of European descent, and much less is

known about the genetics of AD in nonwhite populations.

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,

though many potential disease-modifying therapies are currently

being tested in human trials.

PATIENT AND CAREGIVER EDUCATION

Building rapport with the patient, family members, and other caregivers is essential. 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.

NEUROTRANSMITTER-BASED THERAPIES

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 U.S. 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 (in mild-to-severe

AD dementia) and memantine (in moderate-to-severe AD dementia) have shown them to be associated with modestly 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. Neither

cholinesterase inhibitors nor memantine has proven efficacious in

patients with MCI. 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.

Potential side effects associated with memantine include constipation, dizziness, headache, and somnolence. A common approach to

AD drug therapy is to initiate a cholinesterase inhibitor for a patient

diagnosed with mild AD dementia, and to add memantine when

patients enter the moderate stage of disease. Cholinesterase inhibitors may also be effective in treating delusions and hallucinations,

while memantine can reduce agitation.

THERAPIES TARGETING AMYLOID-a

AD drug development over the past two decades has focused on

the prevention or clearance of Aβ pathology. In June 2021, aducanumab, a monoclonal antibody targeting the N-terminus of the

Aβ peptide, was granted accelerated approval by the FDA based

on reduction in Aβ plaques (measured by PET) in two phase 3,

double-blinded, randomized placebo-controlled trials. However, a

clinical benefit over placebo (measured by slower decline on cognitive and functional scales) was observed with high-dose treatment

(10 mg/kg) in only one of the two trials, and lower antibody doses

did not show a benefit vs. placebo in either trial. Data interpretation was further complicated by differences in dosing between

trials and early termination of both trials based on a prespecified

futility analysis, which ultimately proved erroneous. Given these

circumstances, continued FDA approval will be contingent upon

verification of clinical benefit in confirmatory trials.

According to the FDA label, aducanumab should only be considered for treatment of patients with MCI or early dementia due

to AD, mirroring the early clinical stage of patients enrolled in the

phase 3 clinical trials. Patients with pre-clinical (i.e., asymptomatic, biomarker-positive) AD or patients with moderate-severe AD

dementia should not be treated until data on safety or efficacy in these

populations is available. Expert recommendations further stipulate

that biomarker confirmation of Aβ based on CSF or PET be required

prior to initiating treatment, since clinical diagnosis in isolation is not

sufficient to ensure the presence of Aβ plaques. Patients with confounding neurological or psychiatric conditions, unstable medical illnesses,

evidence of prior brain hemorrhages (including multiple microhemorrhages), or active anticoagulant treatment should be excluded.

Aducanumab is administered as an intravenous infusion every

4 weeks, with gradual dose titration from 1 mg/kg to 10 mg/kg over

seven infusions. Amyloid-related imaging abnormalities (ARIA)

are the most common adverse effect, occurring in 41% of patients

treated with high-dose aducanumab vs. 10% in the placebo groups.

ARIA can manifest as vasogenic edema (ARIA-E) or cortical microhemorrhages and superficial siderosis (ARIA-H). Of ARIA cases in

the phase 3 trials, 74% were asymptomatic and detected by safety

MRIs. The most common symptoms associated with ARIA were

headache, altered mental status, dizziness, visual disturbances, and

nausea. Symptoms were usually mild and transient, though severe

cases with focal neurologic deficits have been described. Most cases

occurred within the first eight infusions, though ARIA can occur at

any time. Baseline and safety surveillance MRI scans (at minimum

following the 7th and 12th infusions) are required for aducanumab

treatment, and an MRI is also indicated in treated patients in whom

ARIA is suspected clinically. Therefore, patients with contraindications to MRI cannot safely receive this therapy. ApoE genotyping

may also be considered to inform risk-benefit discussions prior to

treatment, because ARIA-E is more common in ApoE ε4 carriers

(43%) compared to noncarriers (20%). It is highly recommended

that the antibody only be prescribed by clinicians who have adequate training and access to the resources needed to safely deliver

this complex therapy.

ADDITIONAL THERAPIES

Mild-to-moderate depression is common in the early stages of AD

and may respond to antidepressants or cholinesterase inhibitors.

3375Alzheimer’s Disease CHAPTER 431

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 for use in elderly patients with dementia and thus should

be prescribed only with caution; however, careful, daily, nonpharmacologic behavior management is often not available, rendering

medications necessary for some patients. 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).

Several commonly used medications and supplements, including estrogen hormone replacement therapy, statins, vitamin E,

and ginkgo biloba, appeared to be associated with a decreased

risk of AD in epidemiologic or observational studies, but did not

show efficacy in prospective, randomized, double-blinded, placebocontrolled trials. Many vitamins and dietary supplements are marketed directly to consumers as “memory enhancing” or protective

against AD without clinical evidence. Patients and families may

come across anecdotal reports of “miraculous” responses to aggressive treatments such as anti-interferon intrathecal infusions, intravenous immunoglobulin, antibiotics (purportedly to treat Lyme

disease or another questionable infection), metal chelation, and

stem cell therapies, but there is no scientific evidence to support use

of any of these approaches to treating AD, and significant concern

for harm.

EXPERIMENTAL THERAPIES

The design of AD clinical trials has been transformed by the availability of PET and CSF biomarkers of Aβ and tau. Many trials now

require biomarker evidence of AD for trial inclusion. Biomarkers

help assess target engagement (e.g., changes in CSF or PET Aβ in

an antiamyloid trial) or modification of downstream disease pathophysiology (e.g., changes in CSF or PET tau in an antiamyloid trial),

with the pivotal trials leading to approval of aducanumab being

emblematic of this novel approach. Increasingly, many trials have

shifted toward enrolling patients in the asymptomatic (preclinical)

or very early symptomatic stages of AD, using positive biomarkers

as the primary inclusion criterion. Primary (biomarker-negative)

and secondary (biomarker-positive but no symptoms) prevention

trials are underway in autosomal dominant mutation carriers, ApoE

ε4 homozygotes, and even in the normally aging population.

Beyond aducanumab, several additional anti-Aβ monoclonal

antibodies (e.g., lecanemab, gantenerumab, and donanemab) have

shown evidence of robust amyloid plaque lowering on PET and are

currently being evaluated in clinical trials across the continuum

from preclinical disease to mild dementia due to AD. As with aducanumab, ARIA-E and ARIA-H represent a safety concern for this

class of drugs. Active vaccination against Aβ is another approach

that aims to promote immune-mediated clearance of amyloid

pathology. The first Aβ42 vaccine trial in humans was aborted after

a minority of patients developed meningoencephalitis, but subsequent trials with less immunogenic formulations have shown more

favorable safety profiles.

Oral drugs that inhibit β and γ secretase reduce the cleavage of

APP to Aβ42 and showed promise in ameliorating pathology and

behavioral changes in AD transgenic mice. Unfortunately, placebocontrolled trials failed to show clinical efficacy, and trials of β

secretase inhibitors in particular, consistently found significant

worsening of cognition in treated patients vs. placebo, though fortunately this effect proved transient after discontinuing the drug. It is

unclear whether toxicity of β and γ secretase inhibitors was directly

related to changes in Aβ metabolism or to “off-target” drug effects.

Monoclonal antibodies directed against phosphorylated tau are

in earlier stages of development. These antibodies aim to prevent the transsynaptic spread of tau and have proven effective in

tau-transgenic mice. Safety profiles in human studies have proven

favorable thus far. Additional therapeutic approaches targeting tau

include: active immunization; inhibition of tau phosphorylation,

acetylation, and aggregation; microtubule stabilization; and lowering of

tau expression via antisense oligonucleotides or small interfering RNA.

Other druggable pathways represented in the AD drug development

pipeline include neuroinflammation, metabolism/bioenergetics,

synaptic plasticity, neuroprotection, and neurotransmitter-based

treatment of neuropsychiatric symptoms.

A general approach to the symptomatic management of dementia

is presented in Chap. 25.

OTHER CAUSES OF DEMENTIA

FTD (Chap. 432), vascular dementia (Chap. 433), DLB (Chap. 434),

and prion diseases (Chap. 438) are covered in dedicated chapters.

Prion diseases such as CJD are rare neurodegenerative conditions

(prevalence ~1 per million) that produce dementia. CJD is a rapidly

progressive disorder associated with dementia, focal cortical signs,

rigidity, and myoclonus, causing death <1 year after first symptoms

appear. The rapidity of progression seen with CJD is uncommon in AD

so that the distinction between the two disorders is usually straightforward, although AD can on occasion present as a rapidly progressive

dementia. In general, corticobasal degeneration (CBD) (Chap. 432)

and DLB (Chap. 426), more rapid degenerative dementias with

prominent movement abnormalities, are more likely to be mistaken

for CJD. The differential diagnosis for CJD includes other rapidly progressive dementing conditions such as viral or bacterial encephalitides,

Hashimoto’s encephalopathy, central nervous system (CNS) vasculitis,

lymphoma, or paraneoplastic/autoimmune syndromes (Chap. 94). The

markedly abnormal periodic complexes on EEG and cortical ribboning

and basal ganglia hyperintensities on diffusion-weighted imaging or

fluid-attenuated inversion recovery MRI are diagnostic features of CJD,

although rarely, prolonged focal or generalized seizures can produce a

similar imaging appearance.

Huntington’s disease (HD) (Chap. 436) is an autosomal dominant

degenerative brain disorder. Clinical hallmarks of HD include chorea,

behavioral disturbance, and executive impairment. Symptoms typically

begin in the fourth or fifth decade of life, but there is a wide range, from

childhood to >70 years. Memory is frequently not impaired until late

in the disease, but attention, judgment, self-awareness, and executive

functions are often deficient at an early stage. Depression, apathy, social

withdrawal, irritability, and intermittent disinhibition are common.

Delusions and obsessive-compulsive behavior may occur. Disease

duration is variable but typically lasts ~15 years.

Normal-pressure hydrocephalus is a relatively uncommon but treatable syndrome. The clinical, physiologic, and neuroimaging characteristics of NPH must be carefully distinguished from those of other

dementias associated with gait impairment. Historically, many patients

treated for NPH have suffered from other dementias, particularly AD,

vascular dementia, DLB, and progressive supranuclear palsy (PSP)

(Chap. 432). For NPH, the clinical triad includes an abnormal gait

(ataxic or apractic), dementia (usually mild to moderate, with an

emphasis on executive impairment), and urinary urgency or incontinence. Neuroimaging reveals enlarged lateral ventricles (hydrocephalus) with little or no cortical atrophy, although the Sylvian fissures may

appear propped open (so-called boxcarring), which can be mistaken

for perisylvian atrophy. Crowding of dorsal frontal-parietal gyri helps

distinguish NPH from other movement disorders, such as PSP and

CBD, in which dorsal atrophy with sulcal widening is common. NPH

is a communicating hydrocephalus with a patent aqueduct of Sylvius

3376 PART 13 Neurologic Disorders

(see Fig. 29-3), in contrast to aqueductal stenosis, in which the

aqueduct is small. Lumbar puncture opening pressure falls in the

high-normal range, and the CSF protein, glucose, and cell counts are

normal. NPH may be caused by obstruction to normal CSF flow over

the cerebral convexities and delayed resorption into the venous system.

The indolent nature of the process results in enlarged lateral ventricles with relatively little increase in CSF pressure. Presumed edema,

stretching, and distortion of subfrontal white matter tracts may lead to

clinical symptoms, but the precise underlying pathophysiology remains

unclear. Some patients provide a history of conditions that produce meningeal scarring (blocking CSF resorption) such as previous

meningitis, subarachnoid hemorrhage, or head trauma. Others with

long-standing but asymptomatic congenital hydrocephalus may have

adult-onset deterioration in gait or memory that is confused with NPH.

In contrast to AD, the patient with NPH complains of an early and

prominent gait disturbance without cortical atrophy on CT or MRI.

Numerous attempts have been undertaken to improve NPH diagnosis with various special studies and to predict the success of ventricular

shunting. These tests include radionuclide cisternography (showing

a delay in CSF absorption over the convexity) and various efforts to

monitor and alter CSF flow dynamics, including a constant-pressure

infusion test. None has proven to be specific or consistently useful. A

transient improvement in gait or cognition may follow lumbar puncture (or serial punctures) with removal of 30–50 mL of CSF, but this

finding has also not proved to be consistently predictive of postshunt

improvement. Perhaps the most reliable strategy is a period of close

inpatient evaluation before, during, and after lumbar CSF drainage.

Occasionally, when a patient with AD presents with gait impairment

(at times due to comorbid subfrontal vascular injury) and absent or

only mild cortical atrophy on CT or MRI, distinguishing NPH from

AD can be challenging. Hippocampal atrophy on MRI favors AD,

whereas a characteristic “magnetic” gait with external hip rotation, low

foot clearance, and short strides, along with prominent truncal sway or

instability, favors NPH. The diagnosis of NPH should be avoided when

hydrocephalus is not detected on imaging studies, even if the symptoms otherwise fit. Of those patients identified by careful diagnosis as

having NPH, 30–50% will improve with ventricular shunting. Gait may

improve more than cognition, but many reported failures to improve

cognitively may have resulted from comorbid AD. Importantly, the

presence of positive CSF AD biomarkers or amyloid PET is associated

with lower likelihood of response to shunting. Short-lasting improvement is common. Patients should be carefully selected for shunting,

because subdural hematoma, infection, and shunt failure are known

complications and can be a cause for early nursing home placement in

an elderly patient with previously mild dementia.

Intracranial hypotension, sometimes called sagging brain syndrome,

is a disorder caused by low CSF pressure, leading to downward pressure on the subcortical structures and disruption of cerebral function.

It presents in a variable manner with headache, often exacerbated by

coughing or a Valsalva maneuver or by moving from lying to standing.

Other common symptoms include dizziness, vomiting, disruption of

sleep-wake cycles, and sometimes a progressive behavioral variant

FTD-like syndrome (Chap. 432). Although sometimes idiopathic, this

syndrome can be caused by CSF leaks secondary to lumbar puncture,

head trauma, or spinal cord arachnoid cysts. Treatment consists of

finding and patching the CSF leak.

Dementia can accompany chronic alcoholism (Chap. 453) and

may result from associated malnutrition, especially of B vitamins,

particularly thiamine. Other poorly defined aspects of chronic alcoholism may, however, also produce cerebral damage. A rare idiopathic

syndrome of dementia and seizures with degeneration of the corpus

callosum has been reported primarily in male Italian red wine drinkers

(Marchiafava-Bignami disease).

Thiamine (vitamin B1

) deficiency causes Wernicke’s encephalopathy (Chap. 307). The clinical presentation is usually a malnourished

patient (frequently but not necessarily alcoholic) with confusion,

ataxia, and diplopia resulting from inflammation and necrosis of

periventricular midline structures, including dorsomedial thalamus,

mammillary bodies, midline cerebellum, periaqueductal gray matter,

and trochlear and abducens nuclei. Damage to the dorsomedial thalamus correlates most closely with the memory loss. Prompt administration of parenteral thiamine (100 mg intravenously for 3 days followed

by daily oral dosage) may reverse the disease if given within the first

days of symptom onset. Prolonged untreated thiamine deficiency can

result in an irreversible and profound amnestic syndrome (Korsakoff ’s

syndrome) or even death.

In Korsakoff’s syndrome, the patient is unable to recall new information despite normal immediate memory, attention span, and level of

consciousness. Memory for new events is seriously impaired, whereas

knowledge acquired prior to the illness remains relatively intact.

Patients are easily confused, disoriented, and cannot store information

for more than a few minutes. Superficially, they may be conversant,

engaging, and able to perform simple tasks and follow immediate commands. Confabulation is common, although not always present. There

is no specific treatment because the previous thiamine deficiency has

produced irreversible damage to the medial thalamic nuclei and mammillary bodies. Mammillary body atrophy may be visible on MRI in the

chronic phase (see Fig. 307-6).

Vitamin B12 deficiency, as can occur in pernicious anemia, causes

a megaloblastic anemia and may also damage the nervous system

(Chaps. 99 and 442). Neurologically, it most commonly produces a

spinal cord syndrome (myelopathy) affecting the posterior columns

(loss of vibration and position sense) and corticospinal tracts (hyperactive tendon reflexes with Babinski signs); it also damages peripheral

nerves (neuropathy), resulting in sensory loss with depressed tendon

reflexes. Damage to myelinated axons may also cause dementia. The

mechanism of neurologic damage is unclear but may be related to

a deficiency of S-adenosyl methionine (required for methylation of

myelin phospholipids) due to reduced methionine synthase activity

or accumulation of methylmalonate, homocysteine, and propionate,

providing abnormal substrates for fatty acid synthesis in myelin.

Use of histamine blockers or metformin, vegan diets, autoimmunity

against gastric parietal cells, and various causes of malabsorption are

the typical causes for vitamin B12 deficiency. The neurologic sequelae

of vitamin B12 deficiency may occur in the absence of hematologic

manifestations, making it critical to avoid using the complete blood

count (CBC) and blood smear as a substitute for measuring B12 blood

levels. Treatment with parenteral vitamin B12 (1000 μg intramuscularly

daily for a week, weekly for a month, and monthly for life for pernicious anemia) stops progression of the disease if instituted promptly,

but complete reversal of advanced nervous system damage will not

occur.

Deficiency of nicotinic acid (pellagra) is associated with skin rash

over sun-exposed areas, glossitis, and angular stomatitis (Chap. 333).

Severe dietary deficiency of nicotinic acid along with other B vitamins

such as pyridoxine may result in spastic paraparesis, peripheral neuropathy, fatigue, irritability, and dementia. This syndrome has been seen

in prisoners of war and in concentration camps but should be considered in any malnourished individual. Low serum folate levels appear to

be a rough index of malnutrition, but isolated folate deficiency has not

been proved as a specific cause of dementia.

CNS infections usually cause delirium and other acute neurologic

syndromes. However, some chronic CNS infections, particularly

those associated with chronic meningitis (Chap. 139), may produce

a dementing illness. The possibility of chronic infectious meningitis should be suspected in patients presenting with a dementia or

behavioral syndrome, who also have headache, meningismus, cranial

neuropathy, and/or radiculopathy. Between 20–30% of patients in

the advanced stages of HIV infection become demented (Chap. 202).

Cardinal features include psychomotor retardation, apathy, and

impaired memory. This syndrome may result from secondary opportunistic infections but can also be caused by direct infection of CNS

neurons with HIV. Neurosyphilis (Chap. 182) was a common cause of

dementia in the preantibiotic era; it is now uncommon but can still be

encountered in patients with multiple sex partners, particularly among

patients with HIV. Characteristic CSF changes consist of pleocytosis,

increased protein, and a positive Venereal Disease Research Laboratory

(VDRL) test.

3377Alzheimer’s Disease CHAPTER 431

Primary and metastatic neoplasms of the CNS (Chap. 90) usually

produce focal neurologic findings and seizures rather than dementia,

but if tumor growth begins in the frontal or temporal lobes, the initial

manifestations may be memory loss or behavioral changes. An autoimmune, sometimes paraneoplastic, syndrome of dementia associated

with occult carcinoma (often small-cell lung cancer) is termed limbic

encephalitis. In this syndrome, confusion, agitation, seizures, poor

memory, emotional changes, and frank dementia may occur. Paraneoplastic encephalitis associated with N-methyl-d-aspartate (NMDA)

receptor antibodies presents as a progressive psychiatric disorder with

memory loss and seizures; affected patients are often young women

with ovarian teratoma. Autoimmune etiologies also include antibodies targeting leucine-rich glioma-inactivated 1 (LGI1; faciobrachial

dystonic seizures); contactin-associated protein-like 2 (Caspr2; insomnia, ataxia, myotonia); and α-amino-3-hydroxy-5-methylisoxazole-4-

propionic acid (AMPA)-receptor (limbic encephalitis with relapses),

among others (Chap. 94).

A nonconvulsive seizure disorder (Chap. 425) may underlie a syndrome of confusion, clouding of consciousness, and garbled speech.

Often, psychiatric disease is suspected, but an EEG demonstrates the

epileptic nature of the illness. If recurrent or persistent, the condition

may be termed complex partial status epilepticus. The cognitive disturbance often responds to anticonvulsant therapy. The etiology may

be previous small strokes or head trauma; some cases are idiopathic.

Nonconvulsive temporal lobe seizures can also emerge early in the

course of AD.

It is important to recognize systemic diseases that indirectly affect

the brain and produce chronic confusion or dementia. Such conditions

include hypothyroidism; vasculitis; and hepatic, renal, or pulmonary

disease. Hepatic encephalopathy may begin with irritability and confusion and slowly progress to agitation, lethargy, and coma.

Isolated vasculitis of the CNS (CNS granulomatous angiitis)

(Chaps. 363 and 427) occasionally causes a chronic encephalopathy

associated with confusion, disorientation, and clouding of consciousness. Headache is common, and strokes and cranial neuropathies

may occur. Brain imaging studies may be normal or nonspecifically

abnormal. CSF analysis reveals a mild pleocytosis or protein elevation.

Cerebral angiography can show multifocal stenoses involving mediumcaliber vessels, but some patients have only small-vessel disease that

is not revealed on angiography. The angiographic appearance is not

specific and may be mimicked by atherosclerosis, infection, or other

causes of vascular disease. Brain or meningeal biopsy demonstrates

endothelial cell proliferation and mononuclear infiltrates within blood

vessel walls. The prognosis is often poor, although the disorder may

remit spontaneously. Some patients respond to glucocorticoids or

chemotherapy.

Chronic metal exposure represents a rare cause of dementia. The

key to diagnosis is to elicit a history of exposure at work or home.

Chronic lead poisoning from inadequately fire-glazed pottery has been

reported. Fatigue, depression, and confusion may be associated with

episodic abdominal pain and peripheral neuropathy. Gray lead lines

appear in the gums, usually accompanied by an anemia with basophilic

stippling of red blood cells. The clinical presentation can resemble that

of acute intermittent porphyria (Chap. 416), including elevated levels

of urine porphyrins as a result of the inhibition of δ-aminolevulinic

acid dehydrase. The treatment is chelation therapy with agents such as

ethylenediamine tetraacetic acid (EDTA). Chronic mercury poisoning

produces dementia, peripheral neuropathy, ataxia, and tremulousness

that may progress to a cerebellar intention tremor or choreoathetosis.

The confusion and memory loss of chronic arsenic intoxication is also

associated with nausea, weight loss, peripheral neuropathy, pigmentation and scaling of the skin, and transverse white lines of the fingernails

(Mees’ lines). Treatment is chelation therapy with dimercaprol (British

anti-Lewisite, BAL). Aluminum poisoning is rare but was documented

with the dialysis dementia syndrome, in which water used during renal

dialysis was contaminated with excessive amounts of aluminum. This

poisoning resulted in a progressive encephalopathy associated with

confusion, nonfluent aphasia, memory loss, agitation, and, later, lethargy and stupor. Speech arrest and myoclonic jerks were common and

associated with severe and generalized EEG changes. The condition has

been eliminated by the use of deionized water for dialysis.

Recurrent head trauma in professional athletes may lead to a

dementia previously referred to as “punch-drunk” syndrome or

dementia pugilistica but now known as chronic traumatic encephalopathy (CTE) to signify its relevance to contact sport athletes other

than boxers (Chap. 443). The symptoms can be progressive, beginning

late in an athlete’s career or, more often, after retirement. Early in the

course, a personality change occurs, associated with social instability,

explosive rage, and sometimes paranoia and delusions. Later, memory

loss progresses to full-blown dementia, often associated with parkinsonian signs and ataxia or intention tremor. At autopsy, the cerebral

cortex shows tau-immunoreactive NFTs that are more prominent than

amyloid plaques (which are usually diffuse or absent rather than neuritic). NFTs and tau-positive reactive astrocytes are often clustered in

the depths of cortical sulci and in a perivascular distribution. TDP-43

inclusions (Chap. 432) have also been reported, highlighting the overlap with the FTD spectrum. Loss of neurons in the substantia nigra is a

variable feature, and some with TDP-43 inclusions also develop motor

neuron disease (MND) (Chap. 437).

Chronic subdural hematoma (Chap. 443) is also occasionally

associated with dementia, often in the context of underlying cortical

atrophy from conditions such as AD or HD.

Transient global amnesia (TGA) is characterized by the sudden onset

of a severe episodic memory deficit, usually occurring in persons aged

>50 years. Often the amnesia occurs in the setting of an emotional

stimulus or physical exertion. During the attack, the individual is alert

and communicative, general cognition seems intact, and there are no

other neurologic signs or symptoms. The patient may seem confused

and repeatedly ask about his or her location in place and time. The

ability to form new memories returns after a period of hours, and

the individual returns to normal with no recall for the period of the

attack. Frequently no cause is determined, but cerebrovascular disease,

epilepsy (7% in one study), migraine, or cardiac arrhythmias have all

been implicated. Approximately one-quarter of patients experience

recurrent attacks. Rare instances of permanent memory loss have been

reported in patients with TGA-like spells, usually representing ischemic infarction of the hippocampus or dorsomedial thalamic nucleus

bilaterally. Seizure activity due to AD should always be suspected in

this syndrome.

The ALS/parkinsonian/dementia complex of Guam is a rare degenerative disease that has occurred in the Chamorro natives on the island

of Guam. Individuals may have any combination of parkinsonian features, dementia, and MND. The most characteristic pathologic features

are the presence of NFTs in degenerating neurons of the cortex and

substantia nigra and loss of motor neurons in the spinal cord, although

recent reanalysis has shown that some patients with this illness also

show coexisting TDP-43 pathology. Epidemiologic evidence supports

a possible environmental cause, such as exposure to a neurotoxin or

an infectious agent with a long latency period. One interesting but

unproven candidate neurotoxin is the seed of the false palm tree, which

Guamanians traditionally used to make flour. The amyotrophic lateral

sclerosis (ALS) syndrome is no longer present in Guam, but a dementing illness with rigidity continues to be seen.

Rarely, adult-onset leukodystrophies, lysosomal-storage diseases,

and other genetic disorders can present as a dementia in middle to late

life. Metachromatic leukodystrophy (MLD) causes a progressive psychiatric or dementia syndrome associated with an extensive, confluent

frontal white matter abnormality. MLD is diagnosed by measuring

reduced arylsulfatase A enzyme activity in peripheral white blood

cells. Adult-onset presentations of adrenoleukodystrophy have been

reported in female carriers, and these patients often feature spinal

cord and posterior white matter involvement. Adrenoleukodystrophy

is diagnosed by demonstrating increased levels of plasma very-longchain fatty acids. CADASIL is another genetic syndrome associated

with white matter disease, often frontally and temporally predominant.

Diagnosis is made with skin biopsy, which shows osmophilic granules

in arterioles, or increasingly through genetic testing for mutations

in Notch 3. The neuronal ceroid lipofuscinoses are a genetically

3378 PART 13 Neurologic Disorders

Frontotemporal dementia (FTD) refers to a group of clinical syndromes

united by their links to underlying frontotemporal lobar degeneration

(FTLD) pathology. FTD, like the other major neurodegenerative diseases, is considered a disease of abnormal protein aggregation, with

either tau or transactive response DNA-binding protein of 43 kDa

(TDP-43) implicated in most cases. FTD most often begins in the fifth

to seventh decades of life and is nearly as prevalent as Alzheimer’s

disease (AD) in this age group. Early studies suggested that FTD may

be more common in men than women; however, more recent reports

cast doubt on this finding. Although a family history of dementia is

common, autosomal dominant inheritance is seen in only 10–20% of

all FTD cases.

■ CLINICAL MANIFESTATIONS

Familial and sporadic forms of FTLD present with remarkable clinical

heterogeneity. Three core clinical syndromes have been described

(Fig. 432-1). In the behavioral variant (bvFTD), the most common

FTD syndrome, social and emotional dysfunction manifests as apathy,

disinhibition, compulsivity, loss of empathy, and overeating, often but

not always accompanied by deficits in executive control. Two forms

of primary progressive aphasia (PPA), the semantic and nonfluent/

agrammatic variants, are commonly due to FTLD and are included

under the FTD umbrella. In the semantic variant, patients slowly lose

the ability to decode word, object, person-specific, and emotion meaning, whereas patients with the nonfluent/agrammatic variant develop

profound inability to produce words, often with prominent motor

speech impairment. Any of these three clinical syndromes, but most

often bvFTD, may be accompanied by motor neuron disease (MND)

(Chap. 437), in which case the term FTD-MND is applied. In addition, the corticobasal syndrome (CBS) and progressive supranuclear

palsy–Richardson syndrome (PSP-RS) can be considered part of the

FTLD clinical spectrum. Furthermore, patients may evolve from any

of the major syndromes described above to have prominent features of

another syndrome.

Findings at the bedside are dictated by the anatomic localization

of the disorder. Degeneration with atrophy occurs in the medial and

orbital frontal and anterior insula in bvFTD; the anterior temporal

region in semantic variant PPA; and the lateral frontal and precentral

gyrus of the dominant hemisphere in nonfluent/agrammatic PPA.

Typically, parietal functions such as visuospatial processing and arithmetic calculations are unaffected even late in the FTD syndromes.

Many patients with nonfluent aphasia or bvFTD later develop aspects

of PSP-RS as disease spreads into subcortical or brainstem structures, or CBS-like features appear as disease moves into perirolandic

cortices.

432 Frontotemporal Dementia

William W. Seeley, Bruce L. Miller

heterogeneous group of disorders associated with myoclonus, seizures,

vision loss, and progressive dementia. Diagnosis is made by finding

eosinophilic curvilinear inclusions within white blood cells or neuronal tissue.

Psychogenic amnesia for personally important memories can be

seen. Whether this results from deliberate avoidance of unpleasant

memories, outright malingering, or unconscious repression remains

unknown and probably depends on the patient. Event-specific amnesia

is more likely to occur after violent crimes such as homicide of a close

relative or friend or sexual abuse. It may develop in association with

severe drug or alcohol intoxication and sometimes with schizophrenia.

More prolonged psychogenic amnesia occurs in fugue states that also

commonly follow severe emotional stress. The patient with a fugue

state suffers from a sudden loss of personal identity and may be found

wandering far from home. In contrast to neurologic amnesia, fugue

states are associated with amnesia for personal identity and events closely

associated with the personal past. At the same time, memory for other

recent events and the ability to learn and use new information are preserved. The episodes usually last hours or days and occasionally weeks

or months while the patient takes on a new identity. On recovery, there

is a residual amnesia gap for the period of the fugue. Very rarely does

selective loss of autobiographic information reflect a focal injury to the

brain areas involved with these functions.

Psychiatric diseases may mimic dementia. Severely depressed or

anxious individuals may appear demented, a phenomenon sometimes

called pseudodementia. Memory and language are usually intact when

carefully tested, and a significant memory disturbance usually suggests

an underlying dementia, even if the patient is depressed. Patients in

this condition may feel confused and unable to accomplish routine

tasks. Vegetative symptoms, such as insomnia, lack of energy, poor

appetite, and concern with bowel function, are common. Onset is

often more abrupt, and the psychosocial milieu may suggest prominent reasons for depression. Such patients respond to treatment of the

underlying psychiatric illness. Schizophrenia is usually not difficult

to distinguish from dementia, but occasionally the distinction can be

problematic. Schizophrenia generally has a much earlier age of onset

(second and third decades of life) than most dementing illnesses and

is associated with intact memory. The delusions and hallucinations

of schizophrenia are usually more complex, bizarre, and threatening

than those of dementia. Some chronic schizophrenics develop an

unexplained progressive dementia late in life that is not related to AD.

Conversely, FTD, HD, vascular dementia, DLB, AD, or leukoencephalopathy can begin with schizophrenia-like features, leading to the

misdiagnosis of a psychiatric condition. Later age of onset, significant

deficits on cognitive testing, or the presence of abnormal neuroimaging suggest a degenerative condition. Memory loss may also be part of

a conversion disorder. In this situation, patients commonly complain

bitterly of memory loss, but careful cognitive testing either does not

confirm the deficits or demonstrates inconsistent or unusual patterns

of cognitive problems. The patient’s behavior and “wrong” answers to

questions often indicate that he or she understands the question and

knows the correct answer.

Clouding of cognition by chronic drug or medication use, often prescribed by physicians, is an important cause of dementia. Sedatives,

tranquilizers, and analgesics used to treat insomnia, pain, anxiety, or

agitation may cause confusion, memory loss, and lethargy, especially

in the elderly. Discontinuation of the offending medication often

improves mentation.

■ FURTHER READING

Andrews SJ et al: Interpretation of risk loci from genome-wide

association studies of ‘Alzheimer’s disease. Lancet Neurol 19:326,

2020.

Belloy ME et al: A quarter century of APOE and Alzheimer’s disease:

Progress to date and the path forward. Neuron 101:820, 2019.

Braak H, Del Tredici K: Where, when, and in what form does sporadic Alzheimer’s disease begin? Curr Opin Neurol 25:708, 2012.

Jack CR et al: NIA-AA Research Framework: Toward a biological

definition of Alzheimer’s disease. Alzheimers Dement 14:535, 2018.

Lesman-Segev OH et al: Diagnostic accuracy of amyloid versus 18F-Fluorodeoxyglucose positron emission tomography in autopsyconfirmed dementia. Ann Neurol 89:389, 2021.

Long JM, Holtzman DM: Alzheimer disease: An update on pathobiology and treatment strategies. Cell 179:312, 2019.

Rabinovici GD et al: Association of amyloid positron emission

tomography with subsequent change in clinical management among

Medicare beneficiaries with mild cognitive impairment or dementia.

JAMA 321:1286, 2019.

Rabinovici GD: Late-onset Alzheimer Disease. Continuum 25:14,

2019.

Selkoe DJ, Hardy J: The amyloid hypothesis of Alzheimer’s disease at

25 years. EMBO Mol Med 8:595, 2016.