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0 50 100 Alzheimer Vascular Mixed Frontotemporal Multiple sclerosis Huntington Mitochondrial Lewy body Autoimmune Storage Prion Lupus Vasculitis Alcohol Parkinson Paraneoplastic CorticobasalPercent of patients with dementia
0 50 100 0 50 100 0 50 100
Young onset
(<45 years) Early onset(<65 years) (≥65 years)Late onset (wks - mos)Rapid
▲
▲Figure 5-3. Common causes of dementia based on age at presentation and rate of progression. “Mixed” refers to
combined Alzheimer disease and vascular dementia. Totals of <100% reflect absence of an etiologic diagnosis in some cases. (Data from: Kelley BJ, Boeve BF, Josephs KA. Young-onset dementia: demographic and etiologic characteristics of 235 patients. Arch Neurol. 2008;65:1502-1508. Garre-Olmo J, Genís Batlle D, del Mar Fernández M, et al. Incidence and subtypes of early-onset dementia in a geographically defined general population. Neurology. 2010;75:1249-1255. Geschwind MD, Shu H, Haman A, Sejvar JJ, Miller BL. Rapidly progressive dementia. Ann Neurol. 2008;64:97-108.)
Approximately 15% of patients referred for evaluation of possible dementia instead have other disorders (pseu- dodementias), such as depression. Depression in this set- ting is important to identify because it is readily treatable. Drug intoxication, often cited as a cause of dementia in the elderly, actually produces an acute confusional state, rather than dementia.
Kuruppu DK, Matthews BR. Young-onset dementia. Semin Neurol. 2013;33:365-385.
NeUrODeGeNeratIVe prOteINOpathIeS
In several neurodegenerative diseases, the production of
misfolded proteins and their association to form insoluble aggregates appears to play an important role in pathogene-
sis (Table 5-7). These abnormal proteins can arise from either genetic or acquired modifications, and their patho- logic effects may result from loss of normal protein function, gain of a toxic function, or a combination of these factors. Protein aggregation may be a mechanism for sequestering
proteins that the cell’s proteolytic machinery cannot process, but protein aggregates may also exert adverse effects on the cell, such as by interfering with axonal transport.
Except in rare inherited or infectious cases, the underly- ing cause of neurodegenerative proteinopathies is unknown. However, these diseases share several features. In addition to protein misfolding and aggregation, which sometimes pro- duces characteristic histopathologic findings (see Table 5-7), these diseases may be associated with cell-to-cell prionic
transmission (Figure 5-4), which allows them to spread
through the nervous system to produce characteristic ana- tomic patterns of involvement. Evidence for this mechanism includes the finding that fetal tissue grafted into the brains of patients with Parkinson disease develops the same abnormal protein aggregates found in the recipient’s brain.
ALZHEIMER DISEASE
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`Epidemiology
Alzheimer disease is the most common cause of dementia, accounting in whole or part for an estimated 60% to 70%
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of cases. Alzheimer disease affects approximately 15% of individuals of age 65 years or older and approximately 45% of those age 85 years or over. Its prevalence is >5 million cases in the United States and approximately 30 million
cases worldwide. Men and women are affected with equal frequency, when adjusted for age. However, because women live longer, they account for approximately two-thirds of Alzheimer patients.
Table 5-7. Neurodegenerative Proteinopathies.
protein Dementing Disease(s) transmission histopathologic Features
β-Amyloid (Aβ) Alzheimer disease Sporadic or inherited Amyloid plaques, neurofibrillary tangles
Tau Alzheimer disease Frontotemporal dementia Progressive supranuclear palsy Corticobasal degeneration
Sporadic or inherited Neurofibrillary tangles or amor- phous deposits (pretangles)
TDP-43 Frontotemporal dementia
Frontotemporal dementia with motor neuron disease
Sporadic or inherited TDP-43/ubiquitin-positive inclusions
Fused-in-sarcoma (FUS) Frontotemporal dementia Sporadic or inherited FUS-positive inclusions α-Synuclein Parkinson disease
Lewy body disease (Parkinson disease with dementia, dementia with Lewy bodies)
Sporadic or inherited Lewy bodies
Huntingtin (Htt) Huntington disease Inherited Polyglutamine inclusions Prion protein (PrP) Creutzfeldt-Jakob disease (CJD),
Gerstmann-Sträussler-Scheinker syn- drome (GSS), fatal familial insomnia, kuru
Sporadic, infectious, or inherited PrP-positive plaques (variant CJD, GSS) Passive release or exocytosis Unstable aggregate Misfolded protein Native protein states Passive uptake or endocytosis Stable aggregate Extracellular aggregate Direct transfer via nanotube Neuron 1 Neuron 2 ▲
▲Figure 5-4. Cell-to-cell (prionic) transmission of neurodegenerative proteinopathies. Abnormal proteins associ-
ated with neurodegenerative disease may misfold, leading to the formation of protein aggregates; misfolded pro- teins, protein aggregates, or both may be toxic and contribute to neuronal dysfunction. In addition, toxic protein aggregates may be transferred between cells to propagate the disease.
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Table 5-8. Principal Genes Implicated in Alzheimer Disease.
Gene Gene Locus protein Genotype phenotype
APP 21q21.3–q22.05 Amyloid β A4 precursor
protein Various missense mutations Familial Alzheimer disease (autosomal dominant) PS1 14q24.3 Presenilin 1 (PS1) Various missense mutations Familial Alzheimer disease (autosomal
dominant) with early onset (age 35-55) PS2 1q31–q42 Presenilin 2 (PS2) Various missense mutations Familial Alzheimer disease (autosomal
dominant) in Volga Germans APOE 19q13.2 Apolipoprotein E APOE4 polymorphism Increased susceptibility to Alzheimer
disease Multiple 21 Unknown Trisomy 21 or chromosome 21–14
or 21–21 translocation Down syndrome (early-onset Alzheimer disease)
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`Pathology
Alzheimer disease is defined by characteristic histopatho- logic features, especially neuritic (senile) plaques and neu- rofibrillary tangles. Neuritic plaques are extracellular deposits that contain β-amyloid (Aβ) and other proteins, including presenilin 1, presenilin 2, α1-antichymotrypsin, apolipoprotein E, α2-macroglobulin, and ubiquitin. Plaques may also be found in cerebral and meningeal blood-vessel walls, producing cerebral amyloid angiopathy. Neurofi-
brillary tangles are intracellular deposits containing hyper-
phosphorylated tau (a microtubule-associated protein) and ubiquitin.
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`Etiology
Alzheimer disease is a progressive, degenerative disorder that is caused by a genetic defect in rare cases (see later), but is usually sporadic and of unknown cause. Abnormal metabolism, deposition, or clearance of two proteins—Aβ and tau—appears to be closely linked to pathogenesis.
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`Pathogenesis
1. Genetics—In approximately 1% of patients, Alzheimer disease is a familial disorder that results from a mutation in one of three functionally related membrane proteins (Table 5-8): β-amyloid precursor protein (APP), pre-
senilin 1 (PS1), or presenilin 2 (PS2). Onset of the
disease in these patients is typically between the ages of 30 and 60 years. Patients with Down syndrome (trisomy
21) also develop early Alzheimer disease (mean onset at
age 50 years), which is thought to be related to an extra copy of the APP gene, located on chromosome 21. Although the cause of sporadic Alzheimer disease is unknown, the gene defects in familial Alzheimer disease provide clues, implicating both APP, a protein with neu- rotrophic properties, and the presenilins, which are involved in APP metabolism.
The risk of Alzheimer disease is also influenced by the inheritance pattern of apolipoprotein E (APOE) gene isoforms ε2, ε3, and ε4. Risk increases about three- fold with a single apolipoprotein Eε4 (APOE4) allele and about 12-fold with two copies of APOE4; each copy of APOE4 also lowers the age at onset by about 5 years. In contrast to APOE4, APOE2 appears to confer relative protection from Alzheimer disease. The mechanism through which APOE genotype modifies susceptibility to Alzheimer disease is unknown, but may involve binding of the APOE protein to Aβ.
2. Aβ and neuritic plaques—Aβ is the principal constitu- ent of neuritic plaques and is also deposited in cerebral and meningeal blood vessels in Alzheimer disease. Aβ is a 38- to 43-amino acid peptide produced by proteo- lytic cleavage of the transmembrane protein, APP (Figure 5-5). Normal processing of APP involves its cleavage by the enzyme α-secretase, which does not produce Aβ, and by β-secretase (BACE; β-site APP cleaving enzyme) and γ-secretase, yielding primarily a 40-amino acid fragment (Aβ40), which is secreted and cleared from the brain. In Alzheimer disease, a dispro- portionate amount of Aβ42, a longer form of the mol- ecule with an increased tendency to aggregate, is produced. Presenilins 1 and 2 contribute to γ-secretase activity.
Evidence for a causal role of Aβ in Alzheimer disease includes the involvement of APP mutations in some familial cases and the neurotoxicity of Aβ under some circumstances. However, there is a poor correlation between the extent of amyloid plaque deposition in the brain and the severity of dementia in Alzheimer dis- ease. One explanation for this disparity is that soluble Aβ oligomers, rather than insoluble plaques, may be the toxic agent. Another possibility is that Aβ aggregation produces Alzheimer disease indirectly, such as by pro- moting the formation of tau-containing neurofibrillary tangles.
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3. Tau and neurofibrillary tangles—Tau is a cytoplasmic protein that binds to tubulin and stabilizes microtu- bules, cytoskeletal structures that help maintain cell structure and facilitate intracellular transport. In Alzheimer disease and other tauopathies, tau becomes hyperphosphorylated and dissociates from microtu- bules; the microtubules disassemble and hyperphos- phorylated tau aggregates to form neurofibrillary
tangles (Figure 5-6). How this leads to impaired neuro- nal function is unknown, but may involve a defect in axonal transport. A causal role for tau pathology in Alzheimer disease is supported by the observations that the abundance of neurofibrillary tangles correlates well with disease severity and that other tauopathies (eg, frontotemporal dementia), in which Aβ processing is normal, can also produce dementia.
sAPPα C83 C99 AICD sAPPβ Aβ Aβ breakdown products Nontoxic Aβ oligomers Toxic Aβ oligomers NEP IDE ECE-1 APP γ β α ▲
▲Figure 5-5. Normal and pathologic (amyloidogenic) processing of APP and Aβ. APP, a membrane-spanning pro-
tein, is normally cleaved by α-secretase (α), or by β-secretase (β) and then γ-secretase (γ, a protein complex that includes presenilin 1 or 2, nicastrin, anterior pharynx defective 1 homolog [APH1], and presenilin enhancer 2 [PEN2]) to generate β-amyloid (Aβ), a secreted protein. APP mutations associated with familial Alzheimer disease shift Aβ production from a nontoxic 40-amino acid to a toxic (amyloidogenic) 42-amino acid form, which has a greater ten- dency to form amyloid deposits. Aβ normally undergoes enzymatic breakdown (by neprilysin [NEP], insulin-degrad- ing enzyme [IDE], or endothelin-converging enzyme [ECE-1]) and clearance from the brain. However, it can also aggregate to form oligomers of increasing size, which are thought to be neurotoxic. sAPP, soluble APP; C83 and C99, C-terminal fragments of APP; AICD, APP intracellular domain.
Tau Phospo-tau Hyperphospo-tau
Stable microtubule Unstable microtubule Dissociated microtubule Paired helical filaments Neurofibrillary tangles ▲
▲Figure 5-6. Tau hyperphosphorylation and neurofibrillary tangle formation.
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4. Synaptic dysfunction—Alzheimer disease is accompa- nied by early dysfunction and later loss of synapses, prominently affecting excitatory transmission in hip- pocampus and cerebral cortex. These changes may contribute to memory loss.
5. Neuronal loss and brain atrophy—Certain neuronal populations are preferentially lost in Alzheimer disease, including glutamatergic neurons in the entorhinal cor- tex and the CA1 sector of hippocampus, as well as cholinergic neurons in the basal forebrain. Focal brain atrophy is seen in the affected areas.
6. Vascular involvement—The extent to which vascular pathology may contribute to Alzheimer disease is controversial. Evidence for such a connection includes the overlap between risk factors for vascular disease and Alzheimer disease (including APOE genotype) and the involvement of blood vessels in amyloid pathology.