Page 851 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

important risk factor for AD; the incidence is about 3% in Neurodegenerative Diseases 837
persons 65 to 74 years old, 19% in those 75 to 84 years old, on chromosome 21, and the risk of AD also is higher in those
and 47% in those older than 84 years. Most cases of AD are with an extra copy of the APP gene, such as patients with
sporadic, but at least 5% to 10% are familial. Sporadic cases trisomy 21 (Down syndrome) and persons with small inter-
rarely present before 50 years of age, but early onset is seen stitial duplications of APP, presumably because this too leads
with some heritable forms. to greater Aβ generation. The other major genetic risk factor
is a variant of apolipoprotein E called ε4 (ApoE4). Each
PATHOGE NESIS ApoE4 allele that is present increases the risk of AD by
approximately 4 fold and also appears to lower the age of
Study of the familial forms of AD supports a model in which onset. How ApoE4 influences Aβ accumulation is unknown;
a peptide called beta amyloid, or Aβ, accumulates in the brain it may increase Aβ aggregation or deposition, or decrease
over time, initiating a chain of events that result in AD. Aβ is Aβ clearance.
created when the transmembrane protein amyloid precursor
protein (APP) is sequentially cleaved by the enzymes While large deposits of Aβ are a feature of end-stage AD,
β-amyloid converting enzyme (BACE) and γ-secretase (Fig. small aggregates of Aβ may also be pathogenic, as they alter
22–24). APP also can be cleaved by α-secretase and neurotransmission and are toxic to neurons and synaptic
γ-secretase, which liberates a different peptide that is non- endings. Large deposits, in the form of plaques, also lead to
pathogenic. Mutations in APP or in components of γ-secretase neuronal death, elicit a local inflammatory response that can
(presenilin-1 or presenilin-2) lead to familial AD by increasing result in further cell injury, and may cause altered region-to-
the rate at which Aβ is generated. The APP gene is located region communication through mechanical effects on axons
and dendrites.

The presence of Aβ also leads to hyperphosphorylation of
the neuronal microtubule binding protein tau. This increased

Cleavage β-Secretase Amyloid Soluble fragment
sites for: α-Secretase precursor β-Secretase
protein cleavage
Aβ peptide
Amyloidogenic γ-Secretase
cleavage
γ-Secretase Aβ Monomer

COOH COOH
Non-amyloidogenic
Aβ Oligomers
Soluble fragment
α-Secretase Kinase Synaptic Cell Other
cleavage activation dysfunction death pathways
γ-Secretase of injury
cleavage
Aβ Aggregates

NEURONAL DAMAGE

Tau Microtubule Amyloid fibrils
phosphorylation disassembly

COOH Tau PLAQUES and
aggregation TANGLES

Figure 22–24 Aβ peptide genesis and consequences in Alzheimer disease. Amyloid precursor protein cleavage by α-secretase and γ-secretase pro-
duces a harmless soluble peptide, whereas amyloid precursor protein cleavage by β-amyloid–converting enzyme (BACE) and γ-secretase releases Aβ
peptides, which form pathogenic aggregates and contribute to the characteristic plaques and tangles of Alzheimer disease.