Alzheimer Disease

Alzheimer Disease
Senile dementia of the Alzheimer type (SDAT), or Alzheimer disease
(AD) is becoming more common in developed nations as the
population includes more and more older persons. There is no known
cause for the disease. It is often not known why some people present
as early as 30 or 40 years of age with dementia while others do not
present until their late 70's or 80's. At age 60 less than 1% of persons
have AD, but by age 85 a fourth to a third of persons have evidence for
AD. Thus, in aging populations, AD becomes more prevalent. Familial
cases with a defined inheritance pattern account for about 10% of
Alzheimer disease. Genetic defects in familial cases have been
identified on 4 chromosomes (Blennow et al, 2006):
Amyloid Precursor Protein (APP)
Apolipoprotein E (ApoE)
Presenilin 1 (PSEN1)
Presenilin 2 (PSEN2)
The so-called "early onset" cases of AD in persons in their 30's, 40's,
and 50's may have a genetic basis, linked to the APP, PSEN1, and
PSEN2 genes. AD cases linked to an APP genetic defect on
chromosome 21 may explain the appearance of Alzheimer disease in
persons with Down syndrome surviving to middle age. APP encodes
for amyloid precursor protein, resulting in fibrillar aggregates of betaamyloid that is toxic to neurons. About half of early onset AD cases are
linked to mutations in the presenilin 1 gene on chromosome 14. A
presenilin 2 gene has been discovered on chromosome 1, but this
defect accounts for less than 1% of cases. (Ertekin-Taner, 2007)
The more typical "late onset" cases of AD occurring after age 60 may
have underlying genetic defects. A genetic locus on chromosome 19
encodes for a cholesterol transporter called apolipoprotein E (apoE).
The E4 variant of apoE, which increases deposition of fibrillar betaamyloid, can be found in 40% of AD cases. However, the presence of
apoE4 is neither necessary nor sufficient for development of AD, so
testing for it is not warranted. Mutations in the tau gene which codes for
tau, a protein that is associated with microtubules, can be found in
some AD cases. The abnormal tau may account for helical filaments
found in neurofibrillary tangles. (Ertekin-Taner, 2007)
Regardless of the cause, the diagnosis of AD is made clinically by the
finding of progressive memory loss with increasing inability to
participate in activities of daily living. Late in the course of the disease,
affected persons are not able to recognize family members and may
not know who they are. The definitive diagnosis is made pathologically
by examination of the brain at autopsy. Grossly, there is cerebral
atrophy, mainly in frontal, temporal, and parietal regions. As a
consequence, there is ex vacuo ventricular dilation.
The confirmation of a diagnosis of AD is made at autopsy. The
pathognomonic microscopic feature of AD is an increased number of
neuritic plaques in the cerebral cortex. These neuritic plaques are
composed of tortuous neuritic processes surrounding a central amyloid
core. Reactive astrocytes and microglia may appear at the periphery of
these plaques. Though plaques may easily be found in the
hippocampus, their presence in increased numbers in neocortex is
necessary for a diagnosis of AD. The amyloid core consists primarily of
a small peptide known as Aß which is derived from the larger amyloid
precursor protein (APP). Plaques that have the amyloid proteins but
lack the neuritic processes are known as diffuse plaques, which do not
count toward the diagnosis of AD. Since the number of plaques
increases with age, the number needed for diagnosis of AD is agedependent. Other histologic features of AD include neurofibrillary
tangles, amyloid angiopathy, and granolovacuolar degeneration. (Mirra
et al, 1993) (Perl, 2000)
Biochemical evidence points to a loss of the choline acetyltransferase
and acetylcholine in the cerebral cortex of patients with Alzheimer
disease. Many treatment strategies are based upon reducing the loss
of acetylcholine. However, such medications appear to be able to
produce moderate symptomatic benefits but not to stop disease
progression. There is loss of higher brain functions with AD leading to
profound dementia. The course is usually over 5 to 7 years. The
immediate cause of death for most persons with Alzheimer disease is
pneumonia, typically an aspiration pneumonia. (Klafki et al, 2006