PRIMEVIEW

ALZHEIMERS DISEASE
For the Primer, visit doi:10.1038/nrdp.2015.56

Alzheimers disease is a
neurodegenerative disorder
associated with extracellular
accumulation of amyloid- (A) in plaques
and aggregation of the microtubule
protein tau in neurons. The disease can
remain asymptomatic for years but
ultimately leads to cognitive impairment
and neuropsychiatric abnormalities.

Theclinical
duration of
Alzheimer's disease
averages around 810
years, but is preceded by
preclinical and prodromal
stages that can extend
over two decades

PATHOPHYSIOLOGY
Proteolytic cleavage of the amyloid
precursor protein (APP) by a complex
family of enzymes including the
presenilins (PS1and PS2) results in A

EPIDEMIOLOGY
Alzheimers disease has a high prevalence,
estimated at 1030% in the population
>65years of age. Sporadic Alzheimers disease
is the most common type (>95% of patients),is
characterized by a late onset (8090 years
of age) and is causedby a failure to clear A
peptide. A large number of genetic risk factors
have been identified, of which polymorphisms
in apolipoprotein E (APOE) show the strongest
association. A small proportion of patients
have inherited mutations in genes that affect
processing of A (APP, PS1 and PS2) and develop
the disease at a much younger age (~45years).

APP
A
oligomer

A is produced
throughout an
individuals lifetime;
impaired clearance
of A and/or
confirmational
changes are central
to the development
ofAlzheimer's disease

A brils
plaque

Fibrillar tau

OUTLOOK
Interrupting the accumulation of
A and tau aggregates, synaptic
dysfunction and neuronal loss
(primary prevention) will ultimately
stop Alzheimer's disease from
developing, but would require
treatment from middle-age.

No current intervention can modify the underlying

disease. Management is focused on the treatment
of symptoms (such as cognitive decline and
neuropsychiatric abnormalities, including
agitation, psychosis,
depression,
Trials are ongoing to
apathy and sleep
test if administration of
disturbances) and
A-specific antibodies
co-morbidities.
during the preclinical
The support of
and prodromal phases
social networks
(secondary prevention)
surrounding the
can delay the onset of
patient also has a
clinical symptoms
crucial role.

QUALITY OF LIFE

DIAGNOSIS
The long preclinical and prodromal phases
of Alzheimers disease can make clinical
diagnosis difficult. Indeed, differentiating
dementia from other causes and common
co-morbidities (including cerebrovascular
disease and hippocampal sclerosis) is also a
challenge. Fortunately, several biomarkers have
been identified that could enable diagnosis
up to 20 years before clinical symptoms
develop. Diagnostic tests include A PET
imaging and biomarkers in the cerebrospinal
fluid (A fragments and levels of total and
phosphorylated tau).

MANAGMENT

Active immunization protocols

with different A fragments are
under investigation as alternative
prevention strategies. Drugs that
target APP processing and A
oligomer stabilization are under
investigation, as are nonspecific

Designed by Laura Marshall

protein aggregation inhibitors,

PPAR agonists, tyrosine kinase
inhibitors, serotonin receptor
antagonists and acetylcholine
receptor agonists. Better insight into
the pathophysiology might result in
options to target the tau pathway.

Quality of life (QOL) of patients

with Alzheimer's disease is
impaired, but is rated even
lower by their caregivers. The
presence of depression is an
important factor for the
patient, whereas functional
impairment, behavioural
disturbances and cognitive
impairment are determinants
of the caregiver's view of the
patient's QOL. The impact on
the QOL of caregivers should
not be underestimated and
is mainly confounded by
the patient's behavioural
disturbances (agitation
and depression) and
dependency, caregiver's
isolation, poor quality of
earlier relationship
with the patient and
lack ofresources.

Article number: 15059; doi:10.1038/nrdp.2015.59; published online 15 October 2015

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