Alzheimer's dementia is now endemic and on the increase,
afflicting at least 2 in 10 people over the age of 70 in the USA. From a US
perspective, Boyles wrote:
“The number of Americans with Alzheimer's disease will triple over the next 50
years unless new ways to prevent or treat the degenerative condition are found,
according to newly revised national figures. Thirteen million elderly people in
the U.S. are projected to have the disease in the year 2050, compared to about
4.5 million today. The larger-than-expected increase could easily overwhelm the
nation's health-care system within the next few decades. Alzheimer's Association
president Sheldon Goldberg suggested that the approaching epidemic represents
the health-care crisis of the century.” By 2010, the world cost of dementias was
US $604 billion. Alzheimer's Disease
International foresees an 85%
increase in cost by 2030, with an increasing cost in developing countries.
According to neurologist, Dennis Selkoe:"The loss of memory, judgment and emotional stability that Alzheimer's
disease inflicts on its victims occurs gradually and inexorably, usually leading
to death in a severely debilitated, immobile state between four and twelve years
after the apparent onset. Genes that confer susceptibility influence the
handling of amyloid precursor protein (APP) PS1, PS2, and APP mutations cause
overproduction and accumulation of the neurotoxic derivative, amyloid-peptide,
the main event in AD. APP accumulation triggers the accumulation of tau protein
in neurofibrillary tangles. “
Memory loss in Alzheimer’s disease has become a focus of
research activity. In Alzheimer's patients, an old region of the temporal lobe, the hippocampus, is progressively damaged. The hippocampus and related
medial temporal processors are essential to the processing of memory. A severely
impaired Alzheimer's patient will continue to live, however, and function as a
real-time processor enjoying eating and other routine activities but there is no
remaining sentient being capable of skillful tasks, meaningful connections,
proper sequencing and appropriate decisions. Alzheimer's disease probably
progresses over several years to one or two decades and the diagnosis is usually
made late in the disease.
Cognitive problems are
- Short-term memory loss as revealed by the: inability to repeat three
short words within a minute of hearing them.
- Problems doing simple arithmetic showing up as difficulty with
calculations, balancing checkbooks and making change.
- Repetition and perseveration: repeating the same stories and asking the
- Difficulty driving, especially getting lost on familiar routes.
- Poor judgment and inappropriate behavior.
- Interrupted sequencing and disorganization shows up as the inability to
complete familiar tasks without direction.
- Forgetting names of relatives, friends and neighbors.
- Inability to learn new information.
- Withdrawal from social and recreational events.
- Language impairment in Alzheimer's dementia begins with word-finding
difficulties and semantic confusions or substitutions, such as saying aunt
instead of sister; speech remains fluent and grammatically correct. With dementia progression, anomia is more evident with comprehension
difficulties, and loss of fluency.
Advanced dementia involves complete loss of meaningful communication replaced by
mutism, automatic repetition of words said by somebody else, and repetition of
meaningless words or phrases.
Johnson et al followed 444 volunteers aged 60 to 101 years;
134 progressed to dementia. They concluded that cognitive deficits that predate
the onset of obvious Alzheimer's disease can be detected by tests for global,
verbal, and working memory, executive function, and visuospatial abilities. Decline of cognitive function can be recognized 3 years before the
diagnosis of Alzheimer's disease by visuospatial tests that require coordination
of hand, eye, and visual representation; 2 years before by tests for global
memory, and 1 year before diagnosis by tests for verbal and working memory.
As dementia advances, patients lose the ability to
self-manage and eventually require custodial and nursing care. The disability is
less obvious if the aging person lives in an extended family since other family
members contribute the missing cognitive functions, supply custodial care and
will often minimize or deny the cognitive disability. In family groups,
emotional changes are more disruptive than cognitive decline. A couple or
solitary person living alone will become more disorganized, disoriented and will
eventually fail to sustain self-care. Episodes of confusion, sometimes with
hallucinations will draw attention to deteriorating brain function.
Often dementia is linked to dysphoria and angry outbursts
are common. I recall a retired English teacher in a group home who would dress
in a suit with his tie in disarray. Looking quite eccentric, he played solitaire
everyday in the dining area, arranging chaotic columns of cards in random order;
he hissed and hit the ladies if they dared to assist him.
The brains of Alzheimer's sufferers develop deposits of the
protein, beta amyloid. Amyloid precursor protein breaks down into A 1–42
peptides, which aggregate. Researchers proposed that injecting beta amyloid into
the blood would trigger an immune response that might remove the protein. Tests
in mice showed benefits of the amyloid “vaccination” Trials in human Alzheimer's
patients were halted in January 2002, when patients developed meningitis and
encephalitis – immune-mediated inflammatory responses that suggested that the
vaccinations excited a general attack on brain tissues. Jucker et al injected elderly mice with antibodies against amyloid. Five
months later, the mice had smaller deposits of the amyloid in their brains, but
they developed hemorrhages in cerebral blood vessels. The future prospects for an Alzheimer’s vaccine are dismal. A second
feature of AD is the the intracellular accumulation of hyperphosphorylated tau
protiens that form neurofibillary tangles.
The amyloid theory of causation alone is no longer tenable.
You might argue that the deposits of amyloid proteins, tau proteins and peptides
are late artifacts of a disease process that damages and kills neurons and that
removing the proteins in advanced disease will not incur any benefit. Kerrup
strongly stated the case against the amyloid hypothesis:" Alzheimer's disease
(AD) is a biologically complex neurodegenerative dementia. Nearly 20 years ago,
with the combination of observations from biochemistry, neuropathology and
genetics, a compelling hypothesis known as the amyloid cascade hypothesis was
formulated. The core of this hypothesis is that it is pathological accumulations
of amyloid-β, a peptide fragment of a membrane protein called amyloid precursor
protein, that act as the root cause of AD and initiate its pathogenesis. Yet,
with the passage of time, growing amounts of data have accumulated that are
inconsistent with the basically linear structure of this hypothesis. And while
there is fear in the field over the consequences of rejecting it outright,
clinging to an inaccurate disease model is the option we should fear most. This
Perspective explores the proposition that we are over-reliant on amyloid to
define and diagnose AD and that the time has come to face our fears and reject
the amyloid cascade hypothesis."
Schilling et al summarized the expanding scope of AD
research: "Recent advances in neurobiology and PET have helped redefine
Alzheimer's disease (AD) as a dynamic pathophysiological process, clinically
characterized by preclinical, mild cognitive impairment due to AD and dementia
stages. Though a majority of PET studies conducted within these populations have
to date focused on β-amyloid, various 'nonamyloid' radiopharmaceuticals exist
for evaluating neurodegeneration, neuroinflammation and perturbations in
neurotransmission across the spectrum of AD. Importantly, findings using such
tracers have been shown to correlate with various clinical, cognitive and
behavioral measures. In the context of a growing shift toward early diagnosis
and symptomatic and disease-modifying clinical trials, nonamyloid PET
radiotracers will prove of use, and, potentially, contribute to improved
therapeutic prospects for AD."
Dementia with Lewy bodies (DLB) is diagnosed by the
presence of Lewy bodies in neurons of the brainstem, diencephalon, basal ganglia
and neocortex. Lewy pathology results from protein misfolding and the
accumulation of alpha-synuclein in the cell cytoplasm. There are similarities with Alzheimer's disease and Parkinson’s disease
and there may be a common underlying disease process. In both DLB and AD,
reductions in acetylcholine and abnormalities in acetylcholine receptors are
found. Drugs to improve acetylcholine activity have been disappointing, but
patients with DLB may receive greater benefits from cholinergic therapy.
Patients with DLB who display parkinsonian signs have dopamine deficiencies
similar to patients with PD, although DLB patients may have no benefit from
levodopa treatment. They do have severe adverse reactions to dopamine-blocking
Vascular disease is the second commonest cause of dementia
after Alzheimer's disease. There are difficulties in classifying patients with
cognitive impairment since there are so many variables with arterial disease.
The neuropathology of Alzheimer's and vascular dementia overlap. Increasing
evidence suggests that many of the risk factors that lead to cerebrovascular
disease also increase the incidence of Alzheimer’s disease. For example, the
generation and clearance of beta amyloid in the brain are regulated by
cholesterol. Elevated cholesterol levels increase amyloid beta in cellular and
most animal models of AD. Drugs that inhibit cholesterol synthesis lower amyloid
in these animal models. A variant of the apolipoprotein E (APOE) gene is a
genetic risk factor for Alzheimer’s disease. One gene abnormality that is linked
to vascular disease is also found in AD patients, the ApoE epsilon 4 gene that
leads to deficiency of a protective protein, ApoE. Patients with a history of
severe head injury involving coma have a high risk of developing AD if they have
the ApoE epsilon 4 gene presumably because they lack the protection of ApoE.
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