It looks like the mechanisms (or combination
that interact as the mechanism) that create Alzheimer's involve amyloid-beta
(part of plaques) and tau (the protein that forms tangles in the cells).
The tau protein serves a stabilizing function with respect to the internal
organization and structure of nerve cells. If the tau proteins gets out
of whack, they become threads that get twisted around one another into
"neurofibrillary tangles" and then fail to help stabilize the
cells. So, scientists study how the amyloid-beta is deposited as plaques
and how the modification and clumping of tau into tangles takes place.
There are enzymes that facilitate "cell suicide" or apoptosis
that have their effect by cutting proteins. These enzymes (caspases) seem
to cut the tau, and the amyloid may activate those enzymes. One could
argue that these events are the results of a mechanism such as oxidation
stress, and, according to a few scientists who go even further, postulate
that the plaques work to guard against that stress, maybe analogous to
scar tissue. More likely, there could be a kind of disease-accelerating
feedback loop with the beta amyloid affecting the mitochondria in a way
that increases the beta amyloid. The destruction taking place within the
brain cells affects the plaque in a way that increases the destruction.
The treatment efforts to reduce or counteract beta amyloid are further
along than those designed to directly reduce damage to tau proteins, and
the accumulation of amyloid-beta looks to be earlier in the chain of events
than the tau tangles.
Of course, that leaves the issue of what initiates the
causal chain resulting in Alzheimer's. Presumably, an adequate explanation
will account for the full range of disease-related changes (plaque deposition,
tangles, loss of cells and pattern of cell deaths, and changes in metabolism.
Considerable attention is being given to insulin.* RJ
Castellani (et al**) argue that oxidative stress precedes amyloid
deposits and the lesions targeted for treatment are "compensatory
phenomena... manifestations of cellular adaptation". The legitimate
attention being given to oxidative stress might be more widespread among
serious scientists if that factor wasn't so overly hyped in the nutriceutical
and supplements fields - the den of thieves, longevity fanatics, and weight-obsessed
Even when the set of actions that culminate in AD has
been clarified, a lot of trial and error (such as the first vaccine attempt)
will be necessary to devise an active treatment. The fundamental disease-causing
mechanism might be clarified backwards by treatment success using an agent
that is based upon one theory. Proof about the mechanism should speed
the process dramatically. However, there may be enough fundamental understanding
to luck out soon with an active prevention or damage-reversing agent.
In either of those cases, the demands for the earliest possible treatment
and for early mass screening will expand enormously.
The genetics issues are very complicated, since the rare
early-onset cases of Alzheimer's appear to have much more straight forward
single gene inheritance while the more frequent later-onset cases may
have 4 or more genes that increase the risk of Alzheimer's. Of course,
the genetics researchers believe that genetics is the only way to find
out how the disease occurs and, thus, the only way to develop a real cure.
No trial and error or backwards clarification here, just a long, long
Genetics Update, Philadelphia, July 2004:
Research was reported by Brenda Plassman, Ph.D., at Duke University about
rates of Alzheimer's in fraternal and identical twins. 20% by late 70s
in fraternals (genetic siblings) and 40% in identicals. THis indicates
a strong environmental component.
Earlier Formal research summaries, such as this one concerning
genetics, offer important research specifics:
Genetic Clues to Targets to Therapies for Alzheimer's Disease
"The Latest Links: Genes and Alzheimer's Disease."
National Institute on Aging
Neuroscience and Neuropsychology of Aging - November 10, 2001 San Diego,
Genetic epidemiologic studies have indicated that about 40 percent of
the population variance in risk for Alzheimer disease (AD) is attributable
to genetic factors. Molecular genetic studies focusing on pedigrees with
autosomal dominant inheritance have identified four genes that confer
susceptibility to AD: presenilin 1 (PS1), presenilin 2 (PS2), b-amyloid
precursor protein (bAPP), and apolipoprotein E (ApoE). Analysis of the
biochemical effects of these genes indicates that they all influence the
proteolytic processing of bAPP, causing overproduction and accumulation
of the neurotoxic derivative, amyloid b-peptide (Ab), while one effect
of ApoE e4 is to reduce the clearance of Ab. This commonality suggests
that accumulation of neurotoxic Ab is the central event in most forms
of inherited and noninherited AD. This accumulation then triggers
a series of downstream events, including the misprocessing and accumulation
of tau protein in neurofibrillary tangles (which is likely to be neurotoxic
itself and to aggravate the problem).
Consequently, three therapeutic targets can be envisioned:
One such strategy is to induce an immune response to Ab by active or
passive immunization. Early studies of two independent transgenic mouse
models of AD reveal that immunization against Ab does reduce the learning
deficit (Janus et al., Nature 408:979-982, 2000)
and the neuropathologic abnormalities. This suggests that vaccination
and other strategies directed at removing Ab might be effective, alone
or in combination, in blocking the disease process in humans.
* Rasgon N, Jarvik L. Insulin resistance, affective disorders,
and Alzheimer’s disease: review and hypothesis. J Gerontol A Biol Sci
Med Sci. 2004;59A:178–183.
Steen E, Terry BM, J Rivera E, Cannon JL, Neely TR, Tavares R, Xu XJ,
Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor
expression and signaling mechanisms in Alzheimer's disease - is this type
3 diabetes? J Alzheimer's Dis. 2005 Feb;7(1):63-80.
de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor
expression, signaling, and malfunction in the central nervous system:
Relevance to Alzheimer's disease. J Alzheimer's Dis. 2005 Feb;7(1):45-61.
** Neuropathology of Alzheimer disease: pathognomonic but not pathogenic.
Acta Neuropathol, 2006, 111(6):503-9.