At the request of JDFAF President Mike Minchin, I offer some
personal perspectives on AD ranging from established facts to conjectures
(many controversial). I proceed by answering twelve questions.
Q1. What
is AD? It is a
devastating, progressive loss of memory slowly leading to debility, loss of
functions and death (usually from pneumonia). It has been classically defined,
since 1906, by the presence in the brain at autopsy of extracellular,
insoluble clumps (plaques) and also by distorted neurofibrils (tangles) within
neurons. (On the basis of new knowledge, AD may soon be re-defined more
broadly, but the traditional plaques and tangles criteria still hold.) AD is
strongly age-associated: its prevalence in a population rarely becomes
noticeable before ages 30 – 50 and only about 10% of cases are diagnosed
before age 65 (these are the “early onset” variant). About 20% of the
US
population aged 75-84 years will have clinical manifestations of AD, and after
that the prevalence increases explosively. By ages 85 and older, about 40% of
people will show at least some signs of the disease. (There is no sex
difference in risk.)
Q2. What
are the kinds of normal memory?
Neuropsychological memory tests distinguish among at least six various types,
including learning (all learning is a memory). Of special importance is
spatial memory - Where am I? How did I get here? How do I get home? Some of
the structural bases of these types are known, as are their various neural
circuits. But, we don’t yet have a deep theory of memory and recall. In AD,
notable early losses are of immediate, short-term memory and spatial memory,
but eventually they all go.
Q3. How
accurate are memories? Memories
are not stored as accurate representations of experiences, dreams or thoughts.
In most cases what is recalled is a re-synthesis of scattered fragments of the
original event and the re-creation can be very inventive. Recalled memories
are stories, not to be trusted for accuracy or precision, except in some
special cases such as your signature, over-learned texts (e.g., memorized
poetry), and simple procedures like riding a bicycle.
Q4. Are
there any benefits of forgetting? There
are two aspects of processing memory – the acquisition phase and the recall
phase. Most memories fade with time. There have been reports of a few amazing
cases of people who have a brain dysfunction that doesn’t let them screen
and select inputs (experiences) so too many go into memories. Furthermore, the
memories don’t fade. In effect, these people are unable to forget. Their
conscious life is flooded with distracting trivia.
Q5. What’s
wrong with the AD brain? It
is shrunken, mainly because of loss of synapses (the communication junctions
between neurons) and to a lesser extent by death of neurons. Especially
damaged early in AD is a particular layer of neurons in the hippocampus. In
contrast, the inevitable forgetfulness of normal aging involves dysfunction of
a different region of the hippocampus. The
diminished brain of ordinary forgetful aging is not like that of AD and aging
does not inevitably lead to AD.
Q6. Are
there genetic causes of AD? The
early notion that there is a specific gene for AD has been simplistic and
discredited. So far only one gene
(ApoE4) seems to assure that if you have a double dose (from mother and
father) and live to be 90 years or older, you will be likely to suffer from
AD. Among many other genes (most in mutant forms) whose products have been
postulated to increase risk for AD, or even cause it, two have received most
attention. The protein product of one, APP,
leads to a small soluble molecule that is very toxic to neurons and could be a
direct cause of inter-neuronal (synaptic) communication failures.
The
other putatively causal gene product for AD is tau.
In AD it becomes modified producing the intracellular, dysfunctional
neurofibrillary tangles. The association of plaques with AD is not strong;
that of tangles has a greater influence.
Q7. What
are some possible non-genetic risks for AD? Suggestions are many, including repeated head trauma,
untreated high blood pressure, high fat diets, obesity, elevated cholesterol,
smoking, history of clinical depression, mild cognitive impairment (MCI), lack
of exercise, repeated exposures to general anesthesia , inflammation,
aluminum......
Q8. Are
there any memory-enhancing drugs that actually work in normal people (as well
as in AD patients) that are truly effective and safe? No!
The search for such agents is like that for the Holy Grail of neuropsychology.
Many new drug candidates have been tested, and even patented, but none meet
the desired criteria. Members of
the amphetamine class demonstrably do improve mental performance and
alertness, and so does caffeine. But the amphetamines carry two great
penalties: addiction, and over time, brain damage. The list of scientifically
untested “herbal” memory drugs is long, and includes some substances that
poison livers and kidneys.
Q9.
How is AD diagnosed? If the brain of a suspected AD patient is
available at autopsy, it is easy to examine it for plaques and tangles. Of
course, the hope today is to make the diagnosis in a living person. There are
two chief means currently available to do so:
Brain imaging (there are six
different methods in use but they are not yet well standardized from clinic to
clinic. All imaging is backed up with computer algorithms to provide
interpretation or special views).
Neuropsychological tests.
These have become fairly standardized, and can be sensitive detectors of
dementia, even in early stages. They currently do a better job than the more
expensive imaging methods, but they are very labor-intensive. (There are about
seven types of dementias, not always easy to distinguish. About 70% of cases
are AD.)
The
search for a blood test for AD has made recent progress, yet to be validated.
Q10. Are there
effective treatments for AD? There is no cure. The few drugs approved for treatment of AD
patients are only weakly effective and do not significantly slow the progress
of the disease. However, as our understanding of the underlying
biochemical-cellular brain pathologies increases, new targets for drug
interventions suggest themselves. Currently there many new drugs under
development or testing. “Exercising” the brain with puzzles and memory
games has yet to prove sufficiently effective to justify widespread
endorsement and uses. Music has a place in therapy for AD, and can be calming
for agitated patients.
Q11. Can AD be prevented? In
the absence of proven specific causes for AD, clues for prevention have to be
obtained from epidemiological studies. These are difficult to design, conduct
and control for stray variables. They need to be large. Even then they do not
provide a basis for strong inferences – all we get is hints. Below, in no
particular order, are some hints, viz., to prevent AD you might be well
advised to:
·
Avoid head
injuries. Wear seat belts, and helmets when skiing, horseback riding, cycling,
etc. (The bad effects of multiple concussions are cumulative.)
·
Be fit and
lean. (Ideally exercise at levels that add about 2000 kilocalories energy
expenditure per week. There are exercise-energy tables that help you translate
this criterion into sample fitness programs. This is a very demanding
prescription, and lesser exercise loads are likely to be of some benefit.)
·
Avoid smoking
and secondary smoke.
·
Bias your diet
toward fish, green leafy and cruciferous vegetables, blueberries, whole
grains, low fat content, and fruits. (Fruits seem to count for less benefit
than the vegetables.) Notice that this dietary advice is exactly the same as
we advise to avoid cardiovascular diseases.
·
Avoid aluminum
loaded foods. Most of our exposure from foods probably comes from baking
powders. Most deodorants are aluminum based.
·
Exercise your
brain with novel tasks: games, travel, wide reading- including subjects and
authors you disagree with.
·
Interact
frequently with friends. (Surprisingly, family interactions count for less
benefit!)
Q12. How
about dietary supplements for benefits in AD? There have been hopes for anti-oxidants such as vitamins E
and C and also for ibuprofen and other anti-inflammatory drugs, but they have
all failed in proper clinical trials. There is perhaps a better case for the
fish oils (EPA and DHA). Curcumin is endorsed by some studies, as are alpha-lipoic
acid and resveratrol (in red wine, but you can’t drink enough in one sitting
to get the benefit) and many others. Caveat: purified nutrient supplements seem to be less potent than
the same substances taken in foods.
________________________________________________________________________
One can see from the
above discussion that those in the Alzheimer’s research field are not very
far along in preventing or ameliorating Alzheimer’s dementia, thereby
relieving dedicated care-givers (usually family members who serve the
afflicted) of their terrible economic and emotional burdens.
The JDFAF is
well-positioned through its loyal stable of inventive and talented scientists,
its efficient use of funds, its non-bureaucratic flexibility and willingness
to seek and promptly fund some high risk – high gain proposals, to make
discoveries necessary to move the field of AD research to higher ground. We
already have personally recruited to AD research, and supported, many
promising young scientists. But, given the disappointing current situation the
need is great for fresh ideas and talent in AD research, and JDFAF has the
determination, experience and imagination to make optimal use of new resources
as they may become available to us.
