The failure of the first human Alzheimer’s disease (AD) vaccination trial
[ 1 ] was not noted in Taylor et al.'s review article.
The goal of the vaccine, made of synthetic amyloid peptide, was to reduce
the amyloid load in the brain of patients by means of the body’s immune
reaction to clear amyloid deposits. However, perhaps as a consequence of doing
this, it also caused major complications currently assigned to cerebral
inflammation in 15 of 360 AD patients who had been vaccinated [ 1
]. These side effects led to the halting of the trial.
Unfortunately, this failure was not totally unexpected, and knowing exactly
how it failed is one of the most important issues today. In our opinion,
failure was the result of an ignorance of amyloid beta normal physiological
function(s). In fact, we would venture that there is no direct evidence
on the pathogenic primacy or importance of amyloid beta in Alzheimer’s
disease.
There is accumulating evidence that amyloid beta is a functional and
essential component of brain metabolism. In this regard, amyloid beta is
a structural constituent of high density lipoproteins, modulates oxidative
mechanisms, and is involved in lipid metabolism and membrane dynamics as
a regulatory element [ 2, 3 ].
Therefore, it is notable that, despite rumors
to the contrary, there is no evidence that the accumulation, oligomerization
and aggregation of amyloid beta plays a causal role in the development
of the disease.
The failure of Alzheimer’s "immunotherapy" in our view should now encourage
research on physiologically relevant mechanisms of neural degeneration
and Alzheimer’s disease and related disorders [ 4 ],
and on the normal functional biochemistry of amyloid beta. Further, the
vaccination failure will hopefully withdraw the amyloid hypothesis (read
dogma) that has dominated the stage, thus delaying our understanding of
the disease and the development of efficacious therapeutics for the past
15 years.
Competing interests: none
References: 
1. Check E. Nerve inflammation
halts trial for Alzheimer's drug. Nature. 415, 462
(2002) [ PubMed
] [ AlzForum
Drug News ] [ AlzForum live discussion ]; Koudinov AR, Koudinova NV. Alzheimer’s anti-amyloid
vaccination and statins: two approaches, one dogma. The time for change"
BMJ Published online 20 March, 2002 [ Full
Text ].
2. Chochina SV, Avdulov NA,
Igbavboa U, Cleary JP, O'Hare EO, Wood WG. Amyloid beta-peptide(1-40) increases
neuronal membrane fluidity. Role of cholesterol and brain region. J
Lipid Res.42, 1292-1297 (2001) [ PubMed
] [ Full Text
]; Koudinov AR, Koudinova NV. Essential role for cholesterol in synaptic
plasticity and neuronal degeneration. FASEB J. 15, 1858-60 (2001), originally published online June 27, 2001, 10.1096/fj.00-0815fje
[ PubMed
] [ Full
Text ] [ Post-publication
account in Science ] [ Article
Preface ] [ Related
eLetters ].
3. Kontush A. Amyloid-beta:
an antioxidant that becomes a pro-oxidant and critically contributes to
Alzheimer's disease. Free Radic Biol Med. 31, 1120-1131 (2001)
[ PubMed
]; Bush A. Response: '...and C is for Clioquinol' -- the AbetaCs of Alzheimer's
disease. TINS. 25, 123-124 (2002) [ PubMed
].
4. Mesulam MM. Neuroplasticity
failure in Alzheimer's disease: bridging the gap between plaques and tangles.
Neuron.24,
521-529 (1999). [ PubMed
] [ Full Text
]; Smith MA, Drew KL, Nunomura A et al. Amyloid-beta, tau alterations
and mitochondrial dysfunction in Alzheimer disease: the chickens or the
eggs? Neurochem Int. 40, 527-31 (2002) [ PubMed
]
E-Letters: ![[Read E-Letter]](/icons/misc/sectionDOWN.gif){kind=icon}
