This document discusses whether it is important to determine who will develop Alzheimer's disease. While past studies tried to predict who would develop Alzheimer's, the information had little clinical benefit when there were no effective treatments. New research using blood biomarkers has shown promise in identifying over 90% of cognitively normal individuals who will develop mild cognitive impairment or Alzheimer's within a few years. If pre-clinical individuals can be identified, disease-modifying treatments targeted to prevent irreversible pathological changes may prove useful by preventing manifestation of the disease.

1. Is It Important to Determine Who Will Develop
Alzheimer’s?
The statement in the neurological literature 20 years ago was,
“An accurate prediction of who will develop Alzheimer’s
disease (AD) will become relevant when early treatment is
available to arrest the progression of the disease”. [1] In that
era, countless longitudinal studies, such as The Bronx Aging
Study, administered cognitive tests and followed large cohorts
for decades in an effort to find predictive strategies. Interesting
information arose from these studies, but was of little clinical
benefit.
Knowing that you will suffer from a devastating disease in the
next 10 years, with no hope of effective treatment, only begins
the suffering prematurely unless you can take action.
It is postulated the reason most drug trials for AD yield such
limited results, is because the treatment is initiated after the
pathological fact with little chance of inhibiting the process.
Biomarkers for AD
Abnormal proteins, disease-manufactured by-products and
brain anatomical changes are clues to the pathological process
of preclinical AD and are critical to the development of disease-
modifying and preventative interventions.
There was early enthusiasm with serum ApoE 4 and other
markers, but were found to be reliable primarily in memory-
impaired adults. [2] The recently studied early disease AD
biomarkers available at this point include: cerebrospinal fluid
tau and amyloid-β levels, structural and functional magnetic
resonance imaging and the brain amyloid imaging. These
studies are limited because they are invasive, time-consuming

2. or expensive. This restricts the wider use and epidemiological
benefit of a screening tool.
Recent Advances in Predictive AD testing
Subsequent research following the ApoE 4 marker has been
pursued on additional groups of lipidomic markers and has
proven rewarding.
In a recent study published in Nature Medicine, the
measurement of 10 blood-based lipid biomarkers has shown
promise.[3] This metabolic panel identified over 90% of
cognitively normal individuals who would phenoconvert to
mild cognitive impairment (pre-AD state) or AD within 2–3
years. Additional research with variations on this panel should
confirm, or even improve, these results.
Has the time come that AD prediction is now useful?
Maybe not yet, but we are preparing for that time. The focus is
on Disease Modifying Drugs that are designed to interfere with
the pathological etiology. Disease Modifying Drugs for AD are
in clinical trials and include agents that: reduces β amyloid
production, prevent Aβ aggregation, promote Aβ clearance, or
target tau phosphorylation and assembly. At this point the
Disease Modifying drugs have not demonstrated significant
efficacy in phase III studies, most likely because the drug
treatments are introduced to late in the neuronal cell
pathological process.
This brings us back to the previously discussed, inability to
identify pre-clinical AD patients. It is hypothesized that
initiation of Disease Modifying Drugs that are targeted to
prevent the irreversible onset of the pathological AD changes
in pre-clinical individuals, will prevent the manifestation of the
disease. Once cognitively normal, but AD “positive” individuals

3. can be identified, and then the initiation of Disease Modifying
Treatment can useful. Time will tell, but a similar a strategy
with Disease Modifying Drugs has proven useful in Multiple
Sclerosis.
References.
1. Tierney, M.C., et al., The prediction of Alzheimer disease. The role of patient
and informant perceptions of cognitive deficits. Arch Neurol, 1996. 53(5): p.
423-7.
2. Tierney, M.C., et al., A prospective study of the clinical utility of ApoE genotype
in the prediction of outcome in patients with memory impairment. Neurology,
1996. 46(1): p. 149-54.
3. Mapstone, M., et al., Plasma phospholipids identify antecedent memory
impairment in older adults. Nat Med, 2014. 20(4): p. 415-8.