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

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

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.