Biomarkers and the Diagnosis of Alzheimer's Disease
Abstract & Commentary
By Michael Lin, MD, PhD. Assistant Professor of Neurology and Neurosciences, Weill Cornell Medical College. Dr. Lin reports no financial relationships relevant to this field of study. This article originally appeared in the October 2012 issue of Neurology Alert.
Synopsis: Biomarkers in the cerebrospinal fluid open the possibility of diagnosing early or even presymptomatic cases of Alzheimer's disease, thereby expanding the potential window for therapy.
Sources: Bateman RJ, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 2012;367:795-804. Blennow K, et al. Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol 2012;69:1002-1010. Roh JH, et al. Disruption of the sleep-wake cycle and diurnal fluctuation of beta-amyloid in mice with Alzheimer's disease pathology. Sci Transl Med 2012;4: 150ra122.
Revised guidelines for the diagnosis of alzheimer's disease (AD), published last year by the National Institute on Aging and the Alzheimer's Association, place new emphasis on laboratory and imaging biomarkers.1,2,3 Use of such biomarkers could allow earlier diagnosis, when symptoms are not yet severe enough to meet clinical criteria for AD,2 or possibly even before symptoms arise.3 There is gathering consensus that earlier diagnosis may be critical for successful intervention, as damage already may be severe by the time symptoms appear. Three recent papers highlight this new emphasis on biomarkers.
Bateman and colleagues investigated the timing of various biomarker and clinical changes in patients with autosomal dominant familial AD. Patients with a dominantly inherited AD mutation develop AD with 100% penetrance, and the age of onset is typically consistent between generations. The investigators analyzed baseline biomarker and clinical data from 128 members of dominantly inherited AD pedigrees (88 carriers, 40 noncarriers), and they estimated the time from expected symptom onset based on the parent's age at symptom onset. A characteristic sequence of pathologic changes was found: 1) Cerbrospinal fluid (CSF) Aß42 levels declined as early as 25 years before expected symptom onset; 2) Parenchymal Aß deposition, assessed by PET imaging with Pittsburgh compound B (PiB), was detected 15 years before expected symptom onset. Increased CSF tau levels and hippocampal atrophy were also detected at this time; 3) Glucose hypometabolism and impairment on neuropsychologic memory testing were observed 10 years before expected symptom onset; 4) Decline on Mini-Mental State Exam was detected 5 years before expected symptom onset; 5) Diagnostic criteria for dementia were met 3 years after expected symptom onset. These results support the hypothesis of a characteristic pathophysiologic cascade beginning with changes in Aß, and potentially could form the basis of entry criteria for new trials.
Roh and colleagues investigated the relationship between Aß biomarkers and sleep. The authors had previously shown that synaptic activity induces secretion of Aß, and that Aß levels in brain interstitial fluid (ISF) fluctuate with the sleep/wake cycle. In the current work, they showed that in transgenic mice overexpressing mutant APP and presenilin 1, brain accumulation of Aß with aging is associated with both loss of the diurnal fluctuation in ISF Aß as well as impairment in sleep/wake cycling. Importantly, both the diurnal ISF Aß fluctuations and sleep/wake cycling remained normal if Aß accumulation was prevented by immunizing the mice against Aß. In normal human subjects, they found a similar diurnal fluctuation in CSF Aß concentrations, which was still present in patients who had dominantly inherited AD mutations but no parenchymal Aß deposits (assessed by PET imaging with PiB). In contrast, patients with dominantly inherited AD mutations and parenchymal Aß deposits (assessed by PET imaging with PiB) had loss of the normal diurnal CSF Aß fluctuations. These results suggest that brain Aß accumulation affects both sleep and normal diurnal Aß metabolism, and could be improved by preventing such accumulation. These findings could potentially be highly relevant, given the frequency of sleep disturbance with both aging and AD.
Blennow and colleagues used CSF biomarkers (Aß, phosphotau, and total tau) to monitor response to therapy in two Phase 2, multicenter, randomized, placebo-controlled trials of bapineuzumab, a monoclonal antibody against Aß. Forty-six subjects with mild-to-moderate AD (27 on bapineuzumab, 19 on placebo) were examined over 1 year. Interestingly, there were no clear cut changes in CSF Aß levels compared to baseline. However, CSF phosphotau levels decreased significantly compared to baseline in the bapineuzumab group (-9.9 pg/mL, P = 0.001), and this change was significantly larger than that seen in the placebo group (P = 0.03). CSF total tau levels also decreased significantly compared to baseline in the bapineuzumab group (-72.3 pg/mL, P = 0.03), though the difference between this change and that seen in the placebo group was not quite significant (P = 0.09). Given previous evidence that tau pathology likely follows Aß changes, these results suggest that Aß-directed immunotherapy can have effects "downstream" in disease pathogenesis. Unfortunately, the Phase 3 trials of bapineuzumab failed to show benefit in any of the primary clinical endpoints.4
Commentary
Further work is necessary. For example, the study of Bateman and colleagues on the sequence and timing of biomarker changes was cross-sectional, and results need to be verified by longitudinal follow-up studies. Also, it remains to be seen whether dominantly inherited AD, which accounts for < 1% of cases, is an accurate model for "sporadic" AD. Another important question is what biomarkers, if any, can be used to monitor response to therapy and correlate well with clinical improvement. One interpretation of recent failures in AD therapeutic trials is that it is already too late to intervene by the time symptoms have appeared. If this is true, the only way to intervene pre-symptomatically will be by having reliable biomarkers for the disease. This will clearly be an active area in the immediate future.
References
1. McKhann GM, et al. Alzheimers Dement 2011;7:263-269.
2. Albert MS, et al. Alzheimers Dement 2011;7:270-279.
3. Sperling RA, et al. Alzheimers Dement 2011;7:280-292.
4. Pfizer Press Release. Pfizer announces co-primary clinical endpoints not met in second phase 3 bapineuzumab study of mild-to-moderate Alzheimer's disease patients who do not carry the Apoe4 genotype: Pfizer and Janssen Alzheimer Immunotherapy discontinue bapineuzumab IV phase 3 program. 6 Aug 2012. Available at: www.pfizer.com/news/press_releases/pfizer_press_release.jsp?guid=20120806006130en. Accessed September 12, 2012.
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