New Research Points to Earlier Recognition of AD

June 26, 2015
Veronica Hackenthal, MD

Research into AD pathogenesis and identification of early biomarkers could contribute to the development of new treatments. We present several recent findings.

No current treatments are available to delay or prevent the onset of Alzheimer disease (AD); however, early AD pathology might show up on PET and MRI four to 17 years before dementia begins.1 Research into AD pathogenesis and identification of early biomarkers could contribute to the development of new treatments. Early biomarkers could prove more cost-effective than imaging for detecting early AD, and immunity, including immunosuppression, may play a critical role in AD pathogenesis.

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Twin Study Identifies Two Possible Serum Markers for Early AD  

♦ This is the largest twins study to date using high-throughput technology to look at heritability and blood protein markers of AD in asymptomatic subjects.

♦ Researchers measured the level of 1129 proteins in plasma samples from subjects in a national register of adult female twins in the UK (TwinsUK).

♦ They compared protein levels with regional brain volumes (n=34) and 10-year change in CANTAB-PAL scores (n=195) (CANTAB-PAL tests cognition and may be more sensitive for detecting early AD than the mini mental status exam). 

♦ Researchers also looked at replication of proteins linked to regional brain volumes in subjects in the AddNeuroMed cohort (n=254, includes females and males).

♦ MAPKAPK5 may be a biomarker for early AD

      • Plasma levels of MAPKAPK5 were linked to more total errors on 10-year change in CANTAB-PAL in both individuals and monozygotic twins (Q=0.0059).

      • Results suggested that the association between MAPKAPK5 and cognitive decline is independent of genetic and twin-shared environmental factors.

      • MAPKAPK5 has mostly been studied in rheumatoid arthritis and cancer, and has not been previously linked to AD.

♦ MAP2K4 may be a biomarker for early AD

      • Plasma levels of MAP2K4 were negatively linked to the volume of the entorhinal cortex, which is related to early AD pathology (Q<0.1).

      • MAP2K4 has also been linked to phosphorylation of tau and amyloid precursor protein, both of which are thought to increase AD pathology.

Source: Kiddle SJ, et al. Plasma protein biomarkers of Alzheimer's disease endophenotypes in asymptomatic older twins: early cognitive decline and regional brain volumes. Transl Psychiatry. 2015 Jun 16;5:e584.

Statistical Model More Accurately Predicts Conversion to AD

♦ Past studies have used stepwise regression to identify biomarkers that could predict conversion from mild cognitive impairment (MCI) to AD, but this can lead to data that does not generalize well and may not be biologically plausible.

♦ This study used penalized regression (which weighs the relative importance of each variable), to identify markers that could predict conversion of early AD.

♦ The study sample included 127 patients with late-stage MCI from the AD Neuroimaging Initiative (ADNI-2) with clinical followup between 3 and 31 months, separated into those who converted to AD after 18 months (n=39), and those who did not (n=88).

♦ Researchers looked at partial volume correction of amyloid-PET data using the AV45 isotope, glucose metabolism on FDG-PET, and volumetric MRI.

♦ Penalized regression using only 3 to 9 variables more accurately predicted conversion from MCI to AD than conventional stepwise regression using 12 and 27 variables (66% vs. 72%).

      • Factors highlighted by the stepwise regression model made little biological sense.

      • Factors highlighted by the penalized regression model appeared biologically plausible.

♦ Higher amyloid load on AV45-PET, smaller glucose metabolism on FDG-PET, and smaller gray matter volumes were linked to conversion to AD.

      • The most predictive factor was PET-visible amyloid deposition in various cortical regions.

♦ Penalized regression might predict conversion from MCI to AD better than conventional methods, which could help in the selection of biomarkers entering clinical care.

Sources: Teipel SG, et al. The relative importance of imaging markers for the prediction of Alzheimer's disease dementia in mild cognitive impairment-- beyond classical regression.  Neuroimag Clin.  In press 21 May 2015.

Chase A. Alzheimer disease: Penalized regression can predict conversion to AD. Nat Rev Neurol. Online publication. 2015 Jun 9.

Insights into the Pathogenesis of AD Could Lead to New Treatments

♦ This study presents a new hypothesis for AD pathophysiology and neuronal loss based on immunosuppression.

♦ The group of researchers developed a mouse model (CVN-AD) that showed the cardinal features of AD (amyloid deposition, hyperphosphorylated and aggregated tau, behavioral changes, and age-dependent hippocampal neuronal loss).

      • Other mouse models of AD do not show significant neuronal cell loss.

      • CVN-AD mice demonstrated lowered immune-mediated nitric oxide (iNOS), mimicking the action of human myeloid cells and the low levels of iNOS in humans with AD.

♦ Using CVN-AD mice, the group studied longitudinal changes in brain immunity linked to neuronal loss.

♦ The predominant view is that proinflammatory factors drive AD pathology, but this study linked local immunosuppression and nutrient deprivation to AD pathology in CVN-AD mice.

♦ Arginine deprivation could result in neurodegeneration.

      • Immunosuppressive CD11c+ microglia gathered at sites of beta amyloid accumulation and hippocampal neuronal cell death.

      • Extracellular arginase also accumulated in these regions, decreasing levels of total brain arginine.

♦ Pharmacologic inhibition of abnormal argininine catabolism reversed amyloid production, immunosuppression, and memory impairments in CVN-AD mice.

Source: Kan MJ, et al. Arginine deprivation and immune suppression in a mouse model of Alzheimer's disease. J Neurosci. 2015 Apr 15;35(15):5969-5982.

Take-home Points

♦ A twins study in the UK identified serum proteins MAP2K4 and MAPKAPK5 as potential biomarkers of early AD.

♦ A new statistical model called penalized regression might predict conversion from MCI to AD better than conventional methods, which could help in the selection of biomarkers entering clinical care.

♦ A new study in mice has linked local immunosuppression and arginine deprivation to AD pathology; pharmacologic inhibition of abnormal argininine catabolism reversed signs of AD in these mice.

References:

1. Villemagne VL, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol. 2013 Apr;12(4):357-367.