Reduced platelet amyloid precursor protein ratio (APP ratio) predicts conversion from mild cognitive impairment to Alzheimer’s disease

Abstract

Studies have shown that platelet APP ratio (representing the percentage of 120-130 kDa to 110 kDa isoforms of the amyloid precursor protein) is reduced in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). In the present study, we sought to determine if baseline APP ratio predicts the conversion from MCI to AD dementia after 4 years of longitudinal assessment. Fifty-five older adults with varying degrees of cognitive impairment (34 with MCI and 21 with AD) were assessed at baseline and after 4 years. MCI patients were re-classified according to the conversion status upon follow-up: 25 individuals retained the diagnostic status of MCI and were considered as stable cases (MCI-MCI); conversely, in nine cases the diagnosis of dementia due to AD was ascertained. The APP ratio (APPr) was determined by the Western blot method in samples of platelets collected at baseline. We found a significant reduction of APPr in MCI patients who converted to dementia upon follow-up. These individuals had baseline APPr values similar to those of demented AD patients. The overall accuracy of APPr to identify subjects with MCI who will progress to AD was 0.74 ± 0.10, p = 0.05. The cut-off of 1.12 yielded a sensitivity of 75 % and a specificity of 75 %. Platelet APPr may be a surrogate marker of the disease process in AD, with potential implications for the assessment of abnormalities in the APP metabolism in patients with and at risk for dementia. However, diagnostic accuracy was relatively low. Therefore, studies in larger samples are needed to determine whether APPr may warrant its use as a biomarker to support the early diagnosis of AD.

Platelets, a reliable source for peripheral Alzheimer’s disease biomarkers?

“…One of the studies could also distinguish AD from PD and stroke patients since these values equalled those of controls [158]. Still others correlated the reduced ratio with disease progression [160]. Thus, despite huge variation in the reported values, APP ratio is still the most reproducible and promising AD biomarker in platelets to date (Table 1).…”

Decreased Platelet APP Isoform Ratios in Autosomal Dominant Alzheimer’s Disease: Baseline Data from a DIAN Cohort Subset

“…Across all studies on APPr where AD patients have been compared against control individuals, some have observed a denser upper band (~120 KDa) [4, 11, 14, 26, 28] while others reported a denser lower band (~110 KDa) [5, 12, 13, 15, 27]. These differences may be due to different rates of platelet activation during blood collection and platelet extraction, for instance by the use of a tourniquet or different anticoagulants between laboratories [34].…”

“…Total protein of 20 μg in sample buffer was heated at 95°C for 10 min prior to loading on 4–12% Bis-Tris mini gels (NuPAGE ® ) which was followed by incubation with antibody 22C11 (1:20,000, Millipore ® ). 22C11 binds to amino acid residues 66–81 of APP and several previous APPr studies have also used 22C11 [4, 11, 12, 14]. Samples were tested in duplicates and to avoid day-to-day variations, each method was carried out for all samples simultaneously.…”

“…Several studies have shown significantly lower platelet APP isoform ratios (APPr; 120–130 KDa to 106–110 KDa) in sporadic AD cases compared to healthy controls [11–14]. Padovani and colleagues found an overall sensitivity of 88.2% and specificity of 89.4% with a cut off APPr score of 0.57 when AD (n=85) were compared to controls (n=95) [15].…”

“…However, two previous studies conducted on ADAD platelets did not find a significant difference in APPr between ADAD MC and NC [16, 17], which may have been due to the small sample size of both studies. The upper band at 120–130 KDa is thought to represent the mature form while the lower band at 106–110 KDa may represent the immature form of APP [13, 14]. Since mature APP is subjected to amyloidogenic enzymatic processing [18] and altered APP cleavage activity has been consistently reported in AD, we hypothesized that platelet APPr (120KDa:110Kda) are lower in mutation carriers (MC) compared to non-carriers (NC).…”