Introduction Late-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly 1 , and risk is partially driven by genetics 2 . Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS) 3–8 . To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci ( IQCK , ACE , ADAM10 , and ADAMTS1 ). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants ( P = 1.32 × 10 −7 ) indicating that additional rare variants remain to be identified.
Counts of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and neurofibrillary tangles (NFT) were made in the frontal and temporal cortex from patients with Pick's disease (PD). Lesions were stained histologically with hematoxylin and eosin (HE) and the Bielschowsky silver impregnation method and labeled immunohistochemically with antibodies raised to ubiquitin and tau. The greatest numbers of PB were revealed by immunohistochemistry. Counts of PB revealed by ubiquitin and tau were highly positively correlated which suggested that the two antibodies recognized virtually identical populations of PB. The greatest numbers of PC were revealed by HE followed by the anti‐ubiquitin antibody. However, the correlation between counts was poor, suggesting that HE and ubiquitin revealed different populations of PC. The greatest numbers of SP and NFT were revealed by the Bielschowsky method indicating the presence of Alzheimer‐type lesions not revealed by the immunohistochemistry. In addition, more NFT were revealed by the anti‐ubiquitin compared with the anti‐tau antibody. The data suggested that in PD: (i) the anti‐ubiquitin and anti‐tau antibodies were equally effective at labeling PB; (ii) both HE and anti‐ubiquitin should be used to quantitate PC; and (iii) the Bielschowsky method should be used to quantitate SP and NFT.
In vivo positron emission tomography (PET) using [C11]-labeled Pittsburgh Compound B ([C11]PiB) has previously been shown to detect amyloid-β (Aβ) in late-onset Alzheimer disease (LOAD) brain; however, the sensitivity of this technique for detecting β-amyloidosis in autosomal dominant Alzheimer disease (ADAD) has not been systematically investigated. To validate [C11]PiB PET as a useful biomarker of β-amyloidosis, we measured the cortical and regional standardized uptake value ratios (SUVRs) in 16 ADAD and 15 LOAD cases and compared them with histopathologic measures of β-amyloidosis in postmortem brain. The PiB-PET data were obtained between 40–70 min after bolus injection of ∼15 mCi of [11C]PiB. MRI and PiB-PET images were co-registered and SUVRs were generated for several brain regions. Using Aβ immunohistochemistry (10D5, Eli Lilly), the burden of Aβ plaques was quantified in 16 regions of interest using an area fraction fractionator probe (Stereo Investigator, MicroBrightfield, VT). There were regional variations in Aβ plaque burden with highest densities observed in the neocortical areas and the striatum. On spearman correlations, in vivo PiB-PET correlated with postmortem Aβ plaque burden in both LOAD and ADAD, with strongest correlations seen in neocortical areas. In summary, [C11]PiB-PET has utility as a biomarker in both ADAD and LOAD. LEARNING OBJECTIVES This presentation will enable the learner to: 1. Discuss how PET-PiB beta-amyloid imaging is used as a potential biomarker of Alzheimer disease (AD) 2. Correlate postmortem neuropathologic evidence of beta-amyloidosis with PET-PiB data, and learn that PET-PiB is a potentially useful tool to detect beta-amyloidosis in presymptomatic and symptomatic individuals
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