Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.
J. Thomassen, H. Leonard, Brittany Ulms et al.· Nature Genetics· 0 citations
Background Idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) are neurodegenerative disorders with partly overlapping clinical features. Since the treatment is different, we need better knowledge about how the cognitive profile differs between these conditions. Objective We aimed to compare the cognitive profile of iNPH patients with that of a large cohort of confirmed AD patients. Methods Patients diagnosed with iNPH and accepted for shunt surgery were compared with patients with biomarker verified Alzheimer's disease in The Norwegian Register of Persons Assessed for Cognitive symptoms (NorCog). All patients underwent a standardized cognitive assessment with age and education adjusted z-scores. We used the Clinical Dementia Rating Scale (CDR) to adjust for disease severity. Since the cognitive score distributions were highly skewed, we used nonparametric analyses stratified by CDR stage combined with multinomial logistic regression. Results In total, 276 iNPH patients were compared to 1113 AD patients. iNPH patients performed significantly poorer on phonemic fluency [median z-score difference (AD—iNPH) 0.30, 95% confidence interval (CI) 0.20 to 0.50], but significantly better on other cognitive tests, in particular immediate (median difference −0.35, 95% CI −0.49 to −0.20) and delayed recall (median difference −0.46, 95% CI −0.59 to −0.34). The differences persisted after adjustment for CDR and were most pronounced in early stages of the disease. Conclusions iNPH seems to affect phonemic fluency more and memory less than AD. As the disease progresses, the cognitive profiles become more similar, and the conditions cannot be distinguished by cognitive tests.
Magnhild S. Dejgaard, P. K. Eide, G. Tangen et al.· Journal of Alzheimer's Disea...· 0 citations
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