Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.

β-Amyloid (Aβ), a vasoactive protein, and elevated blood pressure (BP) levels are associated with Alzheimer disease (AD) and possibly vascular dementia. We investigated the joint association of midlife BP and Aβ peptide levels with the risk for late-life AD and vascular dementia. Subjects were 667 Japanese-American men (including 73 with a brain autopsy), from the prospective Honolulu Heart Program/Honolulu Asia Aging Study (1965–2000). Midlife BP was measured starting in 1971 in participants with a mean age of 58 years; Aβ was measured in specimens collected in 1980–1982, and assessment of dementia and autopsy collection started in 1991–1993. The outcome measures were prevalent (present in 1991–1993) and incident AD (n=53, including 38 with no contributing cardiovascular disease) and vascular dementia (n=24). Cerebral amyloid angiopathy, β-amyloid neuritic plaques, and neurofibrillary tangles were evaluated in postmortem tissue. The risk for AD significantly increased with lower levels of plasma Aβ (Aβ1-40 hazard ratio: 2.1 [95% CI: 1.4 to 3.1]; Aβ1-42 hazard ratio: 1.6 [95% CI: 1.1 to 2.3]). Evidence of interaction between diastolic BP and plasma Aβ (1-40 P _interaction <0.05; 1-42 P _interaction <0.07) levels indicated that the Aβ-related risk for AD was higher when BP was higher. Low plasma Aβ was associated with the presence of cerebral amyloid angiopathy ( P _trend <0.05) but not the other neuropathologies. Aβ plasma levels start decreasing ≥15 years before AD is diagnosed, and the association of Aβ to AD is modulated by midlife diastolic BP. Elevated BP may compromise vascular integrity leading to cerebral amyloid angiopathy and impaired Aβ clearance from the brain.

To determine long-term treatment (LTT) of neuromyelitis optica (NMO), we retrospectively reviewed therapies of 26 patients with NMO followed in five French neurological departments. To assess LTT efficacy, the probability of relapse free after LTT was analysed. Patients were divided into two groups according to the first treatment receiving interferon beta (IFN Group, seven patients) or immunosuppressants (IS Group, 19 patients). The probability of relapse was significantly lower in the IS Group (P = 0.0007). From our results, interferon beta is not recommended, and one of the best current therapeutic options for NMO appears to be immunosuppressants. Multiple Sclerosis 2007; 13: 256–259. http://msj.sagepub.com