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.

Senile plaques formed by ␤-amyloid peptides (A␤) and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau , a microtubule-associated protein , are the hallmark lesions of Alzheimer's disease (AD) in addition to loss of neurons. While several transgenic (Tg) mouse models have recapitulated aspects of AD-like A␤ and tau pathologies , a spatiotemporal mapping paradigm for progressive NFT accumulation is urgently needed to stage disease progression in AD mouse models. Braak and co-workers developed an effective and widely used NFT staging paradigm for human AD brains. The creation of a Braak-like spatiotemporal staging scheme for tau pathology in mouse models would facilitate mechanistic studies of AD-like tau pathology. Such a scheme would also enhance the reproducibility of preclinical AD therapeutic studies. Thus , we developed a novel murine model of A␤ and tau pathologies and devised a spatiotemporal scheme to stage the emergence and accumulation of NFTs with advancing age. Notably, the development of NFTs followed a spatiotemporal Braak-like pattern similar to that observed in authentic AD. More significantly , the presence of A␤ accelerated NFT formation and enhanced tau amyloidosis; however , tau pathology did not have the same effect on A␤ pathology. This novel NFT staging scheme provides new insights into the mechanisms of tau pathobiology , and we speculate that this scheme will prove useful for other basic and translational studies of AD mouse models. Alzheimer's disease (AD) is characterized by a triad of neuropathological hallmarks including senile plaques, neurofibrillary tangles (NFTs), and neuron loss. Senile plaques are extracellular lesions composed of ␤-amyloid (A␤) peptides, whereas NFTs are composed mainly of hyperphosphorylated tau, a microtubule-associated protein. Previous reports using the six-stage NFT progression scheme developed by Braak and co-workers defined a spatiotemporal pattern of tangle accumulation which correlates more closely with the severity of dementia in AD patients than the burden of A␤ plaques. [1][2][3] Despite the fact that the burden of A␤ plaques correlates less well with the degree of dementia, the amyloid cascade hypothesis posits that A␤ influences NFT evolution, although other evidence suggests tangles precede plaque formation. 4 -6 Thus, the influence of plaques and tangles on each other remains controversial, and methodological limitations of postmortem studies of AD brains precludes unequivocal resolution of this controversy.Thus, to probe the interplay between plaques and tangles, several transgenic (Tg) mouse models with both plaque and tangle pathology have been described as reviewed elsewhere.7 For example, bigenic mouse models harboring both human mutant tau and APP transgenes display enhanced tau tangle formation when compared to their monogenic counterparts.

Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset (<65years) Alzheimer's disease (AD). We performed a screening for mutations in the coding regions of presenilins, as well as exons 16 and 17 of the APP gene in a total of 231 patients from the Iberian peninsular with a clinical diagnosis of early onset AD (mean age at onset of 52.9 years; range 31-64). We found three novel mutations in PSEN1, one novel mutation in PSEN2, and a novel mutation in the APP gene. Four previously described mutations in PSEN1 were also found. The same analysis was carried in 121 elderly healthy controls from the Iberian peninsular, and a set of 130 individuals NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript from seven African populations belonging to the Centre d'Etude du Polymorphisme Humain-Human Genome Diversity Panel (CEPH-HGDP), in order to determine the extent of normal variability in these genes. Interestingly, in the latter series, we found five new nonsynonymous changes in all three genes and a presenilin 2 variant (R62H) that has been previously related to AD. In some of these mutations, the pathologic consequence is uncertain and needs further investigation. To address this question we propose and use a systematic algorithm to classify the putative pathology of AD mutations.