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.

Despite aging being by far the greatest risk factor for highly prevalent neurodegenerative disorders, the molecular underpinnings of age-related brain changes are still not well understood, particularly the transition from normal healthy brain aging to neuropathological aging. Aging is an extremely complex, multifactorial process involving the simultaneous interplay of several processes operating at many levels of the functional organization. The buildup of potentially toxic protein aggregates and their spreading through various brain regions has been identified as a major contributor to these pathologies. One of the most striking morphologic changes in neurons during normal aging is the accumulation of lipofuscin (LF) aggregates, as well as, neuromelanin pigments. LF is an autofluorescent lipopigment formed by lipids, metals and misfolded proteins, which is especially abundant in nerve cells, cardiac muscle cells and skin. Within the Central Nervous System (CNS), LF accumulates as aggregates, delineating a specific senescence pattern in both physiological and pathological states, altering neuronal cytoskeleton and cellular trafficking and metabolism, and being associated with neuronal loss, and glial proliferation and activation. Traditionally, the accumulation of LF in the CNS has been considered a secondary consequence of the aging process, being a mere bystander of the pathological buildup associated with different neurodegenerative disorders. Here, we discuss recent evidence suggesting the possibility that LF aggregates may have an active role in neurodegeneration. We argue that LF is a relevant effector of aging that represents a risk factor or driver for neurodegenerative disorders.

Emerging experimental evidence suggests that the spread of tau pathology in the brain in Tauopathies reflects the propagation of abnormal tau species along neuroanatomically connected brain areas. This propagation could occur through a “prion-like” mechanism involving transfer of abnormal tau seeds from a “donor cell” to a “recipient cell” and recruitment of normal tau in the latter to generate new tau seeds. This review critically appraises the evidence that the spread of tau pathology occurs via such a “prion-like” mechanism and proposes a number of recommendations for directing future research. Recommendations for definitions of frequently used terms in the tau field are presented in an attempt to clarify and standardize interpretation of research findings. Molecular and cellular factors affecting tau aggregation are briefly reviewed, as are potential contributions of physiological and pathological post-translational modifications of tau. Additionally, the experimental evidence for tau seeding and “prion-like” propagation of tau aggregation that has emerged from cellular assays and in vivo models is discussed. Propagation of tau pathology using “prion-like” mechanisms is expected to incorporate several steps including cellular uptake, templated seeding, secretion and intercellular transfer through synaptic and non-synaptic pathways. The experimental findings supporting each of these steps are reviewed. The clinical validity of these experimental findings is then debated by considering the supportive or contradictory findings from patient samples. Further, the role of physiological tau release in this scenario is examined because emerging data shows that tau is secreted but the physiological function (if any) of this secretion in the context of propagation of pathological tau seeds is unclear. Bona fide prions exhibit specific properties, including transmission from cell to cell, tissue to tissue and organism to organism. The propagation of tau pathology has so far not been shown to exhibit all of these steps and how this influences the debate of whether or not abnormal tau species can propagate in a “prion-like” manner is discussed. The exact nature of tau seeds responsible for propagation of tau pathology in human tauopathies remains controversial; it might be tightly linked to the existence of tau strains stably propagating peculiar patterns of neuropathological lesions, corresponding to the different patterns seen in human tauopathies. That this is a property shared by all seed-competent tau conformers is not yet firmly established. Further investigation is also required to clarify the relationship between propagation of tau aggregates and tau-induced toxicity. Genetic variants identified as risks factors for tauopathies might play a role in propagation of tau pathology, but many more studies are needed to document this. The contribution of selective vulnerability of neuronal populations, as an alternative to prion-like mechanisms to explain spreading of tau pathology needs to be clarified. Learning from the prion field will be helpful to enhance our understanding of propagation of tau pathology. Finally, development of better models is expected to answer some of these key questions and allow for the testing of propagation-centred therapies.

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.

This pilot, double-blind, placebo-controlled, randomized, escalating dose trial explored the safety and efficacy of tideglusib, an inhibitor of glycogen synthase kinase-3, in Alzheimer's disease (AD) patients. Thirty mild-moderate AD patients on chol