New insights into the genetic etiology of Alzheimer's disease and related dementias.

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

New insights into the genetic etiology of Alzheimer's disease and related dementias

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

SELF-REPORTED MEMORY COMPLAINTS: A COMPARISON OF DEMENTED AND UNIMPAIRED OUTCOMES

Background: Subjective memory complaints are common in aged persons, indicating an increased, but incompletely understood, risk for dementia. Objective: To compare cognitive trajectories and autopsy results of individuals with subjective complaints after stratifying by whether a subsequent clinical dementia occurred. Design: Observational study. Setting: University of Kentucky cohort with yearly longitudinal assessments and eventual autopsies Participants: Among 516 patients who were cognitively intact and depression-free at enrollment, 296 declared a memory complaint during follow-up. Among those who came to autopsy, 118 died but never developed dementia, while 36 died following dementia diagnosis. Measurements: Cognitive domain trajectories were compared using linear mixed models adjusted for age, gender, years of education and APOE status. Neuropathological findings were compared cross-sectionally after adjustment for age at death. Results: While the groups had comparable cognitive test scores at enrollment and the time of the first declaration of a complaint, the group with subsequent dementia development had steeper slopes of decline in episodic memory and naming but not fluency or sequencing. Autopsies showed the dementia group had more severe Alzheimer pathology and a higher proportion of subjects with hippocampal sclerosis of aging and arteriolosclerosis, whereas the non-demented group had a higher proportion expressing primary age related tauopathy (PART). Conclusions: While memory complaints are common among the elderly, not all individuals progress to dementia. This study indicates that biomarkers are needed to predict whether a complaint will lead to dementia if this is used as enrollment criteria in future clinical trials.</jats:p

THE EFFECT OF VASCULAR NEUROPATHOLOGY ON LATE-LIFE COGNITION: RESULTS FROM THE SMART PROJECT

Background: Cerebral vascular pathology may contribute to cognitive decline experienced by some elderly near death. Given evidence for mixed neuropathologies in advanced age, preventing or reducing cerebrovascular burden in late life may be beneficial. Objective: To correlate measures of cerebral vascular pathology with cognitive trajectories. Setting: Observational study. Participants: A cohort of 2,274 individuals who came to autopsy at a mean age of 89.3 years and 82 percent of whom had at least two cognitive assessments within the last six years of life was compiled from six centers conducting longitudinal studies. Measurements: For each cognitive domain: immediate and delayed memory, language, and naming, three trajectories were examined: good, intermediate, and poor cognition. The probability of a participant belonging to each trajectory was associated with measures of cerebral vascular pathology after adjustment for demographics, APOE, and Alzheimer neuropathology. Results: A large proportion of the cohort (72-94%) experienced good or intermediate cognition in the four domains examined. The presence of arteriolosclerosis and the presence of lacunar infarcts doubled the odds of belonging to the poor cognitive trajectory for language when compared to the good trajectory. The presence of lacunar infarcts increased the odds of an intermediate or poor trajectory for immediate and delayed recall while the presence of large artery infarcts increased the odds of poor trajectories for all four cognitive domains examined. Microinfarcts and cerebral amyloid angiopathy had little effect on the trajectories. Conclusion: Indicators of cerebral vascular pathology act differently on late life cognition.</jats:p

New insights into the genetic etiology of Alzheimer&apos;s disease and related dementias

Characterization of the genetic landscape of Alzheimer&apos;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/&apos;proxy&apos; 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. © 2022. The Author(s)

New insights into the genetic etiology of Alzheimer’s disease and related dementias

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 ?4 allele

New insights into the genetic etiology of Alzheimer’s disease and related dementias

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. © 2022, The Author(s)