To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Previous studies using a word-naming task have suggested that in demented patients, semantic priming results only from automatic spreading activation and not from attention-dependent processes. If this is true, then on a lexical-decision task where attention-dependent processes are a major source of the semantic-priming effect, demented patients should show little or no priming. To test this prediction, three groups of 16 subjects (young and normal-old individuals and patients with Alzheimer's disease) were given a Word-Naming and a Lexical-Decision task. In both tasks, the amount of semantic priming (the difference in response time to a word preceded by a semantically unassociated vs. a semantically associated word) was determined. Demented patients showed significantly greater semantic priming than either normal group on both tasks. This result argues against the hypothesis that the semantic priming found in demented patients is due solely to automatic processes.

Risk factors for stroke cause ischemic changes in the cerebral white matter that may affect frontal lobe functions more than other brain functions. Therefore, stroke risk could specifically affect performance on behavioral indexes traditionally associated with frontal lobe function such as verbal fluency. The authors examined this hypothesis in 235 healthy older men (mean age = 66.41 years) who received concurrent medical and neuropsychological examinations twice at a 3-year interval. Relations between stroke risk and decline in verbal fluency, memory, and visuospatial performance were analyzed through regression, controlling for age and education. Age was associated with decline in all cognitive functions; stroke risk was associated with decline only on verbal fluency. The relation between stroke risk and fluency decline was 80% as large as that between age and fluency decline. These results suggest that stroke risk rivals the effects of aging on verbal fluency performance.

The authors examined the influence of age and hypertensive status (normotensive, controlled, untreated, or uncontrolled) on several cognitive tests via multiple regression in 357 nondemented, community-dwelling older men (mean age=67 years) whose hypertensive status was stable over 3 years and who had no medical comorbidities. Age was negatively associated with performance on all but 1 test. Age interacted with hypertensive status on verbal fluency and word list immediate recall; older uncontrolled hypertensives exhibited significantly larger age decrements on these tests compared with normotensives. These findings suggest that uncontrolled hypertension produces specific cognitive deficits beyond those attributable to age alone. These and previous findings illustrate that health conditions such as hypertension should be regularly considered in studies of "normal" cognitive aging.