Young-onset dementia: unanswered questions and unmet needs.

We think of dementia as an illness of the old. Regan described the senility of her father, King Lear, as “the infirmity of his age.”1However, dementia can affect younger ormiddleaged adults. Approximately 200000Americans younger than 65 years have dementia.2 Young-onset dementia (YOD) represents 4% to 10%of all dementia cases.2 By convention, YOD is defined as dementia occurring before age 65 years, although this age criterion is a sociological construct. Thediagnosis of YOD is challenging. Young-onset dementia constitutes a heterogeneous groupof disorders. The broad differential diagnosis includes metabolic, genetic, neurodegenerative, infectious, cerebrovascular, autoimmune, and inflammatorydisorders.AdultswithYODcommonlyundergoextensive testing.However,nocause is identified in roughly20% to40%of cases.3,4 Thesediagnostic challenges aremajor concerns for patients with YOD and their families.4 Because of remarkable scientific advances,wenowknow more about the basis of YOD. The identification of several genetic mutations has improved our understanding of the neurobiologic featuresandpathogenesisofYODand late-onsetdementia. We can now apply information from genetics, functionalbrain imaging, and neuropathology to the bedside and correlate these data with the neurologic signs, systemic manifestations, cognitive impairments, and behavioral abnormalities of patients with YOD. Still, there is much about YOD that we do not know. Despite these advances, we cannotpredictwhowill developYODformany individuals and families. ThearticlebyNordstromandcolleagues5providesnew insights about potential risk factors for YOD. The investigators determinedwhether risk factors in lateadolescence (meanage, 18 years) were associated with incident YOD among 488 000 men conscripted for mandatory military service from 1969 through 1979 in Sweden, a countrywithuniversal health care. Information fromstandardized cognitive andphysical examinations performed at the time of conscription was linked to longitudinal administrative data on hospital discharges, demographics,parentalhistoryofdementia,medicationuse, and deaths. The investigators validated the diagnosis of dementia in approximately 95% of cases in a subsample. In thatpopulation,487menwerediagnosedashavingYOD at a median age of 54 years. Median follow-up was 37 years. Three risk factors in late adolescence predicted incident YOD: low level of cognitive function, low height, and high systolic blood pressure. Six additional predictors included paternal dementia, and the occurrence of alcohol or other drug intoxication, stroke,useofantipsychotics, anddepressionduring follow-up. These 9 risk factors explained 68% of the populationattributable risk of YOD. Premorbid cognition and other risk factorsoperated independently to increase theriskofYOD.Men whohadthecombinationof lowbaselinecognitivefunctionand at least 2 risk factors were atmarkedly increased risk of developing YOD (hazard ratio, 20.37). The study has a novel finding. Independent of stroke, higher systolic blood pressure in late adolescence increased theriskof incidentYOD.Althoughstudieshaveestablishedthat highbloodpressure inmidlife is associatedwith late-onsetdementia, studies have not found consistently that high blood pressure in childhood or young adulthood is associated with cognitiveperformanceordementia inmidlife.The finding that high systolic blood pressure in late adolescence is associated with an increased risk of YOD, if confirmed, provides a potential target for intervention studies to prevent YOD and possibly late-onset dementia. Somepreviousdata are confirmedby this study. Lowcognitive performance is associated with late-onset dementia in older adults. Stroke, alcohol or other drug intoxication, and familyhistory of dementia predict YOD.Adolescentswith low heightmayhaveagreater riskofYODbecause their brainsmay be less developed.6 The study also generates somenewquestions.Dodepressionandantipsychoticuserepresent risk factors forYOD,symptoms of YOD, or primary psychiatric disease (and a misdiagnosis ofYOD)?What fetal or early childhoodexposuresmodify the risk of having low cognitive function in late adolescence? Is high blood pressure a modifiable risk factor for YOD? Nordstrom and colleagues5 challenge us to consider the noninherited factors, such as high blood pressure, that may exacerbate genetic, neurodegenerative, or metabolic processes that cause incident YOD. Do some adults who develop YOD have an unidentified vulnerability to dementia because of factors related to genetics, neurobiologic characteristics, or early life development? Do these at-risk adults develop dementia after acquiring a second“hit” or insult that injures vulnerable brain structures or cognitive pathways?What are the pathogenic mechanisms that converge to cause YOD? The study has several strengths. This longitudinal study has information on risk factors from the physical examination, cognitiveperformance, family andmedical histories, and medicationprescriptions because it combinesunique sources of national data. Few population-based studies of YOD have been performed. The study by Nordstrom et al5 appears representative of the larger population of Swedish men because it captures data on nearly all men eligible for military service andmost episodes of inpatient care. The diagnosis of dementia had high sensitivity in a medical record review of a subsample, although diagnostic criteria are not given. The number of dementia cases was large. Related article page 1612 Risk Factors for Young-Onset Dementia in Men Original Investigation