Defining Amyloid Pathology in Persons With and Without Dementia Syndromes: Making the Right Diagnosis

In this issue of JAMA, 2 articles from the Netherlands report findings from meta-analyses that assess the prevalence of amyloidpathologyasdeterminedbybiomarkers inpersonswith normal cognition, subjective cognitive impairment (SCI),or mild cognitive impairment (MCI)1andestimatetheprevalence of amyloid positivity on amyloid-β positron emission tomography (PET) in a wide variety of dementia syndromes.2 These reports are the largest andmost detailed to date and are critical assessments that help define the role of amyloid in the causation of cognitive impairment and dementia. Theearliestpathological change inAlzheimerdisease (AD), aggregationof cerebral amyloid-β, is presentup to 20years beforetheonsetofdementia.3,4Accuracy indeterminingthecause ofcognitive lossandsubsequentdementiaandeliminatingfalsepositivecases inclinical trialsevaluatingamyloid-relatedtherapeutics require a precise determination of the status of amyloid pathology. Further, therapy for AD requires initiation of treatment in the predementia phase when the neuropathology is limited and regeneration can potentially occur. Jansen et al1 conducted an individual participant metaanalysis to provide an estimate of the prevalence of amyloid pathology based on biomarker criteria in personswithout dementia.Theauthors includeddata from2914personswithnormal cognition, 697 with SCI, and 3972 with MCI. Amyloid pathologyprevalencewasestimatedandthe relationwithknown risk factors for AD-type dementia, including age, sex, education, and APOE genotype, was studied. Theauthors includedamyloidPETdata from29studiesand cerebrospinal fluid (CSF) amyloid-β1-42 data from 31 studies and estimated the probabilities of amyloid positivity according tocognitivestatus,APOE-e4status,andanagerangeof18to100 years.Theresultsprovideanappreciationofamyloidpathology across these variables. Amyloid positivity by agewas related to cognitivestatusandAPOEgenotype.Theinvestigatorsfoundthat atage90years,about40%oftheAPOE-e4noncarriersandmore than80%ofAPOE-e4carrierswithnormalcognitionhadevidence ofamyloidpositivity.Educationwas related toamyloidpositivity, but no correlationwas present for sex or biomarkermodality.PatientswithMCIhad20%to30%higherprevalenceratesof amyloidpositivitythanthosewithnormalcognitionorSCI.Thus, these findingsare inaccordwith theviewthatMCI is a risk state forAD.5 SomepatientswithadiagnosisofMCIhadnoevidence of amyloid positivity, suggesting that theMCI phenotype is not alwaysassociatedwithADpathology.Jansenetal1 speculatethat amyloid-negative individualswithMCIhavesyndromes includinghippocampal sclerosis, depression,orvasculardisease.The APOE-e4riskallelecomparedwithAPOE-e3wasassociatedwith an increased likelihoodofamyloidpositivityanddecreasedage atonset.TheAPOE-e2allelewasassociatedwith reduced likelihood of amyloid pathology and a later age of onset. The cognitive reserve hypothesis was supported in their analysis as highly educated persons had a higher prevalence of amyloid pathology than those with reduced levels of education and a lower and later onset for developingAD-type dementia. These findings support the view that education provides increased complexities of synaptic architecture and increased efficiencies of information processing in alternate and increased circuits and thusprovides protection and resistance against amyloid-related pathology. The central observation in thismeta-analysiswas that the identified risk factors for AD-type dementia are also the same risk factors for amyloidpositivity in personswithnormal cognition. This relationship supports the hypothesis that amyloid positivity in these persons indicated early AD. In addition, amyloid positivity in persons without dementia is also associatedwithmemory loss, lossof cognition, increasedamyloid deposition, brain atrophy, and mortality.5-8 The analysis byJansenetal1 indicatesa20to30-year intervalbetweenamyloid positivity and AD-type dementia. In another article, Ossenkoppele et al2 extend the findings related to amyloid pathology with a meta-analysis of individualparticipantdata toestimatethepresenceofamyloidpositivity onPET in awidevariety of dementia syndromes. The authors included data involving 1359 persons with clinically diagnosedADand538participantswithnon-ADdementia.Based on analyses that examined relationships between amyloid PET positivity and age, sex, education cognition, andAPOE-e4, the authorsdemonstratedthattheprevalenceofamyloidonPETdecreasedwithageinAD-diagnosedpatients,mostlywithAPOE-e4 noncarriers, and increased with age in most non-AD dementias.Thevalueoftheseobservationsisthatamyloidimagingmay be most critical in making the correct diagnosis in early-onset dementia, especially to rule in AD dementia.2 In addition, the investigatorsemphasize that theconcordancebetweenPETand pathology indicates that amyloid imaging has the potential to be used to rule out AD dementia regardless of age. Of note, 12% of patients with clinically diagnosed AD dementia had a negative amyloid PET scan, and this finding Related articles pages 1924 and 1939 Opinion