Optimism was high that the first disease-modifying antiamyloid medications would be effective in slowing the rate of decline in those with symptomatic Alzheimer disease (AD). When these studies failed, it set off conversations that still continue about whether the medications were ineffective, the disease was too advanced to be slowed by such agents, or amyloid was the correct pathology to target.
The operationalization of mild cognitive impairment (MCI) led to targeting earlier symptomatic cases of the illness and treatment strategies based less on pathology and more on a chance to halt or slow decline than there would be earlier in the disease.1 With the development of amyloid imaging, MCI due to AD diagnosis was refined,2 and early-stage AD was extended further to include preclinical AD,3 wherein a positive amyloid positron emission tomography (PET) scan or diagnostic low levels of cerebrospinal fluid β-amyloid (Aβ) indicated the presence of pathology in people who were cognitively normal. Data from patients with familial AD with autosomal dominant mutations4 and longitudinal observation of individuals with positive Aβ PET scans and normal cognition led to the observations that amyloid plaque pathology could be present as long as 2 decades prior to the emergence of the first clinical symptoms of AD. Armed with biomarkers of Alzheimer pathology, studies of therapeutics to delay the emergence of symptoms could be undertaken, with the rationale that delay in symptom onset approaches the idea of prevention of dementia.
DeKosky ST, Schneider LS. Preventing Dementia: Many Issues and Not Enough Time. JAMA Neurol. 2017;74(5):508–510. doi:10.1001/jamaneurol.2017.0045
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