Characterizing the preclinical stages of Alzheimer's disease and the prospect of presymptomatic intervention.
Studies of asymptomatic carriers of genes that are known to predispose to Alzheimer's disease (AD) have facilitated the characterization of preclinical AD. The most prevalent genetic risk factor is the ε4 allele of apolipoprotein E (APOE). Neuropathological studies of young deceased ε4 carriers have shown modest but abnormal amounts of neocortical amyloid and medial temporal neurofibrillary tangles that is also reflected in cerebrospinal fluid (CSF) biomarkers, amyloid-β, and phospho-tau in particular. MRI studies have shown progressive hippocampal and gray matter atrophy with the advent of mild cognitive impairment (MCI), and fluorodeoxyglucose PET scans show reduced cerebral metabolism in posterior cingulate and related AD regions evident even in 30 year olds. Cerebral amyloidosis disclosed by more recent amyloid ligand PET studies in asymptomatic 60 year olds increases in parallel with ε4 gene dose. Longitudinal neuropsychological studies have revealed accelerated memory decline in ε4 carriers beginning around age 55-60 years whose severity again parallels ε4 gene dose. The clinico-pathological correlation of declining memory and AD-like neuropathological change defines preclinical AD and has set the stage for the accelerated evaluation of presymptomatic AD treatments. In this article, we briefly consider some of the earliest detectable changes associated with the predisposition to AD, and some of the prevention trial strategies that have been proposed to help find treatments to reduce the risk, postpone the onset of, or completely prevent AD symptoms as soon as possible.
Department of Neurology, Mayo Clinic Phoenix, AZ 85259, USA. caselli.richard@mayo.edu
Richard J
RJ
Caselli
Eric M
EM
Reiman
D000375:Aging; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D042241:Early Diagnosis; D006801:Humans; D062706:Prodromal Symptoms
D001057:Apolipoproteins E