Characterizing the preclinical stages of Alzheimer's disease and the prospect of presymptomatic intervention

Abstract

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.

Figure 1

Reduced posterior cingulate glucose metabolism disclosed by fluorodeoxyglucose positron emission tomography in patients with probable Alzheimer’s disease (left) and similar but less robust changes in cognitively normal young adult APOE e3/4 heterozygotes (right).

Figure 2

Progressively increasing cerebral amyloid burden disclosed by Pittsburgh Imaging Compoud B (PiB) positron emission tomohraphy with increasing APOE e4 gene dose in asymptomatic individuals age 50–69 years old, and in patients with probable Alzheimer’s disease.

Figure 3

Mean longitudinal trajectories of the auditory verbal learning test long term memory score by APOE genotype based on a mixed model (see ref 90). There is increasing acceleration of declining memory performance beginning at age 55–60 with increasing e4 gene dose.

Figure 4

Mean longitudinal trajectories of the auditory verbal learning test long term memory score by cerebrovascular risk factor status in APOE e4 homozygotes based on a mixed model (see ref 91). APOE e4 homozygotes show no test-retest effect from the earliest age in this model (40’s) and have an accelerated pattern of decline relative to e4 homozygotes without any cerebrovascular risk factors.