Imaging and cerebrospinal fluid biomarkers in the search for Alzheimer's disease mechanisms

The pathophysiological process of Alzheimer's disease (AD) begins many years before the emergence of clinical symptoms (preclinical AD). A hypothetical biomarker progression in the pathogenesis of AD has been suggested, beginning with the deposition of amyloid-β (Aβ) and followed by increases in neurofibrillary tangles, synaptic loss, hippocampal atrophy, and lastly, cognitive impairment.

We explored the effect of several risk factors for AD on the pattern of AD biomarker expression in normal subjects.

AD biomarker evidence was examined at baseline in 96 cognitively normal elderly subjects with none or at least one of the following: ApoE4+ allele, a maternal history of AD (mFHx), sleep-disordered breathing (SDB), and longitudinal evidence of decline to mild cognitive impairment or AD (decliners) at follow-up.

Decliners and ApoE4+ subjects presented with expected reduced cerebrospinal fluid Aβ42, elevated P-tau and T-tau. In addition, decliners had fluorodeoxyglucose positron emission tomography hypometabolism in the medial temporal lobe. Individuals with mFHx demonstrated no Aβ42 effect, but had elevations in P-tau and T-tau. SDB was found to be associated with elevated Aβ42, P-tau and T-tau, as well as with reduced medial temporal lobe glucose metabolic rates.

Our results indicate a heterogeneous biomarker expression, suggesting diversity of AD pathways in at-risk presymptomatic subjects.