Synapse-associated neuropathological markers in Alzheimer disease

Abnormal amyloid β and microtubule-associated protein are two intimately related proteinopathies central to the pathophysiology of Alzheimer disease (AD). Both are often accompanied by cholesterol dysmetabolism and/or altered transport of this neutral lipid in carriers of the APOEε4 (apolipoprotein E gene epsilon 4 allele), a causal gene for early-onset (familial) AD and the most important genetic risk factor for late-onset AD. Age, the principal risk factor for sporadic AD, together with comorbidities such as cardiovascular diseases, diabetes, and chronic inflammation converge on synapses to generate cognitive synaptopathies. The latter probably constitute the early and asymptomatic manifestations of AD and other dementias, preceding neuronal loss, disruption of neuronal networks, and the appearance of severe -particularly mnemonic- cognitive impairments. Here, I assess how key biomolecules stemming from synapses can be used as neuropathological markers to identify early signs of AD synaptopathy before overt clinical symptoms. In particular, the review dissects how molecular constituents of the synapse can be analysed by blood plasma proteomics and other state-of-the-art methods for the early diagnosis of cognitive impairment onset and prognosis of evolution. Finally, possible avenues for therapeutic interventions to ameliorate risk factors and comorbidities of AD are reviewed.