Synapse-associated neuropathological markers in Alzheimer's disease

Abnormal amyloid-β and microtubule-associated protein are two intimately related proteinopathies central to the pathophysiology of Alzheimer's disease (AD). Both are often accompanied by cholesterol dysmetabolism and/or altered transport of this neutral lipid in carriers of APOEε4, a causal gene for early-onset (familial) Alzheimer's disease and the most important genetic risk factor for late-onset, also known as sporadic, Alzheimer's disease. Age, the principal risk factor for sporadic Alzheimer's disease, together with comorbidities such as cardiovascular diseases, diabetes and chronic inflammation, converge on synapses to generate cognitive synaptopathies. These probably constitute the early and asymptomatic manifestations of Alzheimer's disease 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 Alzheimer's disease synaptopathy before the appearance of 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 Alzheimer's disease are reviewed.