Paradigm shift: semantic memory decline as a biomarker of preclinical Alzheimer's disease.

Abstract

Uncovering the presence of Alzheimer’s disease (AD) in routine neurological management of middle-aged/elderly adults, and differentiating its combination of symptoms from those induced by the processes of normal aging, neurovascular disease or psychiatric conditions (e.g., depression), are challenges of primary importance. Usually, it is the onset of behavioral symptoms that encourages patients with AD and caregivers to seek medical attention for the first time. Research evidence, however, shows that the earliest changes triggered by the disease on the biology of the brain occur several decades prior to any behavioral change of clinical relevance [1]. Based on this large preclinicalstage/symptomatic-stage temporal discrepancy, it is of paramount importance to identify biomarkers that are more effective than those currently used in clinical practice. An ideal biomarker should be of as early diagnostic help as possible in the disease-progression timeline, as well as highly sensitive and specific. On this note, the use of cognitive tests is among the most proficient sources of clinical information in the early phases of AD, due to their validity, reliability and simplicity/immediateness. A skillful interpretation of neuropsychological performance may offer an indirect, yet fruitful view of the pathological processes affecting the nervous system, which could be the result of incipient AD. Although episodic memory impairment has been classically recognized as the main symptom of the prodromal AD stage characterized by mild cognitive impairment (MCI) [2], a temporally parallel decline of semantic memory has also been described [3,4]. The basic clinical disadvantage associated with episodic memory is that a qualitatively (but certainly not quantitatively) similar memory decline is also ‘physiologically’ visible in the absence of any pathologies in the general population of elderly adults. In contrast, semantic memory remains fairly stable across the lifespan, and aspects of lexical-semantic abilities even appear to improve with age [5]. Based on this, using the same logic argument that sustains all differential diagnoses, measuring semantic memory can be discriminative in separating healthy and pathological aging. Nevertheless, the most recent criteria for the detection of the earliest clinical manifestation of AD [6,7] persist in highlighting the sole role of measures of episodic retrieval. A major reason behind the choice of episodic memory as the cognitive subdomain ‘of reference’ lies in the fact that prodromal, earlysymptomatic AD (manifesting in the form of MCI) corresponds to the pathophysiological moment in which the neurofibrillary pathology intensifies within the hippocampal complex [8]. This mediotemporal structure sustains the neocortical circuitry responsible for context-associated, episodic memory [9]. Based on this, the theoretical convergence of peptidic accumulation of hypephosphorylated TAU protein within hippocampal cells, Paradigm shift: semantic memory decline as a biomarker of preclinical Alzheimer’s disease