Synaptic Function and Dysfunction in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative progressive disease of the elderly leading to dementia. The world Alzheimer report (Alzheimer's disease International, global impact of dementia) of 2015 indicated that 46.8 million people worldwide are living with dementia; this number is expected to double every 20 years [1]. There are two forms of AD. 1. Early onset Familial Alzheimer Disease (eFAD). Abnormalities of the amyloid precursor protein (APP) that render it more amyloidogenic, or defects of processing normal APP cause genetic forms of AD. The literature estimates that eFAD accounts for approximately 2% of all people with dementia (approximately 3-5% of all Alzheimer cases) [1,2]. In these patients, autosomal dominant AD usually develops before age 65 due to mutations of the APP gene on chromosome 21 or the presenilin 1 and 2 genes (PSEN1 and PSEN2) on chromosomes 14 and 1, respectively. 2. Sporadic AD (SAD, late-onset). SAD is very common in the elderly (approximately 70% of patients with dementia are attributed to SAD [1]). The cause of SAD is unknown. The vast majority of SAD is not genetically inherited although some genes such as the APOE may act as a major risk factor [3]. Vascular diseases such as hypertension and brain ischemia [4,5], diabetes [6,7] and obesity [8], traumatic brain injury [9], mood disorders [10] represent risk factors for SAD. The neuropathological changes of AD brain include classical hallmarks such as the senile plaques and neurofibrillary tangles, and dystrophic neurites containing hyperphosphorylated tau [11-13]. Additional changes are represented by astrogliosis [14], microglial cell activation [14,15] and inflammatory reaction [16]. Senile plaques with amyloid cores in the brain of AD patients are often described in close proximity to microvessels with amyloid angiopathy [17]. Whereas considerable heterogeneity exists in the degree to which cognitive functions are affected in patients with AD, learning/memory impairment is almost invariably reported in AD [18,19]; typically, declarative memory is impaired and this quite often represents the initial cognitive deficit in AD. Indeed, the initial brain areas involved in the neurodegenerative progression of AD are the entorhinal cortex, hippocampus and temporal cortex [20,21], i.e., crucial areas for learning/memory. The hypothesis has been advanced that impairment of the entorhinal cortex initiates cortical-hippocampal dysfunction in AD [22]. The olfactory bulb, anterior olfactory nucleus, orbitofrontal cortex and parahippocampal cortices receiving olfactory input are all also affected early in AD [23]. Thus, odor recognition performance, in particular the ability to identify familiar odors, in association with episodic memory is impaired early in AD [24]. In addition to eFAD and SAD there are patients with cognitive decline unusual for their age that does not affect daily living (for example difficulty in remembering names of individuals, misplacing keys and spectacles or difficulty in remembering phone numbers, messages and appointments, therefore mostly verbal episodic memory deficit). This clinical state is called mild cognitive impairment (MCI). Some MCI patients progress to AD (roughly 15%/year; [25]), others progress to vascular dementia, but others remain stable or revert to normal, indicating that MCI has diverse causes and represents a heterogeneous group of patients. MCI patients can be further subdivided in: MCI patients with an amnestic profile [26] (impaired episodic memory retention and retrieval) and MCI patients with an anamnestic profile susceptible to be converted in AD.