On the molecular level we find a downregulation of synaptic genes across multiple brain regions and widespread proteomic signs of synaptic stress or decay in the cerebrospinal fluid (CSF) or blood.32-34 Changes in the molecular fine structure of AD brains also arise independently of atrophy as resonance spectroscopic investigations in AD imply.35Atrophy in a case of AD over 4 years. (A) Reduction of gray matter (lateral view; corrected for age; P<0.05), (B) coronal view of the left hippocampus at baseline and after 4 years (hippocampal gray matter volume at T0 5.3±0.4 mL, at T4 3.5±0.2 ml), (C) average hippocampal volume reduction of 0.2 mL per year (-12%/year), (D) average increase of lateral ventricle volume of 2.7 mL/per year (+ 6.7%/year). (Courtesy of L. Spies, Jung-diagnostics GmbH, Hamburg, Germany)This review aims to highlight some aspects concerning the development of memory deficits in AD that recently have or should have gained attention.Recently workgroups of the Alzheimer's Association and the National Institute on Aging have issued new criteria and guidelines to diagnose Alzheimer's disease supplanting the previous guidelines first published in 1984.36-40 This marks a complete overhaul, and attemps to implement advances in our understanding of the disease in the way we diagnose the disease. Hie most notable differences are the use of biomarkers such as hippocampal atrophy, and the formalization of earlier disease stages before dementia is apparent, such as mild cognitive impairment due to AD and the newly defined preclinical AD stage.38,39 While the recommendations of the preclinical AD workgroup are intended purely for research purposes and the aim of diagnosing the disease earlier appears sensible since it is likely that any intervention has to be started early to be successful, it is also clear that we would almost all be defined as having the disease using this definition, given the increasing prevalence of AD in the very old. From a scientific point of view, it might be more interesting to know why a few of us might not develop AD, even when we are not dying from other diseases. As clinicians AD patients may first approach us with mere subjective concerns about cognitive decline. This can develop into mild cognitive impairment with pathological neuropsychological test results and progress into dementia, at which time daily activities can no longer be performed properly. When brain atrophy progresses other psychiatric and neurological symptoms arise, and typically AD patients lose weight and frequently develop difficulties in swallowing. This may lead to aspiration and subsequently pneumonia, which is often the final cause of death in demented patients.Consensus exists that AD starts clinically with memory complaints, which may affect episodic memory, speech production, with naming or semantic problems, or visual orientation. Memory can be defined as a process of encoding, storing, and retrieving information about outer and inner stimuli, or presentation of information to the nervous system of an organism that can be used to react and position the organism towards new stimuli. Different categories of memory have been defined which also have different neuroanatomical and neurophysiological correlates: short-term memory vs long-term memory or implicit versus declarative memory. Short-term memory is limited to just a few “chunks” in capacity, and lasts only seconds to minutes.41 It depends on regions of the frontal lobe and the parietal lobe. In contrast, long-term memory seems almost limitless regarding its storage capacities, for a potentially unlimited duration. It depends on de novo protein synthesis and changes in the molecular components of the neuronal networks involved in the specific cortical areas that can be attributed to different memory types. Declarative memory, for example, can be further subdivided into semantic memory, where context-independent information is stored, and episodic memory, which stores information specific to a particular context, mainly time and place. Semantic memory is at first impaired in the language of AD patients, affecting verbal fluency and naming. Semantic loss in AD may occur several years prior to diagnosis.42 The hippocampus is essential to the consolidation of information from short-term to long-term memory. Destruction of the hippocampal formation makes the storage of new memories impossible. In the clinical context we use neuropsychological test batteries like the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) examination, the Mini-Mental State examination, and various other test constructs and scales, like the clinical dementia rating scale, that investigate different aspects of memory over a broad range of various cognitive domains.43-45 Patients get profiled in relation to tests they show abnormalities on, compared with a healthy reference group adjusted for age and education.