Human memory is a polygenic trait. We performed a genome-wide screen to identify memory-related gene variants. A genomic locus encoding the brain protein KIBRA was significantly associated with memory performance in three independent, cognitively normal cohorts from Switzerland and the United States. Gene expression studies showed that KIBRA was expressed in memory-related brain structures. Functional magnetic resonance imaging detected KIBRA allele–dependent differences in hippocampal activations during memory retrieval. Evidence from these experiments suggests a role for KIBRA in human memory.

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects more than 15 million people worldwide. Within the next generation, these numbers will more than double. To assist in the elucidation of pathogenic mechanisms of AD and related disorders, such as frontotemporal dementia , genetically modified mice, flies, fish and worms were developed, which reproduce aspects of the human histopathology, such as b-amyloidcontaining plaques and tau-containing neurofibrillary tangles (NFT). In mice, the tau pathology caused selective behavioral impairment, depending on the distribution of the tau aggregates in the brain. b-Amyloid induced an increase in the numbers of NFT, whereas the opposite was not observed in mice. In b-amyloid-producing transgenic mice, memory impairment was associated with increased levels of b-amyloid. Active and passive b-amyloid-directed immunization caused the removal of b-amyloid plaques and restored memory functions. These findings have since been translated to human therapy. This review aims to discuss the suitability and limitations of the various animal models and their contribution to an understanding of the pathophysiology of AD and related disorders. Keywords: Alzheimer's disease; frontotemporal dementia; b-amyloid; tau; transgenic; C. elegans; Drosophila; sea lamprey; mice; behavior; memory; therapy; immunization Alzheimer's disease and related disorders: neuropathology, genetics and clinical featuresIn 1907, the two key histopathological hallmarks of Alzheimer's disease (AD), b-amyloid plaques and neurofibrillary tangles (NFT), were for the first time described by Alois Alzheimer when he examined brain sections of his patient Auguste D. 1 Since then, the number of PubMed entries for 'Alzheimer' steadily increased and, in 2002 alone, added up to 5213 entries. The last 20 years of AD research, with the help of animal models, assisted in the elucidation of aspects of the pathophysiology of AD and the relationship of the two major lesions. Parallel to this increased insight into disease mechanisms, the number of AD patients is rising as the numbers of old people are increasing in many countries. Moreover, the incidence of AD rises from less than 2% for people under the age of 60 to about 30% in people older than 85. 2 b-Amyloid plaques and Ab processing b-Amyloid plaques are one of the histopathological hallmarks of AD. The term amyloid has been introduced to describe a heterogeneous class of protein aggregates with a b-pleated sheet secondary structure, which confers affinity to the histochemical dye congo red. In AD, b-amyloid is deposited around meningeal and cerebral vessels, and in the gray matter as b-amyloid plaques. The major proteinaceous component is a 40-42 amino-acid polypeptide termed Ab (Ab 40 and Ab 42 ), which is derived by proteolysis from the amyloid precursor protein (APP). 3,4 APP can be proteolytically cleaved by the membrane-associated a-secretase, which cleaves APP within the Ab domain and secretes the aminoterminal portion of APP (APP s ). This p...