An exploration of cognitive subgroups in Alzheimer's disease.

Heterogeneity is observed in the patterns of cognition in Alzheimer's disease (AD). Such heterogeneity might suggest the involvement of different etiological pathways or different host responses to pathology. A total of 627 subjects with mild/moderate AD underwent cognitive assessment with the Mini-Mental State Examination (MMSE) and the Dementia Rating Scale-2 (DRS-2). Latent class analysis (LCA) was performed on cognition subscale data to identify and characterize cognitive subgroups. Clinical, demographic, and genetic factors were explored for association with class membership. LCA suggested the existence of four subgroups; one group with mild and another with severe global impairment across the cognitive domains, one group with primary impairments in attention and construction, and another group with primary deficits in memory and orientation. Education, disease duration, age, Apolipoprotein E-epsilon4 (APOE epsilon4) status, gender, presence of grasp reflex, white matter changes, and early or prominent visuospatial impairment were all associated with class membership. Our results support the existence of heterogeneity in patterns of cognitive impairment in AD. Our observation of classes characterized by predominant deficits in attention/construction and memory respectively deserves further exploration as does the association between membership in the attention/construction class and APOE epsilon4 negative status.

Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease.

OBJECTIVE: To identify single-nucleotide polymorphisms (SNPs) associated with risk and age at onset of Alzheimer disease (AD) in a genomewide association study of 469 438 SNPs. DESIGN: Case-control study with replication. SETTING: Memory referral clinics in Canada and the United Kingdom. PARTICIPANTS: The hypothesis-generating data set consisted of 753 individuals with AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria recruited from 9 memory referral clinics in Canada and 736 ethnically matched control subjects; control subjects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The follow-up data set consisted of 418 AD cases and 249 nondemented control cases from the United Kingdom Medical Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King's College London, London, England. MAIN OUTCOME MEASURES: Odds ratios and 95% confidence intervals for association of SNPs with AD by logistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and 95% confidence intervals from Cox proportional hazards regression for age at onset with similar covariate adjustments. RESULTS: Unadjusted, SNP RS4420638 within APOC1 was strongly associated with AD due entirely to linkage disequilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the logistic analysis and 1 in the Cox analysis of the Canadian data set provided additional evidence for association at P< .05 within the United Kingdom Medical Research Council data set: RS7019241 (GOLPH2), RS10868366 (GOLPH2), RS9886784 (chromosome 9), and RS10519262 (intergenic between ATP8B4 and SLC27A2). CONCLUSIONS: Our genomewide association analysis again identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a consequence of the coevolution of more than 1 susceptibility allele, such as APOC1, in this region. We also provide new evidence for additional candidate genetic risk factors for AD that can be tested in further studies.

Evolution in a fully constituted world: Charles Darwin's debts towards a static world in the Origin of Species (1859).

The Transformist Revolution was a long intellectual quest that has expanded from the 18th century to today. One area of inquiry after another has confronted the necessity of recasting its object of study under an evolutionary view: human history, geology, biology, astronomy, etc. No single scholar fully managed to make the transition from a static worldview to an evolutionary one during his or her own lifetime; Charles Darwin is no exception. Many versions of evolutionism were proposed during this revolution, versions offering all sorts of compromises between old and new views. Not sufficiently acknowledged in the historiography is the profoundness of Darwin's debts towards the old static view. As a dual child of the Scientific Revolution and natural theology, Darwin inherited key concepts such as stability, completeness, timelessness, unity, permanence, and uniformity. Darwin took these concepts into consideration while erecting his theory of biological evolution. Unsurprisingly, this theory was ill-equipped to embrace the directionality, historicity, and novelty that came along with a new evolutionary world. This paper analyses a fundamental idea at the heart of Darwin's Origins of Species (1859) inherited from a static, stable, and machine-like conception of the world: the notion of a fully constituted world. Although in principle antithetical to the very idea of evolution itself, Darwin found a way to 'loosen up' this notion so as to retain it in a way that allows for some kind of evolutionary change.

The disciplinary and epistemological structure of paleoanthropology: one hundred and fifty years of development.

This paper aims to provide a reflection on the nature of the several disciplines that contribute to the field of human evolution or paleoanthropology. An historical approach is adopted on the grounds that the nature of their relationship is perhaps more clearly seen if a dynamic perspective is adopted; that is, if paleoanthropology is analysed as an historical entity in constant flux from 1860 to today. By following the debates over human phylogeny and various scenarios of hominization separately, I will show that paleoanthropology was in the early decades of its development only very loosely organized around a host of disciplines, disciplines that went through a unification process as the twentieth century progressed under a rapidly improving empirical basis. Interestingly, to analyse the disciplinary structure of paleoanthropology from an historical approach is also to reveal its epistemological structure as both are intimately intertwined. It will be suggested that paleoanthropology's disciplinary and epistemological structure can be understood as a multi-level organization comprising at least four distinct explanatory levels characterized by unidirectional and/or bidirectional flows of information, depending on the specific circumstances: (1) a meta-theoretical foundation; (2) a level concerned with phylogeny building; (3) a level which takes up evolutionary theories and models; and (4) a level devoted to scenarios of hominization.

Welcome to the Twilight Zone: a forgotten early phase of human evolutionary studies.

The field of paleoanthropology arose out of a strange and unacknowledged early phase of development prior to about the 1930s. It is often assumed that a key pillar of the discipline, the unity of humankind--the notion that humans are clearly separated phylogenetically (genealogically) from other non-human primates--was widely accepted from the inception of paleoanthropology around 1860. However, a final consensus on this fundamental question only appeared later on in the 20th century. This paper will focus on two key areas of disagreement, which reveal the unsettled state of this question during this early period: the question of uncertainty with respect to the number, identity and boundary of primate species (including humans) which prevailed in the 18th, 19th and early 20th centuries; and the matter of uncertainty with respect to the nature of the phylogenetic relationships among the various human populations and the other primate species which prevailed between 1864 and 1931. Consideration of these matters reveals that the modern research structure that paleoanthropologists take for granted today is much more recent than believed.

What was really synthesized during the evolutionary synthesis? A historiographic proposal.

The 1920-1960 period saw the creation of the conditions for a unification of disciplines in the area of evolutionary biology under a limited number of theoretical prescriptions: the evolutionary synthesis. Whereas the sociological dimension of this synthesis was fairly successful, it was surprisingly loose when it came to the interpretation of the evolutionary mechanisms per se, and completely lacking at the level of the foundational epistemological and metaphysical commitments. Key figures such as Huxley, Simpson, Dobzhansky, and Rensch only paid lip service to the conceptual dimension of the evolutionary synthesis, as they eventually realized that a number of evolutionary phenomena could not be explained by its narrow theoretical corpus. Apparently, the evolutionary synthesis constituted a premature event in the development of evolutionary biology. Not only are the real achievements of the evolutionary synthesis in need of reevaluation, but this reassessment also has important implications for the historiography of Darwinism and the current debates about the darwinian movement.

The uncertain foundation of neo-Darwinism: metaphysical and epistemological pluralism in the evolutionary synthesis.

The Evolutionary Synthesis is often seen as a unification process in evolutionary biology, one which provided this research area with a solid common theoretical foundation. As such, neo-Darwinism is believed to constitute from this time onward a single, coherent, and unified movement offering research guidelines for investigations. While this may be true if evolutionary biology is solely understood as centred around evolutionary mechanisms, an entirely different picture emerges once other aspects of the founding neo-Darwinists' views are taken into consideration, aspects potentially relevant to the elaboration of an evolutionary worldview: the tree of life, the ontological distinctions of the main cosmic entities (inert matter, biological organisms, mind), the inherent properties of self-organizing matter, evolutionary ethics, and so on. Profound tensions and inconsistencies are immediately revealed in the neo-Darwinian movement once this broader perspective is adopted. This pluralism is such that it is possible to identify at least three distinct and quasi-incommensurable epistemological/metaphysical frameworks as providing a proper foundation for neo-Darwinism. The analysis of the views of Theodosius Dobzhansky, Bernhard Rensch, and Ernst Mayr will illustrate this untenable pluralism, one which requires us to conceive of the neo-Darwinian research agenda as being conducted in more than one research programme or research tradition at the same time.

Expanding the framework of the holism/reductionism debate in neo-Darwinism: the case of Theodosius Dobzhansky and Bernhard Rensch.

The holism/reductionism debate in evolutionary biology has often been analysed as involving two main phenomenological levels within neo-Darwinism: genetic and organismic. This analytical framework assumes that explanation in evolution is either found in the field of genetics or the field of organismic biology. It is argued here that this framework is far too restrictive to incorporate what at least some founding members of neo-Darwinism had in mind in their search for the ultimate cause of evolution. Dobzhansky's "super-holism" locates this drive in the highest possible entity imaginable--an ontologically unified evolutionary cosmos--while Rensch's ontological "super-reductionism," on the other hand, places it at the lowest possible entity of microphysics, that is, at the level of an energetic field of protopsychical nature. Not only it is suggested that a much-expanded framework is required for analysing the holism/reductionism debate in neo-Darwinism, but also that this new framework may have implications for the conceptualization of the neo-Darwinian movement itself.