Article

The genetics of Alzheimer disease - Current status and future prospects

Harvard University, Cambridge, Massachusetts, United States
JAMA Neurology (Impact Factor: 7.01). 03/1998; 55(3):294-6. DOI: 10.1001/archneur.55.3.294
Source: PubMed

ABSTRACT Four genes involved in the development of Alzheimer disease have been identified. Three fully penetrant (deterministic) genes lead to the development of Alzheimer disease in patients younger than 60 years: the amyloid beta-protein precursor on chromosome 21, presenilin 1 on chromosome 14, and presenilin 2 on chromosome 1. Together, they account for about half of this early-onset form of the disease. One genetic risk factor--apolipoprotein E-4--is associated with late-onset Alzheimer disease. It accounts for a substantial fraction of disease burden but seems to act primarily to lower the age of disease onset. In general, none of these genes can be easily adapted for use as a diagnostic or predictive test for Alzheimer disease. Research activity includes searching for additional genes, especially for late-onset disease, and elucidating the mechanism of action of all identified genes as part of a long-term effort to develop more effective therapeutic and preventive strategies.

1 Follower
 · 
76 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dementia is a major public health problem worldwide. Alzheimer's disease (AD) is a major form of dementia and the APOE*4 allele is an established genetic risk factor for AD. Similarly, stressful life events are also associated with dementia. The objective of this study was to examine the association of APOE*4 and stressful life events with dementia in a Pakistani sample, which to our knowledge has not been reported previously. We also tested for an interaction between stressful life events and APOE*4 on dementia risk. A total of 176 subjects (61 cases and 115 controls) were recruited. All cases and healthy controls were interviewed to assess cognition, co-morbidities, history of stressful life events and demographics. Blood genotyping for the APOE polymorphism (E2/E3/E4) was performed. APOE*4 and stressful life events were each independently and significantly associated with the risk of dementia (APOE*4: P=0.00697; stressful life events: P=5.29E-09). However, we did not find a significant interaction between APOE*4 carrier status and stressful life events on risk of dementia (P=0.677). Although the sample size of this study was small, the established association of APOE*4 with dementia was confirmed the first time in a Pakistani sample. Furthermore, stressful life events were also found to be significantly associated with dementia in this population.
    Neuroscience Letters 04/2014; DOI:10.1016/j.neulet.2014.04.008 · 2.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A Delacourte R é s u m é. – Depuis la précédente édition publiée en 1992, une somme considérable de données nouvelles a contribué à préciser la physiopathologie de la maladie d'Alzeimer (MA), à mieux en définir l'hétérogénéité et de nouvelles thérapeutiques sont apparues. Les projections épidémiologiques pour les décennies à venir sont réellement alarmantes avec une incidence possible en France de 100.000 nouveaux cas par an. Plusieurs gènes distincts ont été identifiés dans les rares formes familiales à transmission dominante autosomique et l'isoforme ε4 de l'apolipoprotéine E est un facteur de risque défini. Certaines protéines (bêta amyloïde, tau) semblent jouer un rôle majeur dans des cascades d'événements associant vraisemblablement des protéines de l'inflammation et des systèmes apoptotiques. L'hypothèse cholinergique, sans être exclusive, reste d'actualité. Les critères de diagnostic sont aujourd'hui bien définis et validés, mais restent insuffisants pour l'identification précoce des malades. Le diagnostic, qui reste purement clinique faute de marqueurs biologiques spécifiques, fait appel au début à une expertise neuropsychologique réservée à des centres spécialisés. Les techniques de volumétrie hippocampique en imagerie par résonance magnétique (IRM), de métabolisme en tomographie d'émission monophotonique peuvent contribuer au diagnostic. L'étiologie de la maladie d'Alzheimer est toujours inconnue, mais la plupart des modèles proposés la considèrent comme plurifactorielle. La thérapeutique reste symptomatique, mais bénéficie de plusieurs drogues cholinomimétiques qui peuvent être associées aux traitements des troubles psychocomportementaux. La prise en charge fait appel à de multiples stratégies médico-psycho-sociales qui sont de mieux en mieux structurées et contribuent à une meilleure qualité de vie des malades.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured the amount of hyperphosphorylated microtubule associated tau (HP-τ), amyloid-β protein (Aβ) and α-synuclein (α-syn) in cases that were neuropathologically diagnosed as mixed Alzheimer's disease (AD) and neocortical Lewy body disease (LBD) but clinically presented either as dementia due to AD or LBD, the latter including dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Our study group consisted of 28 cases (mean age, 76.11 SE: ±1.29 years; m:f, 17:11) of which 19 were neuropathologically diagnosed as mixed AD/DLB. Clinically, 8 mixed AD/DLB cases were diagnosed as AD (cAD), 8 as DLB (cDLB) and 3 as PDD (cPDD). In addition, we investigated cases that were both clinically and neuropathologically diagnosed as either AD (pure AD; n = 5) or DLB/neocortical LBD (pure DLB; n = 4). Sections from neocortical, limbic and subcortical areas were stained with antibodies against HP-τ, Aβ and α-syn. The area covered by immunopositivity was measured using image analysis. cAD cases had higher HP-τ loads than both cDLB and cPDD and the distribution of HP-τ in cAD was similar to the one observed in pure AD whilst cDLB showed comparatively less hippocampal HP-τ load. cPDD cases showed lower HP-τ and Aβ loads and higher α-syn loads. Here, we show that in neuropathologically mixed AD/DLB cases both the amount and the topographical distribution of pathological protein aggregates differed between distinct clinical phenotypes. Large-scale clinicopathological correlative studies using a quantitative methodology are warranted to further elucidate the neuropathological correlate of clinical symptoms in cases with mixed pathology.
    Acta Neuropathologica 03/2015; DOI:10.1007/s00401-015-1406-3 · 9.78 Impact Factor