In Memory of George M. Martin

BMJ, 1998

PLOS Genetics, 2016

The relationship between aging and major age-related diseases, such as cardiovascular diseases (CVDs), Alzheimer disease (AD), type 2 diabetes (T2D), and cancer and the genetic contribution to both phenomena are important questions in biomedicine. Over the past few decades, each disease has been studied separately in hundreds of genome-wide association studies (GWAS) involving increasing numbers of patients and SNPs, generating results that can explain only in part the genetics of the traits of interest. On several occasions, the results obtained in one population have not been replicated in others, and the clinical application of these results is questionable. The new field of "geroscience" [1] proposes a conceptual framework that could lead to more effective approaches for studying the genetics of age-related diseases, starting from the basic observation that their main risk factor is age and aging. Geroscience stresses that the basic molecular and cellular mechanisms underpinning aging and its related pathologies are much more interconnected than previously thought on the basis of purely clinical classifications, and largely overlap. This enables us to study and combat the diseases of the elderly all together, rather than one by one [2].

Acta Neuropathologica, 2011

Human studies are reviewed concerning whether "aging"-related mechanisms contribute to Alzheimer's disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human "accelerated aging" diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical "dementia" and the subset of dementia cases with AD pathology. Additional agingassociated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an "aging-linked" disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging.

Dialogues in Clinical Neuroscience, 2003

psychiatrist, reported the case of a middle-aged woman who developed progressive memory loss and cognitive disorders with autopsy findings of neuritic plaque and neurofibrillary tangles in the cerebral cortex. 1 Thereafter, it was named as Alzheimer's disease (AD). However, it was only in the 1960s that came to be recognized as the most common cause of dementia in the aged. 2 AD currently accounts for at least 60% to 70% of cases of dementia in aged people. 3 In the United States, the total prevalence of AD is greater than 2.3 million and potentially affects more than 4 million individuals. 4 The average duration of AD is 8 to 10 years, or even shorter. AD has been ranked as the fourth leading cause of death in the United States. 2 By the year 2025, over 22 million patients with dementia are expected around the world. 5,6 Pathology of AD The pathologic criteria for diagnosis of AD require the presence of both neuritic plaques and neurofibrillary tangles, together with a progressive decline in cognitive function. 7 The neuritic plaques are composed of aggregations of β-amyloid (Aβ) and are surrounded by dystrophic neurons and astrocytes. 8-10 The neurofibrillary tangles consist of intraneuronal aggregations of hyperphosphorylation microtubule-associated protein tau. 11-14 Reduction in synaptic density and neuronal loss in some specific brain regions, including the cerebral cortex and hippocampus, are also important criteria in the diagnosis of AD.

Neuron, 2001

of novel approaches for treatment and prevention. As Massachusetts General Hospital therapeutic strategies become more effective and our 114 16 th Street grasp of AD genetics is strengthened, reliable and com-Charlestown, Massachusetts 02129 prehensive genetic risk profiling will eventually enable systematic early-prediction/early-prevention procedures. In this minireview, we will present a brief history of AD genetics and discuss its current and future status, focus-Alzheimer's disease (AD) is a genetically complex dising on recent findings suggesting the existence of novel order that accounts for the majority of dementia in and potentially important AD genes on chromosomes the elderly population. Over 100 rare, highly penetrant 12, 10, and 9. mutations have been described in three genes (APP, Genetics of AD: The Early Days PSEN1, PSEN2) for early-onset familial AD. In the more Initial attempts to understand the role of genetics in AD common late-onset form, a polymorphism in the apoliin the early 1980s focused on rare multigenerational poprotein E gene has been associated with increased families with early-onset (Ͻ60), autosomal-dominant, susceptibility. However, recent studies suggest that fully penetrant forms of the disease (EOFAD) using conthese four genes account for less than 30% of the ventional linkage analysis (i.e., measuring cosegregation genetic variance for AD and that more genetic factors of a genetic marker with disease phenotype) and subseremain to be identified. In this review, we present a quent positional cloning. Although the initial findings brief history of AD genetics and preview some of the showing significant linkage of EOFAD to chromosome next frontiers in Alzheimer gene discovery primarily 21 in 1987 were later found to be false positive findings focusing on chromosomes 12, 10, and 9. (the same families were actually linked to another AD locus on chromosome 14, see below), the implied region

Journal of Clinical Epigenetics, 2017

The Neurologist, 2009

Background-Alzheimer disease (AD) is a genetically complex disorder. Mutations in 3 genes, presenilin 1, amyloid precursor protein, and presenilin 2, lead to early-onset familial AD in rare families with onset of disease occurring prior to age 65. Specific polymorphisms in apolipoprotein E are associated with the more common, late-onset AD occurring after age 65. In this review, we discuss current advances in AD genetics, the implications of the known AD genes, presenilin 1, presenilin 2, amyloid precursor protein, and apolipoprotein E, and other possible genes on the clinical diagnosis, treatment, and genetic counseling of patients and families with early-and lateonset AD.

Journal of Alzheimer’s Disease & Parkinsonism

Aging lies on a temporal continuum that starts at conception and ends at death [6]. Aging refers to the aging processes occurring during an individual's lifetime. Aging is a different concept to life span, longevity or life expectancy. Life span refers to the maximum life span observed in a group. Longevity is the average life span expected under ideal conditions. Life expectancy is the average life span expected of a group at birth or any other given point in time after birth. Despite this "grey tsunami", our understanding of senescence remains limited. In the early stages of dementia, distinguishing normal from pathological aging remains complex. As science progresses new treatments are developed for what may be considered to be abnormal

Mutagenesis, 2006

2005