Abstract
Alzheimer's disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, pro-inflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors.
Highlights
With the general increase in the life span of the population across the globe, Alzheimer's disease (AD), a progressive neurodegenerative disorder presenting with insidious loss of memory and cognition, is fast becoming a major disease burden and socio-economic challenge for many countries
The majority of the AD dementia cases belong to sporadic variety of the disease which is a multi-factorial disorder in which both genetic predisposition and environmental factors contribute to the genesis of the disease [1, 2, 3]
One interesting theory, the Latent Early- life Associated Regulation (LEARn) model, has envisaged that exposure to environmental risk factors in early developmental life brings about epigenetic modifications of AD related genes (e.g. Amyloid Precursor Protein or amyloid precursor protein (APP) gene) that remain latent for many years till a second 'hit' results in sustained alterations in the expressions of these early-affected genes manifesting the full-blown disease [9, 10]
Summary
The clinical diagnosis of AD requires thorough history and neuropsychological evaluation following the criteria set by NINCDS/ADRDA (Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association) in 1984, which are comparable to those used by other expert bodies e.g. DSM IV (Diagnostic and Statistical Manual of Mental Disorders) [12]. Over the last two decades, the understanding of the pathogenesis of AD and other types of dementias at the cellular and molecular level has enormously increased, and coupled with this the PET imaging methods of reduced glucose uptake or increased amyloid beta deposition in AD brain and the identifications of CSF biomarkers of this disease condition have been developed. This has necessitated some modifications of the original diagnostic criteria and introduction of new terminologies and classifications, which could help in identifying the AD patients with greater degrees of certainty. The inherent uncertainty and ambiguity of AD diagnosis as outlined here is to be kept in mind in the context of our current discussion on AD and its multiple risk factors, since the former can confound the results of epidemiological studies significantly
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