Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

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.

Keywords: Alzheimer’s disease; Metabolic; pathogenesis; risk factors; sporadic; treatment.

Figure 1.

Risk factors of Alzheimer’s disease. Gene -environment interactions may be the underlying mechanism of sporadic AD. Environmental risk factors include those present in external environment or extra-genetic internal milieu of the body. The risk factors may affect the functions of AD-related genes or their regulatory regions by methylation, oxidation or other mechanisms. Gene polymorphisms, on the other hand, may aggravate the effects of the risk factors on AD pathogenesis. Drugs, diet and life-style may prevent the interaction of risk factors with AD pathogenic mechanisms.

Figure 1.

Metabolic risk factors and molecular pathogenesis of AD. AD pathogenesis is represented by interacting damage pathways spearheaded by soluble oligomers of amyloid beta peptide. Altered levels of metabolic risk factors e.g. hormones, vitamins, cytokines, metabolites etc. can affect APP expression and processing or intracellular trafficking, catabolism and clearance of amyloid beta peptide or induce oxidative stress or inflammatory response through interactions at multiple sites leading to neurodegeneration and characteristic proteinopathy of AD. ER-TGN, Endoplasmic reticulum trans- golgi network; BACE, Beta-site APP cleaving enzyme; IDE, Insulin degrading enzyme; LRP, Low density lipoprotein receptor related protein; NT, Neurotransmitter.