Dementia is characterized by a progressive and debilitating decline in cognition, function and behavior. Its numbers are staggering: according to the World Health Organization, the total number of people with dementia worldwide in 2010 was estimated at 35.6 million and predicted to nearly double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050.
Each year, there are around 7.7 million new cases of dementia, implying one new case every four seconds. Its incidence rate increases exponentially with age, with the highest increase occurring after 70 years of age.
Alzheimer’s disease (AD) is the most common form of dementia worldwide, accounting for around 70% of dementia cases, with North America and Western Europe having the highest prevalence and incidence rates.
Healthcare costs for AD are massive: in the US alone, the estimated healthcare costs are of $172 billion per year. Despite these striking numbers and the extensive amount of research being conducted on AD, its exact pathological mechanisms remain to be determined, with a number of theories having been proposed. Risk factors for AD development include genetic factors, cerebrovascular disease, traumatic brain injury, hypertension, type 2 diabetes, obesity, and smoking. Neuroprotective factors include adequate diets, exercise and intellectual activity.
Hallmarks of the disease
There are some pathological features in AD brain tissue that are considered hallmarks of the disease. Specifically, amyloid plaques – extracellular deposits of the amyloid-beta (A-beta) peptide – and neurofibrillary tangles, intracellular accumulations of the hyperphosphorylated tau (p-tau), a microtubule assembly protein. Other characteristic changes include increased microglial reactivity and widespread loss of neurons, white matter and synapses.
Despite considerable controversy, the predominant line of research in AD has followed the amyloid hypothesis for the pathophysiology of AD, which claims that it is the A-beta peptide that causes AD and that neurofibrillary tangles, cell loss, vascular damage and dementia are a direct consequence of A-beta deposition.
However, evidence supporting this theory is not totally clear. In May, Nature Neuroscience published an interesting perspective article that overviews the arguments for and against this theory.
Supporting the amyloid hypothesis
According to the mentioned article, the strongest evidence supporting the role of A-beta as AD initiator comes from human genetics. There is a form of familial AD that is caused by mutations in genes which are directly involved in A-beta production, namely the gene that encodes the precursor to A-beta, the amyloid precursor protein (APP), and the genes that encode Presenilin 1 and 2, subunits of the complex that cleaves APP to generate A-beta. These mutations induce an enhanced accumulation of amyloid plaques.
In sporadic forms of AD the strongest genetic risk factor is apolipoprotein E (ApoE), mainly produced by astrocytes in the brain, and that is responsible for transporting cholesterol to neurons via ApoE receptors. There are different alternative forms of the APOE gene, each having different effects in the risk of AD development. ApoE3 is the most common form, ApoE2 decreases the risk of AD development, and ApoE4 is known to increase the risk for AD.
An estimated 20–25% of the population carries at least one copy of ApoE4, having an increased risk of AD of around 4-fold; in the 2% of the population that carries two E4 copies, on the other hand, the increased risk is of around 12-fold. Experimental studies have shown that ApoE4 does indeed promote A-beta aggregation and deposition and that the reduction of ApoE levels can decrease amyloid plaque development.
Against the amyloid hypothesis
The tau protein is regarded as essential for AD-associated neurodegeneration. Arguments against the amyloid theory stem from the fact that there are anatomic and temporal mismatches between A-beta pathology, p-tau aggregation and neurodegeneration in AD.
For instance, A-beta deposition occurs first and most severely in regions that do not match those where neuronal death is first observed, whereas tau pathology correlates much more closely with neuronal loss, not only anatomically, but also temporally, since many clinically asymptomatic individuals are known to already have extensive amyloid plaque pathology.
One explanation presented in the mentioned article is that, in addition to amyloid plaques, A-beta can be present in the form of small molecular complexes (oligomers) that can mediate AD pathology. These oligomeric A-beta molecules can actually be found in brain regions showing extensive neuronal loss, and their presence seems to correlate more extensively with the development of dementia than the presence of amyloid plaques. Indeed, A-beta oligomers seem to accumulate with age, and be correlated with tau pathology in humans.
Therefore, a proposed model for AD pathology places A-beta as the primary initiator of AD: age-associated factors may induce oligomeric and fibrillar A-beta accumulation, leading to the appearance of the first plaques; after several years of A-beta aggregation, it somehow triggers the tau pathology, with neurofibrillary tangles, as well as other toxic proteins such as synuclein beginning to accumulate, prompting increased neurodegeneration. At this point, the degenerative changes become extensive, with neuronal loss, oxidative damage, inflammation, and clinical symptoms becoming evident.
What seems unclear is what induces the aggregation and accumulation of A-beta in the first place and how it is related to age. It is possible that multiple factors that may enhance A-beta production and aggregation or suppress its clearance can contribute to this throughout life.
In what concerns AD therapy, it seems that when the disease becomes clearly symptomatic, treatments are less likely to have any major effects. Ideally, preventative strategies for AD would be the best approach, and therapies should be delivered as early in the process as possible; treatment options should focus on conditions that may induce the onset of A-beta accumulation in middle age. Monitoring the appearance of positive A-beta biomarkers would be invaluable for detecting the first signs of disease development and initiating therapeutic strategies.
References
Bettens K, Sleegers K, & Van Broeckhoven C (2013). Genetic insights in Alzheimer’s disease. The Lancet. Neurology, 12 (1), 92-104 PMID: 23237904
Duthey B (2013). Priority Medicines for Europe and the World Update Report, Background Paper 6.11 – Alzheimer Disease and other Dementias. World Health Organization.
Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M, & Alzheimer’s Disease International (2005). Global prevalence of dementia: a Delphi consensus study. Lancet, 366 (9503), 2112-7 PMID: 16360788
Musiek ES, & Holtzman DM (2015). Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nature neuroscience, 18 (6), 800-6 PMID: 26007213
Rapoport M, Dawson HN, Binder LI, Vitek MP, & Ferreira A (2002). Tau is essential to beta -amyloid-induced neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America, 99 (9), 6364-9 PMID: 11959919
Reitz C, & Mayeux R (2014). Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochemical pharmacology, 88 (4), 640-51 PMID: 24398425
Verghese PB, Castellano JM, & Holtzman DM (2011). Apolipoprotein E in Alzheimer’s disease and other neurological disorders. The Lancet. Neurology, 10 (3), 241-52 PMID: 21349439
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