Alzheimers Disease Etiology- Biology and Treatments

Introduction

Alzheimer’s disease (AD) is a type of dementia characterized by the progressive loss in cognitive function due to neurodegeneration that results in gradual memory loss and eventually the inability to carry out tasks of daily living. The two types of AD are distinguished by age of onset and etiologies; early-onset AD develops prior to age 65 and has strong genetic associations while late-onset AD develops after age 65 with a more complex etiology. Late-onset AD accounts for 90-95% of AD cases (Harman 2002). Aging is a strong risk factor for developing late-onset AD. Given that the global population of people ages 65 and up is expected to increase from 26.6 million in 2006 to 106.8 million by 2050 (Brookmeyer et al. 2007) AD is a growing public health concern in regards to disease management and development of innovative treatments.

The prevalence of AD globally is 4.4%, with 1 in 10 people over age 65 and nearly one-third of people over age 85 affected by dementia in developed countries (Qiu et al. 2009). AD prevalence is the greatest in East Asia, followed by Western Europe, South Asia, and North America (Prince et al. 2015). Disease burden is anticipated to be the greatest in low and middle-income countries with the fastest growth in the elderly population and limited access to care (Prince et al. 2015). By 2050, the U.S. population of adults with AD is projected to increase to 13.2 million. With 43% of AD patients requiring a high level of care, the financial and healthcare burden of AD is expected to rise (Qiu et al. 2009). Given that the burden of AD will increase over the coming decades with costly impacts on health care and social services, it is necessary to continue AD research to identify a cause and develop novel therapies.

Etiology

Alzheimer’s disease is a multifactorial disease with several genetic, person, and lifestyle risk factors that contribute to development of disease. Although many risk factors for AD have been identified a cause has not yet been found. Of the genetic risk factors identified, apolipoprotein E alleles, with ethnic and sex variability in risk of developing AD, and TREM2 gene mutations have the strongest associations with AD. Lifestyle risk factors include hypertension, obesity, diabetes, and education. The development of AD requires a combination of these risk factors that induce the production of neurotoxic amyloid beta (Aß) and neurofibrillary tangles (NFTs), the agents of AD.

Apolipoprotein E (apoE) has been identified as playing a role in AD pathology. ApoE is naturally produced and is involved in lipid transport (Ridge et al. 2013; 2018 Feb 27).  In AD it is thought that apoE regulation of Aß is altered (Kanekiyo et al. 2014). There are three apoE alleles that differ in the risk they confer to AD; the ε2 and ε3 alleles are protective but the ε4 allele increases risk for AD (Ridge et al. 2013). Additionally, it appears that ethnicity modulates the risk of AD conferred by the apoE ε4 allele, conferring greater risk among Caucasians and Japanese than African Americans and Hispanics (Ridge et al., 2013). The apoE ε4 allele is an established risk factor for the development of AD however it is not causative and the risk that carrying this gene confers is likely modulated by other factors such as ethnicity and lifestyle.

Mutations in the TREM2 gene have also been implicated in AD pathology. The TREM2 gene codes for a receptor expressed in myeloid cells, the principal innate immune cell in the brain (Hickman and El Khoury 2014) and in greater abundance in the hippocampus and neocortex, brain structures affected by neurodegeneration in AD (Guerreiro et al. 2013 Jan 9). A rare missense mutation in the TREM2 gene was identified in Islanders that confers significant risk of AD (Jonsson et al. 2013 Jan 9) and a loss of function mutation increases the risk of late-onset AD in heterozygous carriers (Hickman and El Khoury 2014). This loss of function mutation promotes the production of Aß and reduces Aß phagocytosis and degradation (Hickman and El Khoury 2014).

In addition to the genetic risk factors discussed above, several lifestyle risk factors for AD have been identified including cardiovascular risk factors and obesity. Cardiovascular risk factors (smoking, hypertension, high cholesterol, and diabetes) in mid-life are associated with a 20-40% increased risk of AD in a dose-dependent fashion (Whitmer et al. 2005). Hypertension that develops in mid-life and persists into late-life is associated with a greater risk of dementia (McGrath et al. 2017). Furthermore, the risk of hypertension for AD in late-life might be influenced by sex, with females having a 65% increased risk of developing dementia if hypertensive in mid-life but no such association among males (Gilsanz et al. 2017). Midlife insulin resistance is also a risk factor for Aß accumulation (Ekblad et al. 2018 Feb 23) and patients with diabetes and the apoE ε4 allele have more Aß plaques and NFTs in the brain (Peila et al. 2002). Obesity is linked to AD via several single-nucleotide polymorphisms (Hinney et al. 2014). In people who are obese, leptin and adiponectin lose their neuroprotective role as the brain becomes resistant to leptin and the levels of adiponectin decrease (Letra et al. 2014). Research conducted by Nuzzo et al. (2015) further supports this association, finding that obese mice fed a high-fat diet had elevated Aß accumulation. Addressing these modifiable risk factors in mid-life may help reduce the risk of developing AD in late-life.

Higher educational attainment and continued cognitive stimulation in later life are protective against AD. Amieva et al. (2014) found that individuals with AD who had education beyond 6 years of primary school showed delayed cognitive decline before diagnosis compared to individuals with less education. Participating in cognitive leisure activities in late-life, like reading books, newspapers, and magazines, solving crossword puzzles, and attending courses and professional training, has a protective effect as well (Sattler et al. 2012). Higher educational attainment may be associated with reduced risk of AD and delayed cognitive decline if AD develops because of its association with increased hippocampi and amygdalae size. In individuals with AD, the hippocampi are larger in those who had 20 years of formal education compared to those with 6 years (Shpanskaya et al. 2014). The role of education in hippocampal size is further implicated by Tang, Varma, Miller, and Carlson (2017) who found that the left hippocampus is larger than the right, possibly due to education honing retrieval of verbal memory by the left hippocampus through increasing intellectual ability and literacy skills.

Biology

Alzheimer’s disease results in the progressive loss of neurons in the cerebrum. The first structures affected are the hippocampi followed by the amygdala (Pini et al. 2016). As the disease progresses so does neuronal loss throughout the cerebrum. In AD, Aß peptides and neurofibrillary tangles (NFTs) formed by tau protein cause synaptic damage that leads to apoptosis. Additionally, the innate immune system in the brain does not function properly in AD and therefore does not remove Aß peptides before they aggregate to form plaques.

Amyloid beta is naturally produced in the brain by the cleavage of amyloid precursor protein (APP), but when APP is cleaved by ß-secretase Aß peptides are formed that can cause synaptic and mitochondrial damage and aggregate to form plaques (Querfurth and LaFerla 2010). In healthy individuals, Aß peptides are cleared by microglia and enzymes but these mechanisms deteriorate in individuals with AD and the Aß peptides accumulate and result in neurodegeneration (Sarlus and Heneka 2017). Aß plaques cause neuronal cell death by accumulating around neurons, impairing normal function and inducing an inflammatory response. More attention recently has been given to Aß peptides, which lead to apoptosis in neurons through synaptic damage and inhibition of mitochondrial function.

Aß peptides cause synaptic damage in the hippocampus by aggregating and creating pores in the cell membranes that allows calcium ion entry into the cell. Over time, these pores become non-selective and allow flux of large molecules like ATP and glucose that alters cell metabolism and disrupts homeostasis resulting in apoptosis (Sepúlveda et al. 2014). Aß also produces reactive oxygen species that initiate oxidative stress which leads to mitochondria in the cell releasing cytochrome C and inducing apoptosis (Querfurth and LaFerla 2010). Both Aß peptides and APP can enter the mitochondria where they disrupt the electron transport chain and ATP production (Caspersen et al. 2005; Reddy and Beal 2008). Synapses are sites of high mitochondrial activity because ATP is needed for neurotransmitter release (Reddy and Beal 2008), so inhibition of mitochondrial activity by Aß also results in synaptic damage.

NFTs are intracellular aggregations of hyperphosphorylated tau protein and also cause neurodegeneration. Tau protein is a component of the cytoskeleton of neural cells but when hyperphosphorylated tau proteins have an affinity for themselves and destabilize the cytoskeleton (Iqbal et al. 2005; Spillantini and Goedert 2013). Tau protein is phosphorylated by glycogen synthase kinase -3ß (GSK-3ß) (Rankin et al. 2007) which can be activated by Aß peptides (Takashima 2006). Tau protein mediates synaptic damage by inhibiting extracellular signal-regulated kinase (ERK) signaling that is key in cell survival (Sun et al. 2016).

Approaches

Current treatment of AD relies on two types of medications: acetylcholine esterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonists. AChEIs work by slowing the degradation of acetylcholine (ACh) by inhibiting acetylcholine esterase which allows more ACh action at the synapses (Nelson and Tabet 2015). When cholinergic neurons are lost during the course of AD, ACh synthesis and receptor signaling are reduced (Auld et al. 2002). AChEIs are most effective in slowing progression of cognitive decline in mild to moderate cases and less effective in severe AD (Gillette-Guyonnet et al. 2011). Memantine is an NMDA receptor antagonist (Tariot et al. 2004) that helps mitigate the loss of NMDA receptor function due to Aß peptides (Snyder et al. 2005). Memantine is not effective for mild cases of AD (Nelson and Tabet 2015) but it is effective in moderate to severe cases, especially when used in combination with AChEIs (Tariot et al. 2004).

Although AChEIs and NMDA receptor antagonists are the current pharmacological treatments available for AD, they are only able to slow the progression of the disease and lose effectiveness as AD progresses. The challenge in designing a drug to prevent or cure AD is the multifactorial nature of the disease with genetic and lifestyle risk factors. Even when non-pharmacologic interventions (controlling blood pressure, cognitive stimulation therapy, healthy diet and exercise, and maintaining social networks) (Nelson and Tabet 2015) are used as part of a comprehensive treatment plan and initiated early in disease progression, the best that current treatments can offer is to slow the natural progression of the disease

With AD prevalence expected to increase worldwide across all races and ethnicities, the culture of different populations is an important consideration when designing intervention strategies. Social and economic barriers that prevent access to health care and social services among different populations need to be understood to identify and implement the best treatment specific to that population. Cultures also differ in how they view AD-related cognitive decline and may consider the memory loss a part of normal aging and therefore delay seeking treatment. An awareness of how cognitive decline in older age is defined culturally, how cultures differ in caring for the elderly, and how barriers to AD care services impacts each culture’s choice of treatment is key to developing successful interventions.

Proposed Solutions

The greatest challenge in developing treatment for AD that can prevent AD development or progression is that a specific cause has not yet been identified. However, recent research has identified new pharmacologic targets involved in the production of Aß and new therapies to reduce Aß and tau pathology.

Research by Hu, Das, Hou, He, and Yan (2018) identified the ß-secretase BACE1 as a potential pharmacological target for the treatment of AD. In a mouse model of AD in adults with BACE1 inhibition, it was observed that synaptic function improved and Aß plaque formation was prevented. Although some clinical trials of BACE1 inhibitors have stalled, with Merck stopping its clinical trial of verubecestat in February 2018 (Merck 2018), there is still hope of developing pharmacologic treatments targeting Aß and tau proteins (Amgen 2017).

A novel therapeutic approach being researched is the use of optogenetic stimulation to reduce Aß and tau phosphorylation. Using a light flickering at 40 hertz, (Iaccarino et al. 2016) found they could stimulate brain waves called gamma oscillations in a mouse model of AD and observed reduced Aß plaque formation and tau phosphorylation. This may lead to new non-invasive AD therapies, but more research is needed to investigate its effectiveness in humans.

With treatment approaches that target the production of toxic Aß and abnormal tau phosphorylation, it is conceivable that in the future we may be better able to prevent and stop the progression of AD.

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