Alzheimer’s disease: still a perplexing problem

What have we learnt about the pathogenesis of Alzheimer’s disease?

When Deter died, Alzheimer asked for her brain to be sent to his laboratory and found neurons containing “a tangled bundle of fibrils” and “storage of a peculiar matter into the cortex”—what we now know as neurofibrillary tangles and amyloid plaques, both considered pathological hallmarks of Alzheimer’s disease.2

Since that first study, understanding of how these lesions develop has been slow. Even by the 1980s, a review concluded that “the pathogenesis and aetiology of Alzheimer’s disease remain unknown territory.”3 Now, there are three main hypotheses.

The most popular model is the amyloid hypothesis. This is based on the pathological formation of the amyloid plaques seen by Alzheimer, which are directly toxic to cells as well as disrupting neurotransmission. These extracellular plaques mainly comprise insoluble fibrils of amyloid beta (Aβ) peptide, which is formed through cleavage of amyloid precursor protein (APP) by the enzymes β-secretase and γ-secretase. The normal roles of Aβ peptide and its precursor protein are unknown, but Aβ peptide circulates in the cerebrospinal fluid and can form toxic soluble oligomers or aggregates, which may precede plaques.

Convincing evidence for the role of amyloid comes from genetics. All three genes responsible for familial or early onset Alzheimer’s disease code for parts of the amyloid cascade: one is the APP gene and the others are presenilin genes that encode proteins interacting with γ-secretase. The most prevalent genetic risk factor for late onset disease is the ε4 allele of APOE, a gene for lipid transport in the brain. Over two thirds of people with Alzheimer’s disease are carriers of ε4, although only about 15% of the population possess it, and this allele is thought to promote deposition of Aβ peptide into plaques.4 People with Down’s syndrome are also at risk of early onset Alzheimer’s disease because of overexpression of the APP gene on chromosome 21.5 Conversely, a protective mutation that prevents β-secretase cleaving amyloid precursor protein leads to reduced Aβ levels and reduced rates of Alzheimer’s disease.6 However Aβ does not correlate strongly with brain atrophy; nor is it always detected in people with early Alzheimer’s-like neurodegeneration.7

The other feature of Alzheimer’s disease—neurofibrillary tangles—is caused by another insoluble protein, Tau. Tau stabilises microtubules, which in turn maintain the axons connecting neurons to one another. In people with Alzheimer’s disease, phosphate is excessively added to tau protein, and this “hyperphosphorylated” tau is the causative agent in the second hypothesis of Alzheimer’s disease.8 Hyperphosphorylated tau may weaken axons because it does not bind to microtubules, and it also forms protein filaments, which later form neurofibrillary tangles. The presence of neurofibrillary tangles correlates better with neuronal loss and with cognitive status than the presence of amyloid plaques.9

The third and oldest hypothesis of Alzheimer’s disease revolves round the neurotransmitter acetylcholine. Less acetylcholine is present in the brains of people with Alzheimer’s disease than in those of people without dementia. This is thought to be due to degeneration of the basal nucleus, the area of the brain that stimulates acetylcholine production and release through projections all over the cortex.10 At a cellular level, acetylcholine is thought to help with long term potentiation, a mechanism of permanently altering neuronal connections that is probably used to store memories. Another neurotransmitter that is found in cortical areas involved in memory and learning is glutamate, and excess glutamate levels in Alzheimer’s disease have been suggested to cause chronic activation of the N-methyl-D-aspartate (NMDA) receptor, allowing intracellular calcium overload and neuronal death from excitotoxicity.11

Difficulty of diagnosis

It was Deter’s unusually young age at onset of dementia that attracted Alzheimer’s attention, and for half a century his eponymous disease was thought to be a rare form of early onset dementia. By the 1980s, however, it was widely accepted that Alzheimer’s disease was the cause of most “senile” dementias and that such dementia was not a normal part of ageing. Nevertheless, identifying it proved tricky, and the widely used 1984 NINCDS-ADRDA criteria (produced by the US National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association) stated that definitive diagnosis was possible only by postmortem examination or brain biopsy.12

Early identification and accurate diagnosis have been recurring problems in research, with up to 25% of participants in a phase III trial this year thought to have been misdiagnosed.13 Even tissue analysis is not accurate in older people with dementia, who often have multiple types of brain abnormality. One study found infarcts in over half of people with probable Alzheimer’s disease, and a quarter of those fulfilling pathological criteria for the disease had normal cognition.14 Plaques and tangles seem to be common in older people and may not correlate with clinical symptoms. Furthermore, cerebrovascular risk factors and disease may contribute to Alzheimer’s disease.15

Clinically, normal ageing is viewed as distinct from dementia. However, age is the single most important risk factor for dementia, with the risk in people over 90 years being 25 times that in people in their late 60s. Some argue that gradual cognitive decline and the development of plaques and tangles may be part of normal ageing, which forms a continuum with Alzheimer’s disease and differs only in the extent of the decline.16 17 The cut-off point for diagnosing disease then becomes arbitrary and socially determined. Further research into normal ageing is needed.

New clinical and research criteria for Alzheimer’s were developed in 2011. As well as noting that the characteristic brain abnormalities could be seen in people with normal cognition, they also incorporated advances in biomarkers and genetics.18 However, the authors said that no one biomarker could give a “high probability” of disease.18

Analysis of Aβ peptide, tau, and other compounds in cerebrospinal fluid can be combined to give >90% sensitivity and >80% specificity in predicting Alzheimer’s disease in people with mild cognitive impairment or to distinguish Alzheimer’s from other dementias.19 20 Blood concentrations of Aβ peptide and tau are unreliable predictors, but a recent study proposed that testing for 10 lipid metabolites (found through screening thousands of compounds) had >90% sensitivity and specificity in predicting who would develop mild cognitive impairment or Alzheimer’s and who would not.21 However, only 28 of those tested developed Alzheimer’s, and further larger studies are awaited.

In 2004, a team at the University of Pittsburgh found a radioactive compound that could bind to Aβ peptide and be detected by positron emission tomography (PET), heralding a potential imaging test for Alzheimer’s.22 However, a recent systematic review found that although amyloid PET scans had a 85% sensitivity and specificity in differentiating Alzheimer’s disease from a normal brain, the specificity was only 56% for detecting which people with mild cognitive impairment would progress to Alzheimer’s disease.23 The review also looked at magnetic resonance imaging, which shows a characteristic pattern of medial temporal lobe and hippocampal atrophy in Alzheimer’s disease and has a sensitivity of 75% compared with healthy controls. Nevertheless, clinical diagnosis remains the most accurate method of identifying the disease.18 24

Treatment prospects

The cholinergic hypothesis has yielded all but one of the few drugs available for treating Alzheimer’s. Anticholinesterases, which inhibit the breakdown of acetylcholine, were developed during the second world war as nerve toxins or pesticides. Tacrine, one of these anticholinesterases, was then shown in 1986 to improve cognition in people with Alzheimer’s disease,25 and second generation derivatives with less hepatotoxicity were soon developed. Donepezil, galantamine, and rivastigmine have a small effect on cognition, activities of daily living, and behaviour at up to one year and are approved by the National Institute for Health and Care Excellence for mild to moderate disease.26

Memantine, an NMDA glutamate receptor antagonist that was originally developed to treat diabetes, also has a small benefit on short term cognition and behaviour.27 It is the only non-anticholinesterase approved by NICE but it is effective only in more severe disease. No other NMDA receptor antagonists have been developed—memantine seems to be unique in blocking the chronic activation of glutamate receptors seen in Alzheimer’s disease without stopping normal transmission.28

No new drug has been licensed for Alzheimer’s since memantine was approved in 2002 in the UK. Decreased numbers of serotonergic neurons are also reported in Alzheimer’s disease, and both monoamine oxidase inhibitors and selective serotonin reuptake inhibitors may improve overall function, but this may be partly due to their antidepressant action.29 Studies are also investigating potential drugs targeting less well researched neurotransmitter pathways, such as histamine, GABA, and adenosine.30

Perhaps the biggest disappointment in Alzheimer’s research over the past decade is the failure of proposed treatments that target Aβ peptide. A trial of active immunisation with the first Aβ vaccine was stopped after it unexpectedly caused meningoencephalitis in 6% of participants, and a later analysis did not show clinical benefit anyway.31 32 A subsequent vaccine was found not to affect Aβ levels in the cerebrospinal fluid or cognitive function.33 Phase III trials of two monoclonal antibodies against Aβ, solanezumab and bapineuzumab, also failed to meet their primary endpoints of improved cognitive function.34 35 Attempts to disrupt production of Aβ peptide with the γ-secretase inhibitors semagacestat and avagacestat were abandoned after unconvincing trial outcomes.36 37 Another drug, tramiprosate, was thought to be able to stop Aβ from aggregating, but this too did not show any clinical benefit.38 Now β-secretase inhibitors are under development.39

The failure of treatments aimed at Aβ peptide has led some researchers to question the validity of the amyloid hypothesis.40 Supporters have suggested that one reason is treatments need to be started much earlier to prevent Aβ deposition. A study in people with familial disease and their children found that Aβ levels are altered 25 years before the onset of symptoms.41

Less interest has been shown in hyperphosphorylated tau, which is also more difficult to target than amyloid because it is intracellular. One potential treatment is modified methylene blue, which seems to prevent tau from aggregating to form the tangles, and showed enough promise in one phase II trial to proceed to phase III trials with a related derivative.42 Trials are also underway for drugs that stop phosphorylation of tau and antibodies against tau.43

Without effective treatment, prevention remains important. This is best characterised as developing a “cognitive reserve” in early life from education and occupation. Thereafter maintenance of this reserve depends on continuing mentally stimulating activities and social engagement, as well as avoiding recognised risk factors, including obesity, hypertension, diabetes, lack of exercise, and poor diet.44

Alzheimer ended his case report with the words “We will gradually arrive at a stage, when we will be able to separate out individual disease from the large illness categories of our textbooks.” Last year, Auguste Deter’s disease was finally understood when German researchers found that her DNA had a rare mutation in the presenilin 1 gene that causes early onset Alzheimer’s disease.45

Research into Alzheimer’s and other dementias now has a budget of £50m (€63m; $86m) a year in the UK. This is still a tenth of cancer research funding, and for every £1m of related health and social care costs, cancer research receives £130 000 whereas dementia research receives £5000.46 At the G8 summit, David Cameron pledged to double dementia research spending by 2025 (by when the average voter’s age will be over 50 years47) and Jeremy Hunt added, “We would like a cure to be available by 2025. It’s a big, big ambition to have. If we don’t aim for the stars we won’t land on the moon.”48

The difficulty is that it is a much harder mission for us to escape plaques, tangles, and atrophy than to escape gravity.