Alzheimer’s Disease

Alzheimer's dementia is now endemic and on the increase, afflicting at least 2 in 10 people over the age of 70 in the USA. From a US perspective, Boyles wrote: “The number of Americans with Alzheimer's disease will triple over the next 50 years unless new ways to prevent or treat the degenerative condition are found, according to newly revised national figures. Thirteen million elderly people in the U.S. are projected to have the disease in the year 2050, compared to about 4.5 million today. The larger-than-expected increase could easily overwhelm the nation's health-care system within the next few decades. Alzheimer's Association president Sheldon Goldberg suggested that the approaching epidemic represents the health-care crisis of the century.” By 2010, the world cost of dementias was US $604 billion. Alzheimer's Disease International foresees an 85% increase in cost by 2030, with an increasing cost in developing countries.

According to neurologist, Dennis Selkoe:"The loss of memory, judgment and emotional stability that Alzheimer's disease inflicts on its victims occurs gradually and inexorably, usually leading to death in a severely debilitated, immobile state between four and twelve years after the apparent onset. Genes that confer susceptibility influence the handling of amyloid precursor protein (APP) PS1, PS2, and APP mutations cause overproduction and accumulation of the neurotoxic derivative, amyloid-peptide, the main event in AD. APP accumulation triggers the accumulation of tau protein in neurofibrillary tangles. “

Memory loss in Alzheimer’s disease has become a focus of research activity. In Alzheimer's patients, an old region of the temporal lobe, the hippocampus, is progressively damaged. The hippocampus and related medial temporal processors are essential to the processing of memory. A severely impaired Alzheimer's patient will continue to live, however, and function as a real-time processor enjoying eating and other routine activities but there is no remaining sentient being capable of skillful tasks, meaningful connections, proper sequencing and appropriate decisions. Alzheimer's disease probably progresses over several years to one or two decades and the diagnosis is usually made late in the disease.

Cognitive problems are

1. Short-term memory loss as revealed by the: inability to repeat three short words within a minute of hearing them.
2. Problems doing simple arithmetic showing up as difficulty with calculations, balancing checkbooks and making change.
3. Repetition and perseveration: repeating the same stories and asking the same questions.
4. Difficulty driving, especially getting lost on familiar routes.
5. Poor judgment and inappropriate behavior.
6. Interrupted sequencing and disorganization shows up as the inability to complete familiar tasks without direction.
7. Forgetting names of relatives, friends and neighbors.
8. Inability to learn new information.
9. Withdrawal from social and recreational events.
10. Language impairment in Alzheimer's dementia begins with word-finding difficulties and semantic confusions or substitutions, such as saying aunt instead of sister; speech remains fluent and grammatically correct. With dementia progression, anomia is more evident with comprehension difficulties, and loss of fluency. Advanced dementia involves complete loss of meaningful communication replaced by mutism, automatic repetition of words said by somebody else, and repetition of meaningless words or phrases.

Johnson et al followed 444 volunteers aged 60 to 101 years; 134 progressed to dementia. They concluded that cognitive deficits that predate the onset of obvious Alzheimer's disease can be detected by tests for global, verbal, and working memory, executive function, and visuospatial abilities. Decline of cognitive function can be recognized 3 years before the diagnosis of Alzheimer's disease by spatial tests that require coordination of hand, eye, and visual representation; 2 years before by tests for global memory, and 1 year before diagnosis by tests for verbal and working memory.

As dementia advances, patients lose the ability to self-manage and eventually require custodial and nursing care. The disability is less obvious if the aging person lives in an extended family since other family members contribute the missing cognitive functions, supply custodial care and will often minimize or deny the cognitive disability. In family groups, emotional changes are more disruptive than cognitive decline. A couple or solitary person living alone will become more disorganized, disoriented and will eventually fail to sustain self-care. Episodes of confusion, sometimes with hallucinations will draw attention to deteriorating brain function.

Often dementia is linked to dysphoria and angry outbursts are common. I recall a retired English teacher in a group home who would dress in a suit with his tie in disarray. Looking quite eccentric, he played solitaire everyday in the dining area, arranging chaotic columns of cards in random order; he hissed and hit the ladies if they dared to assist him.

The brains of Alzheimer's sufferers develop deposits of the protein, beta amyloid. Amyloid precursor protein breaks down into A 1–42 peptides, which aggregate. Researchers proposed that injecting beta amyloid into the blood would trigger an immune response that might remove the protein. Tests in mice showed benefits of the amyloid “vaccination” Trials in human Alzheimer's patients were halted in January 2002, when patients developed meningitis and encephalitis – immune-mediated inflammatory responses that suggested that the vaccinations excited a general attack on brain tissues. Jucker et al injected elderly mice with antibodies against amyloid. Five months later, the mice had smaller deposits of the amyloid in their brains, but they developed hemorrhages in cerebral blood vessels. The future prospects for an Alzheimer’s vaccine are dismal. A second feature of AD is the the intracellular accumulation of hyperphosphorylated tau proteins that form neurofibillary tangles.

The amyloid theory of causation alone is no longer tenable. You might argue that the deposits of amyloid proteins, tau proteins and peptides are late artifacts of a disease process that damages and kills neurons and that removing the proteins in advanced disease will not incur any benefit. Kerrup strongly stated the case against the amyloid hypothesis:" Alzheimer's disease (AD) is a biologically complex neurodegenerative dementia. Nearly 20 years ago, with the combination of observations from biochemistry, neuropathology and genetics, a compelling hypothesis known as the amyloid cascade hypothesis was formulated. The core of this hypothesis is that it is pathological accumulations of amyloid-β, a peptide fragment of a membrane protein called amyloid precursor protein, that act as the root cause of AD and initiate its pathogenesis. Yet, with the passage of time, growing amounts of data have accumulated that are inconsistent with the basically linear structure of this hypothesis. And while there is fear in the field over the consequences of rejecting it outright, clinging to an inaccurate disease model is the option we should fear most. This Perspective explores the proposition that we are over-reliant on amyloid to define and diagnose AD and that the time has come to face our fears and reject the amyloid cascade hypothesis."

Schilling et al summarized the expanding scope of AD research: "Recent advances in neurobiology and PET have helped redefine Alzheimer's disease (AD) as a dynamic pathophysiological process, clinically characterized by preclinical, mild cognitive impairment due to AD and dementia stages. Though a majority of PET studies conducted within these populations have to date focused on β-amyloid, various 'nonamyloid' radiopharmaceuticals exist for evaluating neurodegeneration, neuroinflammation and perturbations in neurotransmission across the spectrum of AD. Importantly, findings using such tracers have been shown to correlate with various clinical, cognitive and behavioral measures. In the context of a growing shift toward early diagnosis and symptomatic and disease-modifying clinical trials, nonamyloid PET radiotracers will prove of use, and, potentially, contribute to improved therapeutic prospects for AD."

Dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is diagnosed by the presence of Lewy bodies in neurons of the brainstem, diencephalon, basal ganglia and neocortex. Lewy pathology results from protein misfolding and the accumulation of alpha-synuclein in the cell cytoplasm. There are similarities with Alzheimer's disease and Parkinson’s disease and there may be a common underlying disease process. In both DLB and AD, reductions in acetylcholine and abnormalities in acetylcholine receptors are found. Drugs to improve acetylcholine activity have been disappointing, but patients with DLB may receive greater benefits from cholinergic therapy. Patients with DLB who display parkinsonian signs have dopamine deficiencies similar to patients with PD, although DLB patients may have no benefit from levodopa treatment. They do have severe adverse reactions to dopamine-blocking psychotropic drugs.