The coming problem of HIV-associated Alzheimer's disease

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Background
Dementia associated with human immunodeficiency virus (HIV) is a subcortical neuropathology that does not resemble Alzheimer's disease. However, several lines of evidence suggest that in the future there may be significant numbers of long-term HIV survivors with true Alzheimer's disease. Age is itself a risk factor Alzheimer's disease, and an aging population and widespread use of highly active antiretroviral therapy (HAART) means more elderly HIV patients. Immune reconstitution inflammatory syndrome, lypodystrophic effects of HAART medications, HIV-induced amyloid deposition and excitotoxic effects of gp120 and TAT protein all could be risk factors for subsequent Alzheimer's disease. Finally, HIV patients will have greater vulnerability to common non-HIV pathogens that may contribute to development of Alzheimer's disease.

Presentation of the hypothesis
It is predicted that in the future there will be seen measurable numbers of long-term HIV survivors on HAART who have Alzheimer's disease, with a cortical deficit profile on neuropsychological tests, pronounced cerebral atrophy seen on brain MRI, and neurofibrillary tangles, senile plaques and neuronal loss in post-mortem brain tissue.

Validating the hypothesis
The hypothesis could be validated through case reports, longitudinal clinical studies, brain bank programs and animal models. Implications of the hypothesis Management of HIV may become more difficult, requiring greater provisions for long-term care of HIV patients with chronic dementia. However, it may be possible to reduce or prevent HIV-associated Alzheimer's disease through early use of cholinesterase inhibitors, glutamate-blocking drugs, insulin sensitizing agents, statins and anti-oxidants.


The coming problem of HIV-associated Alzheimer's disease

Joseph Martin Alisky

Medical Hypotheses 69(5): 1140-1143

2007

Background
As the HIV pandemic enters its third decade, the dementia associated with human immunodeficiency virus (HIV) up to now has been a very different entity than the dementia of Alzheimer's disease [1]. HIV dementia is a subcortical disorder affecting primarily white matter and glia, while Alzheimer's disease is a cortical disorder, with three hallmark findings on post-mortem brain specimens first described by Alois Alzheimer in 1907- neurofibrillary tangles, neuritic plaques and neuronal loss [1] and [2]. Clinical symptoms of HIV dementia are characterized by apathy, amotivation and motor coordination problems [1], [3], [4] and [5]. There are cognitive deficits such as impaired remote memory, apraxia and executive function that can be seen on neuropsychological testing, and some neuronal loss can be demonstrated with brain magnetic resonance imaging (MRI), but one does not see the inexorable, progressive global intellectual deterioration of Alzheimer's disease nor the profound cerebral atrophy that is a hallmark of brain imaging from patients with late stages of Alzheimer's disease [3], [4], [5] and [6]. Furthermore, to a large degree, HIV-associated dementia has been a reversible disorder, with cognitive symptoms generally clearing if viral replication can be suppressed to undetectable levels with highly active anti-retroviral therapy (HAART) [7]. However, recently some patients on HAART with suppressed viral replication have started manifesting persistent cognitive deficits, suggesting that HIV-associated dementia may be evolving [8] and [9]. In light of this, there are now worries that HIV patients will start presenting with Alzheimer's disease, independent of any classical HIV encephalopathy that may be present [1].

The sum of several different factors could produce the above scenario. An aging population will mean more elderly acquiring new HIV infections, and because of HAART more HIV patients will live to an age where Alzheimer's disease is common [1]. Prevalence of dementia in the general population is roughly 10% over age 65 and approaches 50% in the oldest old, with Alzheimer's disease being the single most common cause of dementia [10] and [11]. In addition to simple demographics, a newly observed phenomenon in patients on HAART called immune reconstitution syndrome may increase the incidence of Alzheimer's disease in long-term HIV survivors. Immune reconstitution syndrome is an autoimmune condition that results when reconstituted T cell populations attack opportunistic pathogens that had proliferated while the T cells were under siege from HIV, producing connective tissue disease symptoms or vasculitis [12], [13] and [14]. Given the links between chronic inflammation and Alzheimer's disease [15], it is a reasonable premise that patients with immune reconstitution syndrome might have a higher risk of Alzheimer's disease than they would otherwise. This would also be true for patients who suffer lypodystrophic and metabolic effects of HAART medications, which cause hyperlipidemia, alterations in body fat distribution to metabolically inactive areas, insulin resistance and coronary artery disease, all known Alzheimer's disease risk factors [1], [16], [17] and [18]. In yet another route potential route to Alzheimer's disease pathogenesis, HIV leads to increased amyloid levels in the brain, even in patients without dementia symptoms [1] and [19]. If amyloid is a cause of Alzheimer's disease (rather than a marker), long-term HIV patients will be more vulnerable from heightened amyloid burden. Independent of any amyloid-mediated mechanisms, HIV is also neurotoxic in and of itself, from chemokines and from excitoxic effects of the gp120 and TAT proteins [1], [20] and [21]. This might increase risk for Alzheimer's disease on the grounds that any kind of neuronal injury has such an effect, as has already been shown for prior head injury and stroke [22] and [23]. Finally, it has been speculated that common infectious agents such as Chlamydia pneumonia may accentuate Alzheimer's disease pathogenesis [24]. If so, HIV patients will be at increased vulnerability on this account, since even with HAART, there still seem to be gaps in immune surveillance such that common infections are even more common in people with HIV [25] and [26].

Presentation of the hypothesis

Based on the above lines of reasoning, it is predicted that in the future there will be appreciable numbers of long-term HIV survivors on HAART who have Alzheimer's disease, with a cortical deficit profile on neuropsychological tests, pronounced cerebral atrophy seen on brain MRI, neurofibrillary tangles, senile plaques and neuronal loss in post-mortem brain tissue.

Validating the hypothesis

Initially physicians involved in HIV care should publish case reports of any HIV patients with Alzheimer's disease. This will establish proof of principle that HIV and Alzheimer's disease can coincide. Subsequently, there could be longitudinal clinical studies over months and years. Patients should be encouraged to participate in brain bank programs, in which they agree in advance to provide post-mortem brain tissue for study. When the patients pass on, brain tissue is obtained as soon as possible after death for autopsy definitive diagnosis of Alzheimer's disease.

It may be possible to create animal models of HIV-associated Alzheimer's disease. Cats infected with feline immunodeficiency virus (FIV) and monkeys infected with simian immunodeficiency virus (SIV) already serve as models of HIV encephalopathy, producing a subcortical pathology very similar to that seen in HIV infections [27] and [28]. Nothing in these animals resembles Alzheimer's disease - no neurofibrillary tangles or plaques are seen. Perhaps if one took geriatric animals, especially those transgenic for amyloid overexpression, this might reproduce Alzheimer's disease neuropathology. The animals could be exposed to opportunistic pathogens to induce immune reconstitution syndrome, on the theory that multiple insults increase the likelihood of a final common manifestation of Alzheimer's disease. Successful creation of animal models would provide a means for testing new therapeutics and provide more insight into pathogenesis of HIV-associated Alzheimer's disease.

Implications of the hypothesis

If this hypothesis is correct, providing proper care for patients with HIV will become even more challenging. Just at the point when HIV is becoming in many cases a manageable chronic illness, society will be faced with the prospect of providing long-term care to HIV patients with Alzheimer's disease. If proof-positive of HIV-associated Alzheimer's disease is established, efforts to devise neuroprotective drug regimens should be initiated on an expedited basis. There are currently ongoing investigations looking at using cholinesterase inhibitors and the glutamate-blocking drug memantine in elderly with mild cognitive impairment to head off full-blown dementia [29] and [30]. Presumably, these medications could be used for HIV patients as well. In addition, preliminary research indicates that the insulin sensitizing agents such as pioglitazone, rosiglitazone and metformin and statins can blunt the lypodystrophic effects of HAART medications [31], [32], [33] and [34], and so they might also reduce risk of HIV-associated Alzheimer's disease. Monamine oxamine oxidase inhibitors like selegiline might be yet another way to attenuate HIV-induced neurotoxicity [35].

Investigating the possibility of HIV-associated Alzheimer's disease should be a top priority. If HIV-associated Alzheimer's disease is on the horizon, we have the chance now to pick up on it early and search for neuroprotective drugs. A new tragedy or historic opportunity to stop a problem before it starts- the choice may be ours.