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How all-type dementia risk factors and modifiable risk interventions may be relevant to the first-generation aging with HIV infection? – Dementia Risk in HIV+ is Higher
 
 
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• The burden of dementia risk in aging PLHIV is higher than that in the general population
 
• once PLHIV have reached 60 + premature brain aging found consistently.....in some PLHIV with low comorbidities accelerated brain aging can be detected...... cART early initiation is now standard recommendation. However, there is no definitive evidence that it protects against dementia because no study could have been designed to assess this question. Early treatment is both beneficial against progression to AIDS and the occurrence of non-AIDS events [112]. Importantly, AIDS is a risk factor for HAND, so that a reduction of the prevalence of HAND will have an impact on the rate of potential dementia in PLHIV who will be aging while having been treated early.
 
•Discussed below: HIV-related immune compromise, chronic immune activation, immune senescence; ART neurotoxicity
 
The mildest forms of HAND are the most common in the cART era.. The prevalence of HAND has been recently the focus of some debates [56, 105], but even when taking the most conservative estimates, it is undeniable that a non-negligible part of the first generation who are aging with HIV infection has a much higher brain vulnerability burden compared to the general population entering the dementia age range. Furthermore, age is a risk factor for HAND and HAD and it is estimated that once 50 + PLHIV are considered, HAND prevalence goes up by 10%. .....They seem to still have a relapsing/remitting profile, although with greater intervals between episodes, which translate into long-periods of stability [107]. But when studies have long-term endpoints (> 10 years), or in those aged 60 + , progression is detected and even accelerated brain changes [108, 109, 110]. This is true to a greater extent in those with multiple comorbidities and unsurprising when referenced against what is established in the dementia literature (e.g., The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score, see [19] for an overview). Yet, it seems that even in some PLHIV with low comorbidities accelerated brain aging can be detected [108]. More studies are needed, especially once PLHIV have reached 60 + because the finding of accelerated brain aging is not consistent [28]it is, however, consistent for premature brain aging [111]. How HAND and the probable increasing contribution of vascular brain injury in aging PLHIV will play out deserve attention because these are yet again combined risk factors for all-types of dementia and well-established promoters of neurodegeneration.....Remaining stable on cART is still the best treatment to avoid HAND and avoid HAND progression once it has been diagnosed. Once on stable treatment, between 70 and 80% of PLHIV remain cognitively stable across years [56]. There is a good chance that some strategies to reduce HAND occurrence and progression will also be protective against dementia development, although empirical evidence is needed. cART early initiation is now standard recommendation. However, there is no definitive evidence that it protects against dementia because no study could have been designed to assess this question. Early treatment is both beneficial against progression to AIDS and the occurrence of non-AIDS events [112]. Importantly, AIDS is a risk factor for HAND, so that a reduction of the prevalence of HAND will have an impact on the rate of potential dementia in PLHIV who will be aging while having been treated early.
 
"it is important to recognize that a life-long treated chronic illness whether it is HIV or for example Type I diabetes [18] carries some added risk for dementia as people age. We should, therefore, advocate for an adapted HIV neurogeriatric response and obtain accurate estimates of dementia as people enter the at-risk dementia ages (60 +). This should not be construed as “fear mongering” but rather as appropriate preparedness. It is now widely recognized that there is a pattern of multi-comorbidities in aging PLHIV, some of which are well-established risk factors for dementia [19]-as we will review......A modeling study has projected that by 2030, about 85% of elderly PLHIV will have at least one non-AIDS comorbidity [7], many of which are recognized factors for dementia.....Age as the number one risk factor for dementia should be specifically considered in the aging HIV population. Indeed, data are converging to show that there is evidence of premature systemic aging, but limited evidence of accelerated systemic aging [20, 26]. Similarly, the evidence for premature cognitive and brain aging is stronger than that for accelerated aging. However, this research is based on cohorts where most PLHIV are aged < 60 years old-well before the dementia age range. Furthermore, when looking at specific conditions (i.e., cerebrovascular diseases and stroke), the weight of evidence favors accelerated brain aging.....the prevalence of geriatric syndromes such as frailty [30, 31, 32], multimorbidity [12, 33], polypharmacy and disability [34] is higher amongst older PLHIV than the general population, and the syndromes are observed at a younger age than expected [26, 35, 36, 37, 38]. In addition, the decline rate in physical activity is faster among seniors with HIV than without HIV [39]. Biological aging as measured by epigenetic aging shows evidence of both premature and accelerated aging in the HIV population [40] including in children [41, 42]. Overall, even if we only consider the premature age signal and greater age-prevalence of age-related conditions, this represents a major risk factor for dementia that is higher than in the general population. Its exact effect size determination demands large longitudinal studies with at least 50% age 60 + .......Cardiovascular health and risk factors - ART neurotoxicity - HIV-related immune compromise, chronic immune activation, immune senescence - Historical and ongoing HIV brain involvement - Cardiovascular health and risk factors and HIV - Psychiatric, psychological and emotional health, alcohol and substance use"
 
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How all-type dementia risk factors and modifiable risk interventions may be relevant to the first-generation aging with HIV infection?
 
European Geriatric Medicine (April 2019) Htein Linn Aung1,2,3 · Scherazad Kootar2 · Thomas M. Gates1,2 · Bruce J. Brew1,3 · Lucette A. Cysique1,2,3
 
Abstract
 
Purpose
 
The purpose of this review is to provide an overview of established risk factors for all-type dementia and results of interventions on dementia modifiable risk factors, all with relevance to aging people living with HIV (PLHIV).
 
Methods
 
Narrative literature review.
 
Results
 
Our review identifies a high prevalence of risk factors for dementia in the global HIV population that is entering dementia age range (60 +), in relation to both traditional and HIV-specific risk factors. This includes age (HIV-related premature aging and possibly HIV-related accelerated brain aging and cerebrovascular injury), HIV-related and non-HIV-related cardiovascular diseases burden with related-vascular brain damage, HIV-associated neurocognitive disorders, high mental health burden, low educational/socio-economic status, historical immune compromise, and persistent immune activation with consequent augmented immune senescence. Our review highlights that the results of interventions on all-type dementia modifiable factors show discrepancies between positive observational study results and inconclusive clinical trials. The main reasons for such discrepancies relate to the preventative framework that complex interventions’ trials have difficulty to emulate and the suboptimal measurement of cognitive change. Multi-domain intervention trials are now advocated to concomitantly tackle complex age-related comorbid profiles.
 
Conclusions
 
The burden of dementia risk in aging PLHIV is higher than that in the general population, particularly in the most vulnerable clusters. Epidemiological studies are urgently needed to provide accurate estimates. Lessons from interventions trials in all-type dementia on modifiable factors need to be carefully considered for enhancing trials’ potential in aging PLHIV. A comprehensive and preventative neurogeriatric healthcare response linked with HIV communities and dementia associations should be urgently put in place.
 
Aging does not always mean happy and healthy aging for people with chronic HIV infection [17]. However, this message needs to be explained with nuances to avoid further stigma in the HIV population at large. On the one hand, it is clear that potent ART has led to major health improvements in the health of the HIV population and has reduced the occurrence of the most severe form of HIV-associated neurocognitive impairment, namely HIV-associated dementia (HAD) to a rare diagnosis (2–4% of advanced chronic HIV-infected people, and less in early treated PLWH). On the other hand, it is important to recognize that a life-long treated chronic illness whether it is HIV or for example Type I diabetes [18] carries some added risk for dementia as people age. We should, therefore, advocate for an adapted HIV neurogeriatric response and obtain accurate estimates of dementia as people enter the at-risk dementia ages (60 +). This should not be construed as “fear mongering” but rather as appropriate preparedness. It is now widely recognized that there is a pattern of multi-comorbidities in aging PLHIV, some of which are well-established risk factors for dementia [19]-as we will review.
 
The comorbidities burden is probably the most relevant question in terms of HIV neurogeriatric care, while it is still important to understand the role of HIV even if suppressed. A modeling study has projected that by 2030, about 85% of elderly PLHIV will have at least one non-AIDS comorbidity [7], many of which are recognized factors for dementia.
 
Age and HIV
 
Age as the number one risk factor for dementia should be specifically considered in the aging HIV population. Indeed, data are converging to show that there is evidence of premature systemic aging, but limited evidence of accelerated systemic aging [20, 26]. Similarly, the evidence for premature cognitive and brain aging is stronger than that for accelerated aging [27, 28]. However, this research is based on cohorts where most PLHIV are aged < 60 years old-well before the dementia age range. Furthermore, when looking at specific conditions (i.e., cerebrovascular diseases and stroke), the weight of evidence favors accelerated brain aging [29]. Using the surrogate of biological aging rather than chronological aging probably represents a better marker for the aging process. For example, the prevalence of geriatric syndromes such as frailty [30, 31, 32], multimorbidity [12, 33], polypharmacy and disability [34] is higher amongst older PLHIV than the general population, and the syndromes are observed at a younger age than expected [26, 35, 36, 37, 38]. In addition, the decline rate in physical activity is faster among seniors with HIV than without HIV [39]. Biological aging as measured by epigenetic aging shows evidence of both premature and accelerated aging in the HIV population [40] including in children [41, 42]. Overall, even if we only consider the premature age signal and greater age-prevalence of age-related conditions, this represents a major risk factor for dementia that is higher than in the general population. Its exact effect size determination demands large longitudinal studies with at least 50% age 60 + .
 
Modifiable risk factors
 
Cardiovascular health and risk factors

 
Cardiovascular risk factors have a large modifiable component and are relevant to all-type dementia [58, 59]. All these CVD risk factors are highly pertinent to the global aging PLHIV from midlife onward [60].
 
Hypertension: evidence from observational studies has shown that hypertension in midlife (less than 65 years of age) has a strong positive association with high risk of late-life dementia and AD [21]. The association between hypertension in late-life and dementia is less clear [21]. Antihypertensive treatments are found to have a preventive effect on cognitive decline and dementia. However, the results from RCTs are not conclusive [19]. Methodological issues contribute to the negative RCTs results (e.g., not being able to account for strict placebo-controls, cognition not being the primary outcome, short follow-ups) [61].
 
Obesity: some observational studies, but not all [62], have shown that obesity in midlife is associated with an increased risk of dementia [22, 63]. However, the evidence for obesity with onset in later life is less consistent with some showing a reduced risk of dementia [22]. Possible reasons include a ‘reverse causality’ phenomenon, where early pre-clinical effects of dementia may include body weight loss (sarcopenia) and/or reduced physical activity, among other symptoms [62].
 
Hypercholesterolemia: while hypercholesterolemia in midlife is associated with an increased risk of dementia [64], rapid decline in cholesterol levels during midlife to late-life is a risk factor for dementia and AD [64]. Prospective observational cohort studies show that statin treatment is beneficial at reducing the development of all-type dementia [65]. However, RCTs results have concluded that statins given to individuals in late-life had no beneficial effect and did not prevent dementia or cognitive decline [65]. There is also growing but still controversial evidence for reversible cognitive impairment for a small percentage of the population of statin users [65]. Additional RCTs are required to conclusively determine the global effects of statins on the brain. Such studies should address the pharmacological differences amongst the statins in terms of crossing the blood brain barrier.
 
Diabetes: the 2014 World Alzheimer’s report [63] concludes that diabetes in late-life (and probably in midlife) is strongly associated with an increased risk of dementia, but more studies are needed to confirm this association [63]. Type 2 diabetes has been consistently associated with poor cognitive performance and is associated with a 47% increased risk of dementia [19]. RCTs involving treatment of diabetes with hypoglycemic drugs and insulin have not shown consistent results [66, 67]. In addition, hypoglycemia for both type 1 and 2 diabetes [68] could arise due to complications of diabetes treatment and may be associated with worse cognitive outcomes [68].
 
Stroke: stroke is another powerful risk factor for all-type dementia. A recent systematic review and meta-analysis showed that a history of stroke increases dementia risk by around 70%, while recent strokes doubled the risk of dementia [69].
 
Smoking: smoking is a risk factor for dementia and AD [63]. Current smoking increases the risk for incidence of AD and may increase risk for other dementias. This evidence is sufficient to encourage smoking cessation.
 
Physical activity: physical activity of mild to moderate intensity has been associated with a reduced risk of cognitive decline across several studies (reviewed in [70]). This association is observed when levels of physical activity in midlife are examined, but physical activity is also beneficial if maintained or increased during late life [70]. In contrast to the positive results from observational studies that examined the capacity of physical activity to prevent dementia, evidence from preventative RCTs is inconclusive [19]. These mixed results have stirred controversies and show the needs for more research with improved specifications for exercise types, frequency, duration and intensity [19]. In NeuroHIV, some trials are currently underway.
 
Diet: regular intake of fish, vegetables, fruits and nuts have shown to have a protective effect on brain functions [19, 70]. RCTs of the Mediterranean diet (MEDI), DASH (Dietary Approaches to Stop Hypertension) and MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) have promising results on dementia reduction [19]. Relevant to HAND, participants on the DASH diet exhibited greater improvements in psychomotor speed as compared to the usual diet control.
 
Cardiovascular health and risk factors and HIV
 
Studies have reported that the CVD risk is 1–2 times higher among older PLHIV than the general population of the same age [71, 72], and in advance of 10 years compared to the normative chronological age [39]. Another study found that HIV itself is associated with atherosclerosis irrespective of viral load, CD4-T cell count levels and ART [71]. Some ART drugs such as Protease Inhibitors (PI) and Abacavir have been shown to contribute to CVD burden amongst some PLHIV [26], although some controversy [73] and complexities [74] remain. Low CD4-T cell count has also been identified as an independent predictor of CVD among aging PLHIV [39]. Traditional risk factors such as smoking and obesity play a prominent role in CVD in the general population, and because they are even more prevalent in aging PLHIV [75], they could have a disproportionate impact on HIV-related CVD prevalence [9, 26, 76]. Metabolic alterations such as insulin resistance and dyslipidemia potentially caused and compounded by HIV and ART drugs also contribute to the high risk of CVD incidence among older PLHIV [76, 77]. In addition, HIV has been reported to be independently associated with hypertension [4], heart failure [78] and diastolic dysfunction [37]. Overall, it is increasingly recognized that HIV is a CVD risk factor [79]. There is emerging evidence that this is associated with vascular brain damage burden in aging PLHIV [80], so much that HAND may include an increasing mild and moderate (i.e., stroke) Vascular Cognitive Impairment component (see [29] for details). CVD is treatable but tremendous challenges remain [74]. In this regard, international data show vast inequalities in CVD treatment access in PLHIV across the gender and resource setting gaps [60]. Because it is midlife CVD that contributes the most to dementia risk [22], it would be important to link the dementia risk in PLHIV to their CVD health at that particular age and assess to what extent aggressive CVD treatment has a positive impact, especially when considering the controversies on statins, and the persisting CVD abnormalities in some PLHIV despite CVD treatment [60].
 
Psychiatric, psychological and emotional health, alcohol and substance use
 
Depression with onset in later-life has been shown to be a clear and consistent risk factor for dementia, with increased risk of up to 90% for AD [81] and 85–100% for all-type dementia [82]. However, it remains controversial as to whether depression has a causal role or is rather a prodromal symptom of dementia. It is less clear whether anxiety is a risk factor, although recent reviews have suggested that midlife anxiety may confer an additional risk [83]. Other psychosocial factors that possibly impact on dementia risk are only starting to be more systematically studied including various markers of well-being such as loneliness and stress. Therefore, their current level of evidence as dementia risk factors is limited and more studies need to be carried out. Alcohol use disorders have been linked to earlier onset of all-type dementia [63, 84]. More specifically, there is evidence from a cohort study that people who abstained from alcohol or consumed more than 14 units of alcohol per week during midlife were at a higher risk of developing dementia [85]. Conversely, studies involving older adults show that light to moderate levels of alcohol per week have a lower risk of dementia as compared to those who do not drink at all [63, 85]. Light to moderate drinking is typically defined as 1-14 standard drinks per week, though it must be noted that there are country variations on the definition of what is a standard drink. Due to the paucity of studies assessing dementia risk in long-term substance users, there is no knowledge on this potential extra risk that is highly relevant to the HIV population [86]. Direct (drug-reward brain pathway damage) and indirect (CVD) substances neurotoxicity may be at play, and in some instances be further compounded by the poorer socio-economic status that is characteristic of PLHIV with a substance use disorder [86].
 
Psychiatric, psychological and emotional health, alcohol and substance use, and HIV
 
The mental health burden is high in the global HIV population for multiple reasons [87]. For example, depression, which is often under recognized and treated, is highly prevalent among HIV-infected in general and even more so in elder PLHIV [36, 39, 88, 89]. In the aging PLHIV, the long-term chronic illness and stigmatization may exacerbate psychological symptoms [88, 90]. For many, depression is linked to social isolation [91] which in part is due to the loss of their loved ones to AIDS. Having multiple age-comorbidities and enduring the chronic illness may lead to poor quality of life (QOL) and reduced wellbeing amongst elderly PLHIV [38, 88]. A Dutch study reported that HIV status is independently associated with poor quality of life amongst PLHIV despite treatment and viral control [88]. Although having a greater comorbidity burden was associated with worse physical QOL, it did not change the effect of HIV status on the quality of life, meaning that there can be residual effect of chronic HIV on the QOL even when comorbidities are prevented and treated. Mental health burden especially in its chronic form [92] and traumatic life events (e.g., childhood trauma) are increasingly recognized as major risk factors for dementia [93, 94]. Further adding to the mental health burden is the well-recognized high prevalence of recreational drug use in PLHIV compared to the general population [95], some of which are both cardiotoxic and neurotoxic (methamphetamine) [96]. In other words, a substantial number of PLHIV-at the global level-are likely to be very vulnerable for dementia, in virtue of the high level of psychiatric burden that is often comorbid to the other risk factors we reviewed.
 
Educational attainment, socio-economic status and mental stimulation
 
There is cumulative evidence that higher education has a protective effect against development of dementia. Higher levels of education probably confer added direct benefit through enhancing and diversifying brain networks and/or through enhancing opportunities for mental stimulation, such as access to more cognitively demanding jobs [97]. Higher educational attainment also tends to be associated with higher socio-economic status, and in many countries, better awareness of healthy nutrition/diets, access to better medical care and lower incidence of cardiovascular risk factors and disease [97]. A few studies have suggested that having a wider social network and more engagement in socially enriching activities is associated with a reduced risk of dementia [97], although it is difficult to disentangle the relative contributions of cognitive stimulation and physical activity from purely social aspects. Cognitively stimulating activities should be conceived as a broad concept including work complexity, engagement in cognitively stimulating activities during leisure time like reading, writing and using computers [98]. In terms of cognitive training RCTs, the best evidence for some potential benefit comes from The Advanced Cognitive Training for independent and Vital elderly (ACTIVE) trial, which showed that the intervention group improved their cognitive skills of reasoning and processing speed but did not improve memory function [19]. Meta-analyses of RCTs have shown that cognitive training interventions might improve cognitive abilities in healthy and cognitively impaired participants but with no effect on the incidence of dementia [21].
 
Educational attainment, socio-economic status and mental stimulation and HIV
 
There is good evidence that low education and lower socio-economic status are associated with a greater prevalence and incidence of HAND [99]. Conversely, greater cognitive reserve has been associated with lower prevalence of HAND [100]. These results largely mimic those from the dementia literature [101]. However, dementia research has also cumulatively shown that a higher education level is not associated with a slower progression of dementia [102]. This research needs to be also conducted in NeuroHIV. Considering the wide range of educational achievement across the HIV population internationally, but also within each country, it will be important to properly account for education effects in the detection of early dementia in aging PLHIV. The use of optimal normative neuropsychological data could not be more emphasized in this population so as to avoid both under and over diagnosis of dementia. Cognitive training trials in PLHIV are underway.
 
Specific HIV dementia risks factors
 
Historical and ongoing HIV brain involvement

 
A sometimes forgotten finding from the early cART NeuroHIV research is that any form of historical HIV brain involvement that has resolved on treatment remains a risk for cognitive deterioration [103]. It should be noted that at the global population level HAD and CNS opportunistic infections still occur and with treatment access are more likely to survive [104]. This finding confirms results in dementia research showing that previous brain trauma is a risk factor for dementia [97]. The prevalence of HAND has been recently the focus of some debates [56, 105], but even when taking the most conservative estimates, it is undeniable that a non-negligible part of the first generation who are aging with HIV infection has a much higher brain vulnerability burden compared to the general population entering the dementia age range. Furthermore, age is a risk factor for HAND and HAD and it is estimated that once 50 + PLHIV are considered, HAND prevalence goes up by 10% [106]. The mildest forms of HAND are the most common in the cART era. They seem to still have a relapsing/remitting profile, although with greater intervals between episodes, which translate into long-periods of stability [107]. But when studies have long-term endpoints (> 10 years), or in those aged 60 + , progression is detected and even accelerated brain changes [108, 109, 110]. This is true to a greater extent in those with multiple comorbidities and unsurprising when referenced against what is established in the dementia literature (e.g., The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score, see [19] for an overview). Yet, it seems that even in some PLHIV with low comorbidities accelerated brain aging can be detected [108]. More studies are needed, especially once PLHIV have reached 60 + because the finding of accelerated brain aging is not consistent [28]-it is, however, consistent for premature brain aging [111]. How HAND and the probable increasing contribution of vascular brain injury in aging PLHIV will play out deserve attention because these are yet again combined risk factors for all-types of dementia and well-established promoters of neurodegeneration.
 
Remaining stable on cART is still the best treatment to avoid HAND and avoid HAND progression once it has been diagnosed. Once on stable treatment, between 70 and 80% of PLHIV remain cognitively stable across years [56]. There is a good chance that some strategies to reduce HAND occurrence and progression will also be protective against dementia development, although empirical evidence is needed. cART early initiation is now standard recommendation [112]. However, there is no definitive evidence that it protects against dementia because no study could have been designed to assess this question. Early treatment is both beneficial against progression to AIDS and the occurrence of non-AIDS events [112]. Importantly, AIDS is a risk factor for HAND, so that a reduction of the prevalence of HAND will have an impact on the rate of potential dementia in PLHIV who will be aging while having been treated early. The relation of non-AIDS condition (the main one being cancer) to dementia in PLHIV is unknown. The reduction of chronic HIV-related CVD because of early treatment would also have beneficial impact on dementia reduction in the HIV population at large. However, it would be important to follow-up early treated PWHIV to old age to extract accurate estimates. Furthermore, it is unknown if some ARV drugs taken 50 + years may eventually have adverse neurological impact. Finally, by virtue of genetic risk factors, some PLHIV will be destined to develop dementia. In these cases, it is unknown if being treated early, having controlled HIV, having a chronic illness that means routine health monitoring will impact dementia risk in one way or the other.
 
HIV-related immune compromise, chronic immune activation, immune senescence
 
There is strong immune and HIV basic science rationale to the parallels between how aging and chronic-treated HIV infection affects the immune system [36, 37, 113, 114]. In chronic PLHIV, premature aging is probably caused through an integrated pathway of aetiologies converging towards chronic immune activation [115], which is worse as a function of HIV-related immune compromise. Beyond the scope of this review, HIV basic science research shows that the mechanisms driving systemic immune activation in chronic HIV infection are multifactorial (i.e., translocation of microbial products from the gastrointestinal tract, low-level detectable virus, persistent viral reservoirs, and co-infections with other highly common viral pathogens such as the human herpes viruses especially cytomegalovirus) [115]. The chronic state of immune activation leads to an inflammatory response characterized by excessive production and/or accumulation of proinflammatory cytokines (TNFα, IL-1β and IL-6), excessive activation of macrophages and monocytes activation markers (CD14, CD163), increased non-specific inflammation (elevated C-reactive protein (CRP) and cystatin C [116]) that further promotes immune activation. And those inflammatory markers are associated with vascular inflammation and coronary atherosclerosis in PLHIV as well as the general population [117]. As individuals grow older, this vicious cycle probably intensifies because of immune senescence [118].
 
Supporting this rationale are findings relating to the Immune Risk Profile [119] in PLHIV. The Immune Risk Profile distinctly identifies an immunological profile of individuals at increased risk of morbidity and mortality in the general population [119] and not surprisingly this profile has been described in treated HIV+ individuals at significantly younger ages [120] lending credence to the hypothesis of premature and potentially accelerated aging in this population. Importantly, there is evidence that the Immune Risk Profile in resource-limited setting is increased due to higher rates of baseline immune compromise [121], and higher background level of immune activation linked in part to a higher exposure to common human herpes viruses [122]. Finally, with increasing focus on chronic immune dysregulation as a direct contributor to AD [123], and an indirect cause through immune-driven vascular damage [124], there is in addition to non-HIV driven age-comorbidities, a plausible pathophysiological pathway of increased dementia risk even in those PLHIV aging with low comorbidities [125].
 
ART neurotoxicity
 
Ethical reasons and the trade-off benefit of being HIV-infected and off therapy have precluded the study of potential ART neurotoxicity in RCTs. Nevertheless, pre-cART studies have demonstrated abnormal neurochemical metabolism in HIV-infected adults on reverse transcriptase inhibitors related to brain mitochondrial toxicity [126] similar to the pathophysiological pathway in the peripheral nervous system leading to peripheral neuropathy. Most of the Nucleoside reverse transcriptase inhibitors (NRTIs) used then are not on the market anymore, but their length of use may have caused some vulnerability to brain damage, nevertheless. One drug that has known adverse neuropsychiatric effects (Efavirenz) [127] has been associated in a least a subset of PLHIV with neurocognitive impairment. Any link to dementia in old age is unknown. In all, it is not impossible that some aging PLHIV may be more vulnerable to dementia in part due to ART neurotoxicity. Recent findings including new types of ART would support this hypothesis [128].
 
ART-related chronic kidney disease
 
While the prevalence of HIV-associated nephropathy is low, PLHIV are developing chronic kidney diseases as a result of the higher prevalence of hypertension, Diabetes Mellitus, inflammatory markers and widespread use of Tenofovir DF [129]. A study conducted among veterans in US found out that PLHIV have a higher risk of chronic kidney disease compared to those without HIV and it occurred at a younger age among them compared to the general population [130]. Chronic kidney disease markers have been associated with cognitive decline in PLHIV [131]. This may, therefore, represent an added dementia risk factor as PLHIV age although Tenofovir DF will be increasingly replaced by a less toxic version.

 
 
 
 
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