Researchers explore age-associated dementia risk as people with HIV live longer

Research has found that with effective treatment (antiretroviral therapy; ART) people with HIV can suppress the level of this virus in their blood. A suppressed viral load leads to better health outcomes over the long term. Studies increasingly project that many people with HIV who take ART as directed will live well into their senior years.

Many of these studies have focused on the dramatic decrease in AIDS-related infections and cancers that has occurred since the introduction of ART in high-income countries in 1996. However, as people with HIV are living longer, thanks to ART, issues seen in older people without HIV are also likely to occur in aging people with HIV. One such issue is age-associated dementia, such as Alzheimer’s disease and other forms of dementia, including those related to an insufficient blood supply to the brain (usually caused by cardiovascular disease).

According to researchers in the United States, in 2019 nearly 40% of people with HIV were 55 years and older. Over time, the proportion of people with HIV who are in their 70s and 80s will increase. However, as more people with HIV approach their life expectancy, the risk for age-associated dementia increases.

A Harvard study

A team of researchers primarily at Harvard University conducted a computer simulation of the consequences of aging in both HIV-positive and HIV-negative people. The researchers focused on the risk of age-associated dementia. They used data and methods that had been previously validated in other studies.

At the start of the simulation, the researchers made the following assumptions:

• 75% of people with HIV would be taking ART; at least 70% of whom would be virally suppressed
• the average CD4+ count would be 600 cells/mm³
• 25% of people with HIV would not be taking ART; their average CD4+ cell count would be 325 cells/mm³

Included in the simulation was the idea that a small proportion of people with HIV would stop visiting their clinic and stop taking ART. Some of these people would eventually re-engage with care and treatment.

The researchers stated that they incorporated deaths “due to substance use, systemic racism, and poverty, among other structural barriers […].”

Results

The simulation predicted the following scenarios:

Men

A 60-year-old man with HIV who entered the simulation now would have the following risks for age-associated dementia:

• at age 70 – 9%
• at age 80 – 16%
• across his lifetime – 34%

Here are the equivalent figures for a 60-year-old man without HIV:

• at age 70 – 5%
• at age 80 – 16%
• across his lifetime – 34%

Women

A 60-year-old woman with HIV who entered the simulation now would have the following risks for age-associated dementia:

• at age 70 – 5%
• at age 80 – 16%
• across her lifetime – 28%

Here are the equivalent figures for a 60-year-old woman without HIV:

• at age 70 – 3%
• at age 80 – 13%
• across her lifetime – 40%

Although these figures seem high, they are based on data collected from a representative sample of the population without HIV.

Life expectancy

The simulation projected that, on average, age-associated dementia could cause the life expectancy of men with HIV to be reduced by four years. For women with HIV, the loss of life expectancy was greater—up to nine years. The researchers noted that studies have found that women with HIV “often experience a substantially higher risk of non-HIV-related mortality compared to females in the general population.”

Bear in mind

The computer simulation predicted that among 60-year-old men with HIV today, 34% would ultimately be at risk for age-associated dementia in their lifetime. This risk is the same as that of men without HIV.

For 60-year-old women with HIV today, the simulation predicted that their lifetime risk of dementia would be 28% (vs. 40% among women without HIV). As mentioned earlier, women with HIV face numerous obstacles to better health and this takes its toll on their survival. As more women with HIV died earlier in the simulation, less women with HIV were at risk for age-associated dementia—hence the discrepancy in lifetime risk of dementia between HIV-positive and HIV-negative women.

According to the researchers, the reasons for reduced life expectancy among people with HIV are likely due to one or more of the following factors (some of which are more common in people with HIV due to a combination of shared risk factors, trauma, stigma and discrimination):

• smoking
• substance use disorder
• serious mental illness
• “disadvantageous social determinants of health”

The researchers also noted that life-threatening infections are more common among people with HIV who are not taking ART.

A different study

A study from Northern California among people in the Kaiser Permanente health system compared dementia risk in 13,296 people with HIV and 155,354 people without HIV from 2000 to 2016. The researchers found that the overall risk of dementia among people with HIV was almost twice as great as that in people without HIV. This difference persisted to even the final year of the study.

Interventions

To improve life expectancy and reduce the risk of age-associated dementia, the Harvard researchers stated that “interventions to counter disadvantageous social determinants of health, reduce tobacco use, and treat substance use disorder are therefore essential […].”

Among people without HIV, analyses have found that interventions that aim to reduce cardiovascular risk factors (which contribute to age-associated dementia risk) can be cost effective. Similar analyses are needed for populations with HIV.

The researchers also noted the following:

• People with HIV “often encounter structural barriers to care.” They will need help to overcome such barriers.
• National guidelines for the care of people with HIV need to include advice about screening for cognitive impairment.
• “Many people with HIV experience stigma at facilities that care for older persons.” The researchers underscore the need for health policy planners to consider this issue when developing support programs and services for aging people with HIV.

Study limitations

No simulation is perfect. The Harvard researchers acknowledge that their simulation relied disproportionately on data from White people.

Also, issues such as the COVID-19 pandemic and increasing deaths from a poisoned drug supply are important to consider.

Future simulations need to address at least these issues.

Other interesting research

Increasingly, there are reports of studies that seek to predict the risk for age-associated dementia in populations of people without HIV. Some of these studies measure levels of proteins found in blood samples stored a decade or more prior to the onset of dementia. The levels of some of these proteins can then be used to retrospectively calculate the risk of age-associated dementia. The results of such studies should be considered promising but experimental. They require validation in tens of thousands of people. However, these studies need to include more people with HIV.

If some of the proteins under investigation are found to predict a high risk for age-associated dementia, they can ultimately be used to screen for the risk for such conditions. People at high risk for age-associated dementia could be screened for and offered treatment (or have their treatment optimized) for the following conditions:

• high blood pressure
• type 2 diabetes
• high cholesterol
• abnormal heart rhythms

Additionally, screening for and treatment of the following could be offered when necessary:

• mental health conditions
• smoking
• substance use disorders

HIV clinical care has come a long way in many high-income countries over the past 40 years. Before the widespread availability of ART, the focus of care was on preventing and treating life-threatening infections. In the current era, as more people with HIV get older thanks to ART, care needs to include screening for dementia and its risk factors as well as interventions when necessary.

By Sean R. Hosein

REFERENCES:

1. Hyle EP, Wattananimitgul N, Mukerji SS, et al. Age-associated dementia among older people aging with HIV in the US: a modeling study. AIDS. 2024; in press.
2. Lam JO, Lee C, Gilsanz P, et al. Comparison of dementia incidence and prevalence between individuals with and without HIV infection in primary care from 2000 to 2016. AIDS. 2022 Mar 1;36(3):437-445.
3. Guo Y, You J, Zhang Y, et al. Plasma proteomic profiles predict future dementia in healthy adults. Nature Aging. 2024 Feb;4(2):247-260.
4. Li X, Yucel R, Clervius H, et al. Plasma biomarkers of Alzheimer disease in women with and without HIV. JAMA Network Open. 2023 Nov 1;6(11):e2344194.
5. Krentz HB, Lang R, McMillan J, et al. The changing landscape of both causes and locations of death in a regional HIV population 2010-2021. HIV Medicine. 2024; in press.
6. Weber MSR, Duran Ramirez JJ, Hentzien M, et al. Time trends in causes of death in people with HIV: Insights from the Swiss HIV Cohort Study. Clinical Infectious Diseases. 2024; in press.
7. Trickey A, McGinnis K, Gill MJ, et al. Longitudinal trends in causes of death among adults with HIV on antiretroviral therapy in Europe and North America from 1996 to 2020: a collaboration of cohort studies. Lancet HIV. 2024 Jan 24: S2352-3018(23)00272-2.
8. Hainsworth AH, Markus HS, Schneider JA. Cerebral small vessel disease, hypertension, and vascular contributions to cognitive impairment and dementia. Hypertension. 2024 Jan;81(1):75-86.
9. Johnson AC. Hippocampal vascular supply and its role in vascular cognitive impairment. Stroke. 2023 Mar;54(3):673-685.
10. Nagata C. Soy intake and chronic disease risk: findings from prospective cohort studies in Japan. European Journal of Clinical Nutrition. 2021 Jun;75(6):890-901.
11. Custodero C, Ciavarella A, Panza F, et al. Role of inflammatory markers in the diagnosis of vascular contributions to cognitive impairment and dementia: a systematic review and meta-analysis. Geroscience. 2022 Jun;44(3):1373-1392.
12. Fulop GA, Tarantini S, Yabluchanskiy A, et al. Role of age-related alterations of the cerebral venous circulation in the pathogenesis of vascular cognitive impairment. American Journal of Physiology: Heart and Circulatory Physiology. 2019 May 1;316(5):H1124-H1140.
13. Calcagno A, Celani L, Trunfio M, et al. Alzheimer dementia in people living with HIV. Neurology: Clinical Practice. 2021 Oct;11(5):e627-e633.
14. van Zoest RA, Underwood J, De Francesco D, et al. Structural brain abnormalities in successfully treated HIV infection: Associations with disease and cerebrospinal fluid biomarkers. Journal of Infectious Diseases. 2017 Dec 27;217(1):69-81.
15. Cummings TH, Magagnoli J, Sikirzhytskaya A, et al. Exposure to angiotensin-converting enzyme inhibitors that cross the blood-brain barrier and the risk of dementia among patients with human immunodeficiency virus. MedRxiv [Preprint]. 2024; submitted.
16. Amod F, Holla VV, Ojha R, et al. A review of movement disorders in persons living with HIV. Parkinsonism & Related Disorders. 2023 Sep; 114:105774.
17. Yu X, Kuo YF, Raji MA, et al. Dementias among older males and females in the U.S. Medicare system with and without HIV. JAIDS. 2023 Jun 1;93(2):107-115.