A study of over 6000 patients shows how Alzheimer’s risk is shaped by sex and age of onset, offering clues that could change diagnosis and treatment options for millions.
Study: Sex differences in clinical risk factors for Alzheimer's dementia patients with early-onset and late-onset. Image credit: Lucigerma/Shutterstock.com
A recent study published in Frontiers in Global Women’s Health explored sex-specific differences in the risk factors underlying Alzheimer’s disease (AD) in men and women, focusing on the onset-dependent subtypes separately.
Introduction
AD is the most common neurodegenerative condition in the world, often leading to complete disability. It is number six among causes of death in the United States. Its correlation with aging and the global increase in life expectancy poses a grave public health challenge. It is estimated that AD prevalence could triple over the next few decades.
AD risk is higher in females, making up 66% of all cases. This could perhaps be explained by the reduced ability of the female brain to cope with damage and maintain cognitive function (cognitive reserve) with age. Differences in sex hormones, especially in the postmenopausal period, a longer lifespan, and sex-linked genetic susceptibility are other potential mechanisms. In the future, AD risk among women is projected at 21.2%, vs 11.6% among men.
Pathologically, AD has long been linked to increased levels of plaque-forming amyloid-beta (Aβ) protein outside the neurons, and intracellular hyperphosphorylated tau proteins that form neurofibrillary tangles.
AD presentation varies largely, sometimes beginning with language deterioration or abnormalities with vision. Memory loss and behavioral changes often follow later, with impaired cognition, until patients can no longer complete the routines of daily living on their own.
Only about 10% or less of patients develop early-onset AD (EOAD), before 65 years, in contrast to late-onset AD (LOAD). People who snore because of obstructive sleep apnea, have heart disease, obesity, or diabetes are more likely to develop LOAD.
EOAD is more likely to occur between 45 and 65 years old, but the symptoms are unpredictable. These patients may find it hard to remember something they just learned, easily forget dates, keep asking the same questions, or struggle to find the right word. Acts of poor judgment, abnormal mood swings, or personality changes accompany this. Eventually, EOAD patients may find swallowing, speaking, or walking difficult.
Given that females have multiple sex-specific risk factors for AD, the current study sought to identify the differences in their risk profiles compared to men.
About the study
The study included a cohort of 6,212 AD patients diagnosed between February 2016 and August 2020. The majority (~89%) had LOAD, vs EOAD in 11%. In either subtype, women comprised 60% to 65% of the cases, vs 30% to 35% of men.
LOAD vs EOAD
As expected, LOAD patients were older on average, at 86 years, vs 75 years in the EOAD group.
EOAD patients were twice as likely to drink (27%) as LOAD patients, and more likely to have cancer or to be anxious. Down syndrome occurred in 3%, 30 times higher than for LOAD patients, while lung adenocarcinoma risk was 23-fold higher. Drugs prescribed to EOAD patients were more often cholinesterase inhibitors, second-generation antipsychotics, and memantine compared to LOAD patients.
LOAD patients had a much higher risk of arteriosclerosis and congestive heart failure. Other cardiovascular risk factors were also more common, such as atrial fibrillation, insomnia, and hypertension. Osteoporosis and urinary infections were also significantly more common.
Males vs females with AD
Males with AD (early- or late-onset) presented more often with high blood lipids, abnormal gait, peripheral vascular disease, or obstructive sleep apnea. Down syndrome, alcohol, and memantine were other associated risk factors.
Females with AD more often presented with osteoporosis, urinary infection, mild cognitive impairment, or congestive heart failure. In some onset subtypes and primarily in unadjusted analyses, higher odds of anxiety and hallucinations were observed. Hypertension was associated with males rather than females in adjusted LOAD analyses. Traumatic head injury, chronic obstructive pulmonary disease, and rheumatoid arthritis were also more likely in specific subtypes.
Males vs females – LOAD
Corroborating earlier research, the findings show that males with LOAD were more likely to have metabolic or vascular disease (including high blood cholesterol, peripheral vascular disease, and obstructive sleep apnea) and pneumonia. Alcohol and tobacco use were more common, as was treatment with memantine and valproate.
The picture among females was different. These patients were older, on average, and less likely to be hypertensive and to have congestive heart failure. Osteoporosis, urinary infections, and rheumatoid arthritis were also more likely. However, in adjusted analyses, hypertension was significantly less likely in females than in males.
Males vs females – EOAD
For EOAD males, gait abnormalities were much more likely, as were peripheral vascular disease and chronic obstructive pulmonary disease. Alcohol use was also more common. Treatment was more often with cholinesterase inhibitors and memantine. Prior research also suggests that EOAD presents with gait slowing and difficulties with turning, preceding cognitive impairment.
In EOAD females, the mean age was higher. These patients had a higher risk of osteoporosis and anxiety, and in unadjusted analyses, more often had strokes, with males showing higher adjusted odds, along with more infections. These conditions enhance the risk of disability and cognitive decline with AD. They are more likely to receive second-generation antipsychotics and valproate.
Conclusions
The study suggests that men and women have different risk markers for AD overall, as well as its subtypes. Vascular and lung conditions occur more often in males with AD, but osteoporosis is strongly linked to females. However, different risk factors are more prominent in either sex with EOAD or LOAD.
Peripheral vascular disease and alcohol use are common to both forms of AD in males, suggesting the prime role of vascular dysfunction in this neurodegenerative disease. Alcohol is the most significant modifiable risk factor in dementia prevention and confers independent increases in risk for multiple other conditions. For women, osteoporosis and, in some cases, stroke-related damage may be a significant risk factor.
“These patterns highlight the importance of sex-specific considerations in the clinical management of EOAD and LOAD patients.” This understanding is essential in developing accurate diagnostics and appropriate interventions, helping improve these patients' health outcomes.
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