The heart-weight connection.

Which is worse: dropping dead of a heart attack or stroke at age 75 or dying in a nursing home with Alzheimer's disease at age 85?

Most people would take roughly 10 milliseconds to choose the heart attack or stroke. But recent evidence suggests that by keeping a lid on your blood pressure, blood sugar, and weight, you can boost your odds of dodging the cardiac care unit and the nursing home.

"Cardiovascular risk factors also appear to have an impact on the brain and the risk of Alzheimer's disease," says David Knopman of the Mayo Clinic.

If you think there's nothing you can do to keep your mind sharp as your hair grays, think again.

An estimated 20 to 40 percent of people aged 85 or older have Alzheimer's disease. And Alzheimer's accounts for only 60 to 70 percent of what researchers call "progressive cognitive impairment" in older people.

In other words, your odds of reaching a ripe old age without losing your marbles aren't terrific. And scientists haven't come up with any magic bullets--prescription or otherwise--to keep your mind intact.

But that doesn't mean that all is hopeless. Researchers are finding that people with diabetes, high blood pressure, and the metabolic syndrome have a greater risk of dementia. So there's a good chance that a healthy diet and exercise can keep both your body and your brain in shape.

Until recently, researchers gave most older patients with dementia one of two diagnoses: Alzheimer's disease or vascular dementia. Experts used the term "vascular" when they found signs of a stroke, mini-strokes, or clogged arteries. All three can kill the brain's nerve cells (neurons) by cutting off their oxygen supply.

"If the person had a stroke or hypertension or another vascular condition, doctors ruled out Alzheimer's disease," explains Mary Haan, professor of epidemiology at the University of Michigan School of Public Health.

In fact, autopsy studies show that many people have both types of dementia. "When you look at pathology in the brain, it's the rare person who doesn't have both Alzheimer's and vascular disease," says Haan.

Those studies led researchers to ask whether people who were diagnosed with either Alzheimer's or vascular dementia had other things--like high blood pressure or diabetes--in common.

"And as we started to look at risk factors for vascular dementia and Alzheimer's disease, lo and behold, we found that they overlap," says David Knopman, professor of neurology at the Mayo Clinic College of Medicine in Rochester, Minnesota.

Researchers no longer think that's a coincidence. "We began to realize that vascular risk factors contribute to Alzheimer's disease pathology," says Haan.

Whatever triggers Alzheimer's disease is still unknown. Something makes the brain accumulate two abnormal structures: neurofibrillary tangles and beta-amyloid plaques (see "Tangle Trouble," p. 4, and "Plaque Puzzle," p. 6). Both disrupt and eventually destroy the brain's nerve cells.

And it looks as though Alzheimer's may somehow be triggered or sped up by high insulin levels, high blood pressure, and inflammation--some of the same risk factors that cause heart attacks, strokes, and diabetes. (1)

Exactly how do those risk factors gum up and eventually wreck your brain? "That's the million dollar question," says Lenore Launer, chief of the neuro-epidemiology unit at the National Institute on Aging in Bethesda, Maryland.

High Insulin

"Diabetes is a strong risk factor for dementia," says Knopman. Five years ago, the Rotterdam Study in the Netherlands found that people with diabetes had nearly double the risk of dementia. (2)

Instead of measuring dementia, which can take years or even decades to develop, recent studies have looked for "cognitive decline." Researchers give memory and other mental tests at the beginning of a study and again after, say, five years.

"Cognitive decline is a proxy for dementia," explains Knopman.

In a study of 7,000 post-menopausal women, those with diabetes--or even pre-diabetes--were almost twice as likely as other women to score in the "impaired" range four years after the first test. (3)

Experts estimate that 40 percent of U.S. adults aged 40 to 74 have pre-diabetes. Most don't know it. An estimated nine percent of middle-aged Americans and 19 percent of those over 60 have diabetes. From 20 to 35 percent of them don't know it.

(If your fasting blood sugar is at least 126, you have diabetes. If it's 100 to 125, you have pre-diabetes, which is also called impaired fasting glucose or glucose intolerance.)

It's not clear how diabetes harms the brain. One possibility is fairly straightforward.

"Diabetes causes microvascular disease," explains Knopman. In other words, diabetes may lower your IQ by damaging the small arteries that carry blood and oxygen throughout the brain.

"Microvascular changes in the brain arteries could influence circulation and the survival of neurons," explains Rita Peila of the National Institute on Aging.

Another possibility: "Higher than normal levels of glucose [blood sugar] may be toxic to neurons," suggests Alka Kanaya of the University of California at San Francisco.

The latest explanation is even more intriguing. People with diabetes or pre-diabetes usually have high blood insulin levels, or hyperinsulinemia. "It's possible that hyperinsulinemia itself is bad for the brain," says Knopman.

One of the enzymes that break down insulin--called insulin degrading enzyme--may be at fault.

"Insulin degrading enzyme also happens to degrade beta-amyloid peptide, the Alzheimer's protein," explains Knopman. "If there's more insulin around, it could compete for the enzyme with the beta-amyloid, so less of the Alzheimer's protein gets broken down."

It's not practical to measure blood insulin levels, so usually only researchers do it. Instead, doctors look for signs of high insulin--pre-diabetes, diabetes, or the metabolic syndrome.

High Blood Pressure

"It's well established that people with hypertension have worse cognitive function," says the University of Michigan's Mary Haan.

In the Framingham Heart Study, for example, men with high blood pressure were more likely than those with normal blood pressure to perform poorly on tests of learning, memory, and abstract reasoning four to six years after first getting tested. (4)

Researchers know that hypertension can lead to cognitive decline or dementia by precipitating a stroke. Stroke usually occurs when a blood clot or clogged arteries blocks the blood supply to parts of the brain. Without oxygen, brain cells die.

"A stroke leads to a loss of neurons," explains the National institute on Aging's Lenore Launer. "The neurotransmitters aren't working any more, so data doesn't get transferred throughout the brain."

But the transfer of data also gets blocked in many people who have no outward signs of a stroke or even a transient ischemic attack (TIA), which is also called a mini-stroke.

"We now know from imaging studies of the brain that many strokes are not manifested as a weakness in the hand, an inability to speak, or other symptoms," says Teri Manolio, director of the epidemiology and biometry program at the National Heart, Lung, and Blood Institute in Bethesda, Maryland. "But they can still damage the brain."

"These small, silent strokes are very common," she adds. "They occur in up to a quarter of people over 65, most of whom have no evidence at all of having had a neurological event."

But high blood pressure also seems to impair thinking even if it doesn't cause small, silent strokes. In the Cardiovascular Health Study, which tracks more than 5,000 people over age 65, those with risk factors for stroke--but no evidence of having had a stroke or ministroke on an MRI--had a greater cognitive decline than those without risk factors. (5)

And it's not just elders. Elevated blood pressure was linked to lower test scores in a study of more than 5,000 school-aged children. (6)

How? "The exact mechanism isn't known," says Manolio. "But high blood pressure seems to interfere with blood flow to the brain, probably because the very small blood vessels thicken in response to raised pressure."

Using MRI (magnetic resonance imaging), scientists can now see signs of impaired blood flow in tile brains of people with high blood pressure. "If you do an MRI on people with hypertension, you see an increase in white matter intensities in the brain," says Mary Haan. "That probably reflects less circulation in those areas."

People who lower their blood pressure--with drugs or diet--may cut their risk of cognitive decline. "But treatment doesn't completely wipe away the effect of high blood pressure," says Manolio, "because most people have hypertension for a long time before they get treated."

What's more, many people with hypertension have pressures that are too high, either because they haven't been diagnosed or because they're not doing enough to lower their pressure.

"It's amazing that over two-thirds of people with hypertension are not controlled," says Manolio. "And the elderly are the least likely to have their blood pressure controlled, even though they're at the most risk."

That's because doctors used to think that blood pressure is supposed to rise as you age. "There's still a carryover feeling among many physicians that higher blood pressure is normal in an older person," says Manolio.

"We've had study after study show that that isn't true and that treatment prolongs life and improves function. We just have to keep hammering home the message."

And doctors are more likely to know that hypertension can cause a stroke than a loss of mental capacity. "The link with cognitive decline is not as well appreciated," she adds.

The Metabolic Syndrome

If high insulin levels and high blood pressure are independently bad for your brain, it's no surprise that the metabolic syndrome is, too.

People with the syndrome have a cluster of symptoms (see "Insulin on the Rise"). One is higher-than-optimal blood pressure. Two others--a large waist and elevated blood sugar--are often signs of high insulin levels.

In fact, the metabolic syndrome is sometimes called insulin resistance. As the body's cells become resistant to insulin, levels of the hormone in the bloodstream climb.

"The cells don't activate their insulin receptors, so you need more insulin to get the same effect," explains the National Institute on Aging's Rita Peila.

An estimated 27 percent of U.S. adults have the metabolic syndrome, and its consequences aren't pretty. "It's a pre-diabetic stage, but it's also linked to cardiovascular events including heart attack and stroke," says the University of California at San Francisco's Alka Kanaya.

Five years ago, the Honolulu-Asia Aging study of more than 3,700 Japanese-American men found a greater risk of dementia in those with the metabolic syndrome. (7)

And last November, researchers reported a new twist.

Inflammation

In a five-year study of more than 2,600 people aged 70 to 79, cognitive decline was more likely in those with the metabolic syndrome, but only if they also had high levels of inflammation. (8)

(Those levels aren't high enough to cause swelling, fever, or any other visible sign of inflammation. They're only "high" compared to people with lower levels.)

It's the combination of the metabolic syndrome and inflammation that puts you at added risk," explains co-author Kanaya. Roughly a quarter of the people in her study had high levels of inflammation, which she measured by looking at C-reactive protein (CRP) in their blood.

What role does inflammation play? "Studies of the Alzheimer's brain suggest that an inflammatory cascade in the brain is part and parcel of the disease," explains Steven Ferris, executive director of the Aging & Dementia Research Center of the New York University Medical Center. In one study of 1,000 middle-aged men, those who had high C-reactive protein levels were more likely to be diagnosed with dementia 25 years later. (9)

But so far, it's not certain if inflammation causes the brain to wither or is simply a sign that withering is already under way.

One reason for the uncertainty: studies on anti-inflammatory drugs haven't panned out. But that could also be because researchers haven't tested the right one (see "The Latest," p. 7). Says Ferris: "Most people think inflammation is at least a player in the degenerative process."

Homocysteine

"A blood protein called homocysteine is elevated in the brains of people with Alzheimer's," says Ferris.

Numerous studies have found a higher risk of heart disease and stroke in people with high homocysteine levels. "Most of what we know about homocysteine comes from heart research," Ferris explains.

But three years ago, researchers at Boston University reported on a study of roughly 1,000 healthy men and women. Those with high homocysteine levels (over 14 micromoles per liter of blood) were twice as likely as those with low levels to be diagnosed with Alzheimer's disease eight years later. (10)

How might homocysteine harm the brain? "High levels of homocysteine appear to be toxic to the endothelial cells that line arteries," says Ernst Schaefer, chief of the Lipid Metabolism Laboratory at Tufts University in Boston.

The good news about homocysteine is that taking vitamins B-6, B-12, and folic acid at levels found in an ordinary multivitamin usually knocks it down to safe levels. "And there's a clinical trial that's treating Alzheimer's patients with a cocktail of B-vitamins versus a placebo to see if the disease can be slowed down," adds Ferris.

That trial won't tell researchers whether B-vitamins might prevent cognitive decline, but it's a first step.

In the meantime, researchers are cautious. "So far, studies using B-vitamins to lower the risk of stroke and heart disease haven't panned out," notes Jose Luchsinger of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center in New York. "So we don't know how the cognition story will turn out either."

Diet

A healthy diet is critical for preventing high blood pressure, stroke, pre-diabetes, and the metabolic syndrome (see "Food for Thought," p. 6). But do certain foods offer some extra protection for your brain?

So far, the evidence is scant and inconsistent. For example, in 2003, researchers at the Rush-Presbyterian-St. Luke's Medical Center in Chicago reported a higher risk of Alzheimer's in seniors who ate more saturated and trans fat and less unsaturated fat. (11) But the larger, longer Rotterdam study in the Netherlands found no link with any kind of fat. (12)

The strongest evidence is for fish and its omega-3 fats, especially DHA (docosahexaenoic acid). For example, when researchers tracked about 1,000 healthy people in the Framingham Heart study for nine years, those who had the highest blood levels of DHA were half as likely as those with the lowest levels to be diagnosed with dementia. (The study hasn't been published yet.)

"The higher levels correspond to about three servings of fish a week versus less than one serving a week in the lowest levels," says Tufts's Schaefer.

How might DHA keep people clearheaded? DHA comprises about four percent of the fatty acids in the blood, but about 40 to 50 percent of the fats in the brain, he points out. "The brain accumulates DHA because it's important for the fluidity of membranes."

That may also explain why DHA is found in cold-water fish. "They're cold-blooded and have to maintain fluidity at temperatures that are close to freezing," Schaefer notes.

Still, researchers would like to see studies that test DHA on brain-power. "We urgently need randomized trials to show if fish can affect cognitive function and the development of dementia," says Schaefer.

In the meantime, it makes sense to shoot for three servings of fish a week. The American Heart Association and others already recommend fish at least twice a week to keep your heartbeat healthy. If that's not feasible, you can buy a supplement with DHA alone or a fish oil supplement, which contains DHA plus EPA (eicosapentaenoic acid).

"From our data, you probably need 180 milligrams of DHA a day" to have sufficiently high blood levels, says Schaefer. To play it safe, he recommends two 200-milligram doses of DHA a day.

"I tell my patients with heart disease to take two capsules a day to reduce the risk of sudden death," he says, "but it may also help prevent brain rot as we get older."

No-Risk Strategy

As America grows older and rounder, the odds are that the nation's brain reserves are going to shrink.

"About 60 percent of adults are overweight and a good chunk of them are obese," says the University of Michigan's Mary Haan. "We're seeing more hypertension, stroke, and diabetes, and we're seeing them earlier--in kids and 20-year-olds. So it's likely that we'll also see an increase in the risk of cognitive impairment and dementia."

Maybe people would care more about a risk factor like blood pressure if they knew that it could not just prevent a stroke, but keep them lucid. "Strokes don't happen as often as cognitive decline," says the National Heart, Lung, and Blood Institute's Teri Manolio.

"People are understandably afraid of cognitive decline," she adds. "Preventing it may give them another reason to lower their high blood pressure, exercise, and eat a healthy diet."

While keeping a lid on blood pressure, insulin, blood sugar, and weight may or may not preserve brain cells, you don't have much to lose.

"It's a no-risk strategy," says Columbia University's Jose Luchsinger. "A healthy weight, exercise, and a balanced diet are likely to be important for cognitive disorders."

If worse comes to worst, all they do is cut your risk of a heart attack, stroke, and diabetes. Says Luchsinger: "The benefits are so large that even if it doesn't help with cognition, there's no downside."

Tangle trouble

Inside healthy nerve cells are microtubules that guide nutrients and other molecules from the body of the cell to its ends. A protein called tau holds the microtubules together. In Alzheimer's disease, the tau gets tangled with other tau. That makes the tubules disintegrate and stops the cell from transporting messages to other cells.

Source: Alzheimer's Disease Education & Referral Center (www.alzheimers.org)

Insulin on the rise

If you have at least three of the following five risk factors, you probably have the metabolic syndrome (also known as insulin resistance syndrome), which raises your risk of heart disease. diabetes, and probably dementia. The underlying cause: too much weight and too little exercise.

1. Abdiminal Obesity     Women: more than 35-inch waist
                         Men: more than 40-inch waist *

2. Triglycerides         150 or higher

3. HDL cholesterol       Women: under
                         Men: under 40

4. Blood pressure        Systolic: 130 or higher or
                         Diastolic: 85 or higher

5. Fasting blood sugar   110 or higher **

* For some men, a 37- to 39-inch waist can be a risk factor.

** Recent recommendations classify a tasting blood sugar of 100 to 125
as "pre-diabetes."

Source: National Heart, Lung, and Blood Institute.

Plaque Puzzle

Amyloid precursor protein (APP) usually helps repair damaged nerve cells. But when--for reasons researchers don't understand--an enzyme starts to sever APP molecules, one of the fragments, called beta-amyloid, forms indissolvable deposits of protein and other cellular gunk. These plaques can strangle nerve cells and cut off communication with other cells.

Source: Alzheimer's Disease Education & Referral Center (www.alzheimers.org).

Food for Thought

It's too early to say which foods can protect your brain. But experts do know that diet can lower your risk of high blood pressure, diabetes, inflammation, and elevated homocysteine levels--all risk factors for dementia.

* High blood pressure. In the DASH study (Dietary Approaches to Stop Hypertension), blood pressure dropped in people who cut back on saturated fat, sweets, sodium, and cholesterol and boosted their fruits, vegetables, and low-fat dairy foods (see "Pressure Points," April 2004).

* Diabetes. Studies suggest that people who consume more fiber, fewer soft drinks (and other sweets), and less bacon, sausage, and hot dogs have a lower risk of diabetes (see "The Gathering Storm," June 2004). However, staying lean and active matter far more than which foods you eat.

* Inflammation. Staying lean is your best bet to keep levels of inflammation low.

* Homocysteine. Take an ordinary multivitamin with the Daily Value for folic acid (400 mcg), vitamin B-6 (2 mg), and vitamin B-12 (6 mcg).

Here are some rules of thumb that could keep your brain intact.

                                At least
Fish                   3 servings a week
Vegetables            4-5 servings a day
Fruit                 4-5 servings a day
Low-fat dairy         2-3 servings a day
Nuts and beans       4-5 servings a week
Fiber 25 grams a day
Walking (or other
  aerobic exercise)   1 1/2 hours a week

                            No more than
Sodium                    2,400 mg a day
               (ideally, 1,500 mg a day)
Sweets                 5 servings a week

(1) Lancet 363:1139, 2004.

(2) Neurology 53:1937, 1999.

(3) Neurology 63: 658, 2004.

(4) Int. J. Obes. Relat. Metab. Disord. 27: 260, 2003.

(5) Neurology 63: 793, 2004.

(6) J. Pediatr. 143: 720, 2003.

(7) Arterioscler. Thromb. Vasc. Biol. 20: 2255, 2000.

(8) J. Amer. Med. Assoc. 292: 2237, 2004.

(9) Ann. Neurol. 52:168, 2002.

(10) New Eng. J. Med. 346: 476. 2002.

(11) Arch. Neurol. 60: 194. 2003.

(12) Neurology 59: 1915. 2002.

RELATED ARTICLE: The latest.

Experts are cautious about what people can do to keep their minds in working order. That's because they've been wrong before--most recently with hormone replacement therapy.

"The story of estrogen and dementia shows that things are not as straight-forward as they seem," says the Mayo Clinic's David Knopman.

Earlier studies tracking women who took the hormone had found a lower risk of dementia. But when researchers randomly assigned women to take estrogen or a placebo in a clinical trial, they were dumbfounded. (1)

"The Women's Health Initiative found that estrogen increased the risk of dementia--he opposite of what the original theory said," says NYU's Steven Ferris.

The take-home message, says Knopman: "Association doesn't prove causality."

With that caveat, here's where the evidence stands on other means of preserving your brainpower:

* NSAIDs, "NSAIDs is an idea that died and has now re-emerged," says Ferris. Early studies had detected a lower risk of dementia in people who frequently take NSAIDs (non-steroidal anti-inflammatory drugs), usually for arthritis.

But when researchers compared NSAIDs to a placebo in people with Alzheimer's or mild cognitive impairment (which usually leads to Alzheimer's), the NSAIDs did nothing. (2)

"We have a growing number of trials on naproxen and the cox-2 inhibitors like Celebrex and Vioxx--which has recently been taken off the market," says Ferris. "So far, none has helped to slow the progression of Alzheimer's."

But NSAIDs aren't out of the picture yet.

"The intriguing part of this story is that over the last several years, lab studies have found that certain NSAIDs, like ibuprofen, seem to reduce the production of beta-amyloid," adds Ferris. Ibuprofen did the same in mice. (3)

So researchers went back to the studies of people who took NSAIDs for their arthritis. "To everyone's surprise, the NSAIDs that lowered the risk of dementia were the NSAIDs that had the anti-amyloid effect in the lab," says Ferris.

That boils down to ibuprofen--not aspirin, which is also an NSAID--or prescription NSAIDs in the works mat may curb amyloid without upsetting your stomach, as ibuprofen can. But Ferris stops short of recommending that people take ibuprofen to prevent dementia.

"No one knows what kind of dose you need to get this anti-amyloid effect." he says. "We need a clinical trial.

* Statins. "Several large studies mostly in Europe, show a lowered risk of Alzheimer's in people who have taken statins to lower their cholesterol," says Ferris.

But the statin story is incomplete. Statins like Lipitor and Pravachol slash LDL ("bad") cholesterol but that may not matter.

"Neither LDL nor HDL ['good' cholesterol] is strongly linked to cognitive decline," says Teri Manolio of the National Heart. Lung, and Blood Institute.

It's possible that statins protect the brain not by cutting LDL, but by curDing inflammation. It's just too early to say.

So far, only one trial has compared cognitive decline r healthy elderly people who were randomly assigned to taKe either a statin (Pravachol) or a placebo. (4)

"Statins didn't help, but the Study didn't have many measures of cognitive function," says Neil Buckholtz head of the Dementias of Aging branch of the National Institute on Aging. Another flaw: the study lasted on y three years.

Other trials are now testing statins in people who have Alzheimer's. "We'll know in two years if statins are effective for treatment," he adds. "But so far no prevention mats are under way.

* Vitamin E, Could antioxidants like vitamin E prevent dementia by curbing damage from free radicals? "The early data on vitamin E was intriguing," says Ferris.

A two-year trial found that high doses of vitamin E (2,000 IU a day) delayed the time it took for patients to end up in a nursing home, die. or reach other milestones. (5)

"We interpreted the study as suggesting a slowing of the disease, but it was disturbing that the cognitive tests didn't show anything," says Ferris.

Since then researchers nave tested vitamin E in people with mild cognitive impairment. "They're in the gray zone between normal and Alzheimer's." he explains.

The results were reported at a meeting last summer. "For three years, they received either a placebo, vitamin E, or Aricept, a drug marketed for Alzheimer's." says Ferris. "The vitamin E snowed absolutely nothing, which was a big disappointment to people like me WhO had been taking vitamin E."

Aricept, a prescription drug, showed a clear benefit for up to 18 months, but after that it was no different from the placebo. "That confirms that Aricept has short-term benefits but doesn't slow the disease."

"There's growing evidence that oxidative stress prays a role in aging and neurodegenerative disease, including Alzheimer's," says Ferris. "So antioxidants might reduce the speed of degeneration. But there's no strong clinical trial evidence yet."

* Walking & crossword puzzles.

"Physical and intellectual activity are good for you," says Neil Buckholtz. But so far the evidence comes mostly from studies that find a lower risk in people who choose to be active. (6, 7) So it's possible that something else about them lowers their risk.

"Those studies are good for generating hypotheses rather than proving them." says Ferris. "Trials are under way to see whether mental or physical exercises can reduce age-related cognitive decline."

Exercise could help simply by keeping your blood pressure, blood sugar, insulin, and waistline under control.

"We have no trial data, but it's safe to recommend that people exercise and eat a healthy diet to reduce the risk of Alzheimer's and other cognitive disorders." says Columbia University's Jose Luchsinger.

(1) J. Amer. Med. Assoc. 291:2947, 2004.

(2) Neurology 62: 66, 2004

(3) J. Neurosci. 23: 7504, 2003.

(4) Lancet 360: 1623, 2002.

(5) New Eng. J. Med. 336: 1216, 1997.

(6) J. Amer. Med. Assoc. 292: 1447, 1454, 2004.

(7) New Eng. J. Med. 348: 2508, 2003.