By SAM MEDNICK, JOSEF FEDERMAN and BASSEM MROUE (Associated Press)

JERUSALEM (AP) — The Israeli army ordered about 100,000 Palestinians on Monday to begin evacuating from the southern city of Rafah in Gaza, signaling that a long-promised ground invasion there could be imminent and further complicating efforts to broker a cease-fire.

Israel’s closest allies, including the United States, have repeatedly said that Israel shouldn’t attack Rafah. The looming operation has raised global alarm over the fate of around 1.4 million Palestinians sheltering there.

Aid agencies have warned that an offensive will worsen Gaza’s humanitarian catastrophe and bring a surge of more civilian deaths in an Israeli campaign that in nearly seven months has killed 34,000 people and devastated the territory.

U.S. President Joe Biden spoke Monday with Israeli Prime Minister Benjamin Netanyahu and reiterated U.S. concerns about an invasion of Rafah. Biden said that a cease-fire with Hamas is the best way to protect the lives of Israeli hostages held in Gaza, a National Security Council spokesperson said on condition of anonymity to discuss the call before an official White House statement was released.

Hamas and key mediator Qatar said that invading Rafah will derail efforts by international mediators to broker a cease-fire. Days earlier, Hamas had been discussing a U.S.-backed proposal that reportedly raised the possibility of an end to the war and a pullout of Israeli troops in return for the release of all hostages held by the group. Israeli officials have rejected that trade-off, vowing to continue their campaign until Hamas is destroyed. Hamas has been designated as a terrorist organization by the United States, Canada and the European Union.

Netanyahu said Monday that seizing Rafah, which Israel says is the last significant Hamas stronghold in Gaza, was vital to ensuring the group can’t rebuild its military capabilities and repeat the Oct. 7 attack on Israel that triggered the war.

Lt. Col. Nadav Shoshani, an army spokesman, said about 100,000 people were being ordered to move from parts of Rafah to a nearby Israel-declared humanitarian zone called Muwasi, a makeshift camp on the coast. He said that Israel has expanded the size of the zone and that it included tents, food, water and field hospitals.

It wasn’t immediately clear, however, if that material was already in place to accommodate the new arrivals.

Around 450,000 displaced Palestinians already are sheltering in Muwasi. The U.N. agency for Palestinian refugees, known as UNRWA, said it has been providing them with aid. But conditions are squalid, with few bathrooms or sanitation facilities in the largely rural area, forcing families to dig private latrines.

After the evacuation order announcement Monday, Palestinians in Rafah wrestled with having to uproot their extended families once again for an unknown fate, exhausted after months living in sprawling tent camps or crammed into schools or other shelters in and around the city. Few who spoke to The Associated Press wanted to risk staying.

Mohammed Jindiyah said that at the beginning of the war, he had tried to hold out in his home in northern Gaza after Israel ordered an evacuation there in October. He ended up suffering through heavy bombardment before fleeing to Rafah.

He’s complying with the order this time, but was unsure now whether to move to Muwasi or another town in central Gaza.

“We are 12 families, and we don’t know where to go. There is no safe area in Gaza,” he said.

Sahar Abu Nahel, who fled to Rafah with 20 family members including her children and grandchildren, wiped tears from her cheeks, despairing at a new move.

“I have no money or anything. I am seriously tired, as are the children,” she said. “Maybe it’s more honorable for us to die. We are being humiliated.”

Israeli military leaflets were dropped with maps detailing a number of eastern neighborhoods of Rafah to evacuate, warning that an attack was imminent and anyone who stays “puts themselves and their family members in danger.” Text messages and radio broadcasts repeated the message.

UNRWA won’t evacuate from Rafah so it can continue to provide aid to those who stay behind, said Scott Anderson, the agency’s director in Gaza.

“We will provide aid to people wherever they choose to be,” he told the AP.

The U.N. says an attack on Rafah could disrupt the distribution of aid keeping Palestinians alive across Gaza. The Rafah crossing into Egypt, a main entry point for aid to Gaza, lies in the evacuation zone. The crossing remained open Monday after the Israeli order.

Jan Egeland, secretary-general of the Norwegian Refugee Council, condemned the “forced, unlawful” evacuation order and the idea that people should go to Muwasi.

“The area is already overstretched and devoid of vital services,” Egeland said. He said that an Israeli assault could lead to “the deadliest phase of this war.”

Israel’s bombardment and ground offensives in Gaza have killed more than 34,700 Palestinians, around two-thirds of them children and women, according to Gaza health officials. The tally doesn’t distinguish between civilians and combatants. More than 80% of the population of 2.3 million have been driven from their homes, and hundreds of thousands in the north are on the brink of famine, according to the U.N.

Tensions escalated Sunday when Hamas fired rockets at Israeli troops positioned on the border with Gaza near Israel’s main crossing for delivering humanitarian aid, killing four soldiers. Israel shuttered the crossing — but Shoshani said it wouldn’t affect how much aid enters Gaza as others are working.

Meanwhile, Israeli airstrikes on Rafah killed 22 people, including children and two infants, according to a hospital.

The war was sparked by the unprecedented Oct. 7 raid into southern Israel in which Hamas and other terrorists killed around 1,200 people, mostly civilians, and abducted around 250 hostages. After exchanges during a November cease-fire, Hamas is believed to still hold about 100 Israelis captive as well the bodies of around 30 others.

The mediators over the cease-fire — the United States, Egypt and Qatar — appeared to scramble to salvage a cease-fire deal they had been trying to push through the past week. Egypt said it was in touch with all sides Monday to “prevent the situation from … getting out of control.”

CIA Director William Burns, who had been in Cairo for talks on the deal, headed to meet the prime minister of Qatar, an official familiar with the matter said. It wasn’t clear whether a subsequent trip to Israel that had been planned would happen. The official spoke on condition of anonymity to discuss the closed-door negotiations.

In a fiery speech Sunday evening marking Israel’s Holocaust memorial day, Netanyahu rejected international pressure to halt the war, saying that “if Israel is forced to stand alone, Israel will stand alone.”

On Monday, Netanyahu accused Hamas of “torpedoing” a deal by not budging from its demand for an end to the war and a complete Israeli troop withdrawal in return for the hostages’ release, which he called “extreme.”

Bassem Mroue reported from Beirut. Zeke Miller contributed to this report from Washington.

By LAURAN NEERGAARD (AP Medical Writer)

WASHINGTON (AP) — For the first time, researchers have identified a genetic form of late-in-life Alzheimer’s disease — in people who inherit two copies of a worrisome gene.

Scientists have long known a gene called APOE4 is one of many things that can increase people’s risk for Alzheimer’s, including simply getting older. The vast majority of Alzheimer’s cases occur after age 65. But research published Monday suggests that for people who carry not one but two copies of the gene, it’s more than a risk factor, it’s an underlying cause of the mind-robbing disease.

The findings mark a distinction with “profound implications,” said Dr. Juan Fortea, who led the study the Sant Pau Research Institute in Barcelona, Spain.

Among them: Symptoms can begin seven to 10 years sooner than in other older adults who develop Alzheimer’s.

An estimated 15% of Alzheimer’s patients carry two copies of APOE4, meaning those cases “can be tracked back to a cause and the cause is in the genes,” Fortea said. Until now, genetic forms of Alzheimer’s were thought to be only types that strike at much younger ages and account for less than 1% of all cases.

Scientists say the research makes it critical to develop treatments that target the APOE4 gene. Some doctors won’t offer the only drug that has been shown to modestly slow the disease, Leqembi, to people with the gene pair because they’re especially prone to a dangerous side effect, said Dr. Reisa Sperling, a study coauthor at Harvard-affiliated Brigham and Women’s Hospital in Boston.

Sperling hunts ways to prevent or at least delay Alzheimer’s and “this data for me says wow, what an important group to be able to go after before they become symptomatic.”

But the news doesn’t mean people should race for a gene test. “It’s important not to scare everyone who has a family history” of Alzheimer’s because this gene duo isn’t behind most cases, she told The Associated Press.

HOW DO GENETICS AFFECT ALZHEIMER’S?

More than 6 million Americans, and millions more worldwide, have Alzheimer’s. A handful of genes are known to cause rare “early-onset” forms, mutations passed through families that trigger symptoms unusually young, by age 50. Some cases also are linked to Down syndrome.

But Alzheimer’s most commonly strikes after 65, especially in the late 70s to 80s, and the APOE gene – which also affects how the body handles fats — was long known to play some role. There are three main varieties. Most people carry the APOE3 variant that appears to neither increase nor decrease Alzheimer’s risk. Some carry APOE2, which provides some protection against Alzheimer’s.

APOE4 has long been labeled the biggest genetic risk factor for late-in-life Alzheimer’s, with two copies risker than one. About 2% of the global population is estimated to have inherited a copy from each parent.

RESEARCH POINTS TO A CAUSE FOR A SUBSET OF ALZHEIMER’S

To better understand the gene’s role, Fortea’s team used data from 3,297 brains donated for research and from over 10,000 people in U.S. and European Alzheimer’s studies. They examined symptoms and early hallmarks of Alzheimer’s such as sticky amyloid in the brain.

People with two APOE4 copies were accumulating more amyloid at age 55 than those with just one copy or the “neutral” APOE3 gene variety, they reported in the journal Nature Medicine. By age 65, brain scans showed significant plaque buildup in nearly three-quarters of those double carriers – who also were more likely to have initial Alzheimer’s symptoms around that age rather than in the 70s or 80s.

Fortea said the disease’s underlying biology was remarkably similar to young inherited types.

It appears more like “a familial form of Alzheimer’s,” said Dr. Eliezer Masliah of the National Institute on Aging. “It is not just a risk factor.”

Importantly, not everyone with two APOE4 genes develops Alzheimer’s symptoms and researchers need to learn why, Sperling cautioned.

“It’s not quite destiny,” she said.

HOW THE NEW FINDINGS MAY AFFECT ALZHEIMER’S RESEARCH AND TREATMENT

The drug Leqembi works by clearing away some sticky amyloid but Sperling said it’s not clear if carriers of two APOE4 genes benefit because they have such a high risk of a side effect from the drug – dangerous brain swelling and bleeding. One research question is whether they’d do better starting such drugs sooner than other people.

Masliah said other research aims to develop gene therapy or drugs to specifically target APOE4. He said it’s also crucial to understand APOE4’s effects in diverse populations since it’s been studied mostly in white people of European ancestry.

As for gene tests, for now they’re typically used only to evaluate if someone’s a candidate for Leqembi or for people enrolling in Alzheimer’s research – especially studies of possible ways to prevent the disease. Sperling said the people most likely to carry two APOE4 genes had parents who both got Alzheimer’s relatively early, in their 60s rather than 80s.

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The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.