Six guidelines to navigate the Aduhelm controversy and (hopefully) help patients with Mild Cognitive Impairment and early-stage Alzheimer’s Disease

The approval of a con­tro­ver­sial new drug for Alzheimer’s dis­ease, Aduhelm, is shin­ing a spot­light on mild cog­ni­tive impair­ment — prob­lems with mem­o­ry, atten­tion, lan­guage or oth­er cog­ni­tive tasks that exceed changes expect­ed with nor­mal aging.

After ini­tial­ly indi­cat­ing that Aduhelm could be pre­scribed to any­one with demen­tia, the Food and Drug Admin­is­tra­tion now spec­i­fies that the pre­scrip­tion drug be giv­en to indi­vid­u­als with mild cog­ni­tive impair­ment or ear­ly-stage Alzheimer’s, the groups in which the med­ica­tion was studied.

Yet this nar­row­er rec­om­men­da­tion rais­es ques­tions. What does a diag­no­sis of mild cog­ni­tive impair­ment mean? Is Aduhelm appro­pri­ate for all peo­ple with mild cog­ni­tive impair­ment, or only some? And who should decide which patients qual­i­fy for treat­ment: demen­tia spe­cial­ists or pri­ma­ry care physicians?

Con­tro­ver­sy sur­rounds Aduhelm because its effec­tive­ness hasn’t been proved, its cost is high (an esti­mat­ed $56,000 a year, not includ­ing expens­es for imag­ing and month­ly infu­sions), and its poten­tial side effects are sig­nif­i­cant (41% of patients in the drug’s clin­i­cal tri­als expe­ri­enced brain swelling and bleeding).

Fur­ther­more, an FDA advi­so­ry com­mit­tee strong­ly rec­om­mend­ed against Aduhelm’s approval, and Con­gress is inves­ti­gat­ing the process lead­ing to the FDA’s deci­sion. Medicare is study­ing whether it should cov­er the med­ica­tion, and the Depart­ment of Vet­er­ans Affairs has declined to do so under most circumstances.

Clin­i­cal tri­als for Aduhelm exclud­ed peo­ple over age 85; those tak­ing blood thin­ners; those who had expe­ri­enced a stroke; and those with car­dio­vas­cu­lar dis­ease or impaired kid­ney or liv­er func­tion, among oth­er con­di­tions. If those cri­te­ria were broad­ly applied, 85% of peo­ple with mild cog­ni­tive impair­ment would not qual­i­fy to take the med­ica­tion, accord­ing to a new research let­ter in the Jour­nal of the Amer­i­can Med­ical Association.

Giv­en these con­sid­er­a­tions, care­ful­ly select­ing patients with mild cog­ni­tive impair­ment who might respond to Aduhelm is “becom­ing a pri­or­i­ty,” said Dr. Ken­neth Lan­ga, a pro­fes­sor of med­i­cine, health man­age­ment and pol­i­cy at the Uni­ver­si­ty of Michigan.

Dr. Ronald Petersen, who directs the Mayo Clinic’s Alzheimer’s Dis­ease Research Cen­ter, said, “One of the biggest issues we’re deal­ing with since Aduhelm’s approval is, ‘Are appro­pri­ate patients going to be giv­en this drug?’”

Here’s what peo­ple should know about mild cog­ni­tive impair­ment based on a review of research stud­ies and con­ver­sa­tions with lead­ing experts.

1. The Basics. Mild cog­ni­tive impair­ment is often referred to as a bor­der­line state between nor­mal cog­ni­tion and demen­tia. But this can be mis­lead­ing. Although a sig­nif­i­cant num­ber of peo­ple with mild cog­ni­tive impair­ment even­tu­al­ly devel­op demen­tia — usu­al­ly Alzheimer’s dis­ease — many do not.

Cog­ni­tive symp­toms — for instance, dif­fi­cul­ties with short-term mem­o­ry or plan­ning — are often sub­tle but they per­sist and rep­re­sent a decline from pre­vi­ous func­tion­ing. Yet a per­son with the con­di­tion may still be work­ing or dri­ving and appear entire­ly nor­mal. By def­i­n­i­tion, mild cog­ni­tive impair­ment leaves intact a person’s abil­i­ty to per­form dai­ly activ­i­ties independently.

Accord­ing to an Amer­i­can Acad­e­my of Neu­rol­o­gy review of dozens of stud­ies, pub­lished in 2018, mild cog­ni­tive impair­ment affects near­ly 7% of peo­ple ages 60 to 64, 10% of those 70 to 74 and 25% of 80- to 84-year-olds.

2. The Caus­es. Mild cog­ni­tive impair­ment can be caused by bio­log­i­cal process­es (the accu­mu­la­tion of amy­loid beta and tau pro­teins and changes in the brain’s struc­ture) linked to Alzheimer’s dis­ease. Between 40% and 60% of peo­ple with mild cog­ni­tive impair­ment have evi­dence of Alzheimer’s‑related brain pathol­o­gy, accord­ing to a 2019 review.

But cog­ni­tive symp­toms can also be caused by oth­er fac­tors, includ­ing small strokes; poor­ly man­aged con­di­tions such as dia­betes, depres­sion and sleep apnea; respons­es to med­ica­tions; thy­roid dis­ease; and unrec­og­nized hear­ing loss. When these issues are treat­ed, nor­mal cog­ni­tion may be restored or fur­ther decline forestalled.

3. The Sub­types. Dur­ing the past decade, experts have iden­ti­fied four sub­types of mild cog­ni­tive impair­ment. Each sub­type appears to car­ry a dif­fer­ent risk of pro­gress­ing to Alzheimer’s dis­ease, but pre­cise esti­mates haven’t been established.

Peo­ple with mem­o­ry prob­lems and mul­ti­ple med­ical issues who are found to have changes in their brain through imag­ing tests are thought to be at great­est risk. “If bio­mark­er tests con­verge and show abnor­mal­i­ties in amy­loid, tau and neu­rode­gen­er­a­tion, you can be pret­ty cer­tain a per­son with MCI has the begin­nings of Alzheimer’s in their brain and that dis­ease will con­tin­ue to evolve,” said Dr. Howard Chertkow, chair­per­son for cog­ni­tive neu­rol­o­gy and inno­va­tion at Bay­crest, an aca­d­e­m­ic health sci­ences cen­ter in Toron­to that spe­cial­izes in care for old­er adults.

4. The Diag­no­sis. Usu­al­ly, this process begins when old­er adults tell their doc­tors that “some­thing isn’t right with my mem­o­ry or my think­ing” — a so-called sub­jec­tive cog­ni­tive com­plaint. Short cog­ni­tive tests can con­firm whether objec­tive evi­dence of impair­ment exists. Oth­er tests can deter­mine whether a per­son is still able to per­form dai­ly activ­i­ties successfully.

More sophis­ti­cat­ed neu­ropsy­cho­log­i­cal tests can be help­ful if there is uncer­tain­ty about find­ings or a need to bet­ter assess the extent of impair­ment. But “there is a short­age of physi­cians with exper­tise in demen­tia — neu­rol­o­gists, geri­a­tri­cians, geri­atric psy­chi­a­trists” — who can under­take com­pre­hen­sive eval­u­a­tions, said Kathryn Phillips, direc­tor of health ser­vices research and health eco­nom­ics at the Uni­ver­si­ty of Cal­i­for­nia-San Fran­cis­co School of Pharmacy.

The most impor­tant step is tak­ing a care­ful med­ical his­to­ry that doc­u­ments whether a decline in func­tion­ing from an individual’s base­line has occurred and inves­ti­gat­ing pos­si­ble caus­es such as sleep pat­terns, men­tal health con­cerns and inad­e­quate man­age­ment of chron­ic con­di­tions that need attention.

Mild cog­ni­tive impair­ment “isn’t nec­es­sar­i­ly straight­for­ward to rec­og­nize, because people’s think­ing and mem­o­ry changes over time [with advanc­ing age] and the ques­tion becomes ‘Is this some­thing more than that?’” said Dr. Zoe Arvan­i­takis, a neu­rol­o­gist and direc­tor of Rush University’s Rush Mem­o­ry Clin­ic in Chicago.

More than one set of tests is need­ed to rule out the pos­si­bil­i­ty that some­one per­formed poor­ly because they were ner­vous or sleep-deprived or had a bad day. “Admin­is­ter­ing tests to peo­ple over time can do a pret­ty good job of iden­ti­fy­ing who’s actu­al­ly declin­ing and who’s not,” Lan­ga said.

5. Pro­gres­sion. Mild cog­ni­tive impair­ment doesn’t always progress to demen­tia, nor does it usu­al­ly do so quick­ly. But this isn’t well under­stood. And esti­mates of pro­gres­sion vary, based on whether patients are seen in spe­cial­ty demen­tia clin­ics or in com­mu­ni­ty med­ical clin­ics and how long patients are followed.

A review of 41 stud­ies found that 5% of patients treat­ed in com­mu­ni­ty set­tings each year went on to devel­op demen­tia. For those seen in demen­tia clin­ics — typ­i­cal­ly, patients with more seri­ous symp­toms — the rate was 10%. The Amer­i­can Acad­e­my of Neurology’s review found that after two years 15% of patients were observed to have dementia.

Pro­gres­sion to demen­tia isn’t the only path peo­ple fol­low. A siz­able por­tion of patients with mild cog­ni­tive impair­ment — from 14% to 38% — are dis­cov­ered to have nor­mal cog­ni­tion upon fur­ther test­ing. Anoth­er por­tion remains sta­ble over time. (In both cas­es, this may be because under­ly­ing risk fac­tors — poor sleep, for instance, or poor­ly con­trolled dia­betes or thy­roid dis­ease — have been addressed.) Still anoth­er group of patients fluc­tu­ate, some­times improv­ing and some­times declin­ing, with peri­ods of sta­bil­i­ty in between.

You real­ly need to fol­low peo­ple over time — for up to 10 years — to have an idea of what is going on with them,” said Dr. Oscar Lopez, direc­tor of the Alzheimer’s Dis­ease Research Cen­ter at the Uni­ver­si­ty of Pittsburgh.

6. Spe­cial­ists ver­sus gen­er­al­ists. Only peo­ple with mild cog­ni­tive impair­ment asso­ci­at­ed with Alzheimer’s should be con­sid­ered for treat­ment with Aduhelm, experts agreed. “The ques­tion you want to ask your doc­tor is, ‘Do I have MCI [mild cog­ni­tive impair­ment] due to Alzheimer’s dis­ease?’” Chertkow said.

Because this med­ica­tion tar­gets amy­loid, a sticky pro­tein that is a hall­mark of Alzheimer’s, con­fir­ma­tion of amy­loid accu­mu­la­tion through a PET scan or spinal tap should be a pre­req­ui­site. But the pres­ence of amy­loid isn’t deter­mi­na­tive: One-third of old­er adults with nor­mal cog­ni­tion have been found to have amy­loid deposits in their brains.

Because of these com­plex­i­ties, “I think, for the ear­ly roll­out of a com­plex drug like this, treat­ment should be over­seen by spe­cial­ists, at least ini­tial­ly,” said Petersen of the Mayo Clin­ic. Arvan­i­takis of Rush Uni­ver­si­ty agreed. “If some­one is real­ly and tru­ly inter­est­ed in try­ing this med­ica­tion, at this point I would rec­om­mend it be done under the care of a psy­chi­a­trist or neu­rol­o­gist or some­one who real­ly spe­cial­izes in cog­ni­tion,” she said.

– By Judith Gra­ham. This sto­ry was pro­duced by KHN, a nation­al news­room that pro­duces in-depth jour­nal­ism about health issues. Togeth­er with Pol­i­cy Analy­sis and Polling, KHN is one of the three major oper­at­ing pro­grams at KFF (Kaiser Fam­i­ly Foundation). 

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