Alzheimer’s Disease

Polygenic risk scores add up many small genetic effects into one number, but existing Alzheimer's scores work less well outside European populations. This team built a score that excludes APOE and draws on genetic studies from European, African American, Caribbean Hispanic and East Asian groups, then tested it in independent multiancestry datasets. It was associated with Alzheimer's disease in European, African American, Caribbean Hispanic and Native American Hispanic participants, and with cognitive decline and brain changes found after death.

Copy-number variants are stretches of DNA that are duplicated or missing. Duplications of the APP gene are already known to cause inherited Alzheimer's disease, but the role of such changes in ordinary late-onset disease was unclear. Analysing the exomes of 22,319 people, this study links very rare copy-number changes in Alzheimer's-associated genes, and deletions at the chromosome region 22q11.21, to higher risk, while duplications of the same region appear to lower it.

In autosomal dominant Alzheimer's disease, families carry a variant that will cause the disease, so researchers can study what changes before symptoms and roughly when. This study measured 124 proteins in 270 blood samples from 113 people in a long-running cohort, 73 of them carriers and 40 not. The aim was to identify which proteins separate carriers from non-carriers and to place those changes in order along the years leading up to symptom onset.

Valiltramiprosate, also called ALZ-801, is an oral drug tested in a phase 3 trial restricted to people carrying two copies of APOE e4, the group at highest inherited risk. This modelling study built a simulation of amyloid build-up and hippocampal shrinkage by APOE genotype, calibrated against data from other anti-amyloid drugs, then projected treatment over two to ten years. Simulations are not trial results, but they help set expectations for how much benefit to look for.

Alzheimer's risk differs by sex and by APOE genotype, yet drug discovery rarely accounts for either. Researchers read gene activity in frontal cortex tissue donated by 369 people, split by sex and APOE genotype, to find the patterns unique to each group. They then searched a database of drug effects for approved medicines predicted to reverse those patterns, and checked the four leading candidates against insurance claims records to see whether people already taking them had less Alzheimer's.

A rare APOE variant called Christchurch has protected some members of a large Colombian family who carry a PSEN1 mutation that otherwise causes Alzheimer's in their forties. This study measured brain glucose use on PET scans in seven protected carriers against 48 typical carriers, and in 29 healthy Christchurch carriers across adulthood. Protected carriers lost brain metabolism far more slowly and held onto memory better. Understanding natural protection like this is one route toward a drug that mimics it.

A polygenic risk score estimates inherited susceptibility to Alzheimer's, but whether it also predicts how fast someone declines after diagnosis was unclear. Researchers followed 7,233 people attending a memory clinic in Barcelona for an average of 5.4 years, with 863 people from a North American study as an independent check. They measured yearly change on a standard thinking test and tested the score against it, allowing for age, education and APOE genotype.

APOE e4 is the strongest common genetic risk factor for late-onset Alzheimer's, but how common it is, and how much it matters, varies between populations, and no study had looked at Syria. Researchers sequenced the APOE gene in 52 people diagnosed with Alzheimer's and 38 cognitively healthy older adults. The e3/e4 combination appeared in about a quarter of patients and in none of the controls. The numbers are small, so the estimate is imprecise.

Two people carrying the PSEN1 E280A mutation escaped dementia for more than twenty years beyond the expected age, and one of them carries a protective variant in the RELN gene. This study examined the entorhinal cortex, one of the first regions the disease attacks, in protected and unprotected carriers alongside sporadic cases and controls. It found distinctive nerve cell and myelin-making cell populations in the protected brain, and identified a receptor that lets the altered protein act.

The Flemish mutation is a single change in the amyloid precursor protein that causes a rare, early-onset Alzheimer's disease marked by heavy amyloid deposits in blood vessel walls and unusually large plaque cores. Using cryo-electron microscopy, researchers determined the structure of amyloid filaments taken from the brains of two people, one from each of the only two known families worldwide. The filaments adopt a fold distinct from those seen in other forms of the disease.

Shrinkage in parts of the hippocampus shows up early in dementia, but not all of it is caused by Alzheimer's, because a separate age-related condition affects the same subregions. Using MRI from 1,859 people without dementia, this study tested whether a polygenic risk score for Alzheimer's, and individual risk variants, were linked to loss in two specific subregions. Separating which genetic signals drive which kind of damage matters, because the two conditions often occur together.

ABCA1 is a transporter that adds fats to apolipoprotein E, the protein made by the APOE gene, and it has long been linked to Alzheimer's disease without a clear mechanism. Drawing on three large sequencing datasets, including the Alzheimer's Disease Sequencing Project and UK Biobank, this study tested whether variants that change how well ABCA1 works alter risk differently depending on which APOE version a person carries, and looked for statistical interaction with e2 and e4.

This study asked whether the blood proteins that signal Alzheimer's risk are the same for everyone or depend on inherited risk. It followed 18,212 UK Biobank participants aged 60 and over for nearly 13 years, measuring thousands of proteins alongside APOE genotype and a polygenic risk score. Different sets of proteins predicted the disease in e4 carriers and non-carriers, with 94 not previously reported. Three proteins accounted for much of the risk carried by APOE e4 itself.

APOE comes in three common versions: e3 carries average Alzheimer's risk, e4 raises it sharply, and e2 lowers it. This work describes a silence-and-replace approach aimed at people carrying two copies of e4, using a harmless virus to deliver both a molecule that switches the e4 gene off in the brain and a working copy of the protective e2 gene. It builds on earlier mouse work showing each half worked alone. Treatment in people is still some way off.

Lecanemab can cause brain swelling or small bleeds visible on MRI, known as ARIA, and the risk rises with APOE e4 copies. Across eight Korean centres, 508 people with early Alzheimer's disease were escalated to different target drug levels according to their APOE genotype, with lower targets for e4 carriers, and monitored by MRI. The study reports how that approach affected swelling compared with bleeding, suggesting the two may arise by different mechanisms.

SORL1 is one of the strongest genetic contributors to Alzheimer's disease. It makes a sorting receptor that directs the amyloid precursor protein through the cell's internal delivery system. Using human nerve cells and three-dimensional brain organoids grown from stem cells, identical except for the SORL1 gene, researchers compared normal cells with ones carrying a single-letter change or no working copy. Losing normal SORL1 function misrouted the precursor protein, disturbed endosome transport along axons and impaired neuronal function.

An extra copy of the APP gene causes Alzheimer's disease, whether it comes as a duplication in a family or as part of the extra chromosome in Down syndrome, yet the age at which symptoms start varies widely. Researchers compared 100 people carrying an APP duplication with 957 people with Down syndrome, testing whether APOE e2 and e4 and a genetic risk score built from common Alzheimer's variants shifted that age. Onset averaged slightly earlier in duplication carriers.

African Americans face a higher risk of Alzheimer's disease and related dementias than European Americans, yet genetic risk scores have mostly been tested in European populations. This study applied a standard dementia polygenic risk score in the Chicago Health and Aging Project, 4,336 participants of whom 61% were African American, followed for an average of 8.4 years. The score predicted diagnoses less accurately in African Americans, but a high score carried greater risk.

Most of a person's Alzheimer's risk comes from many common gene variants adding up, summarised as a polygenic risk score. This study split more than 11,000 people of European ancestry by that score and then hunted for rare variants within each group. Rare risk variants turned up more often in people whose common-variant background was low, and protective ones in people whose background was high. Sorting by genetic background this way makes rare variants easier to find, including protective ones.

Polygenic risk scores add up many small genetic effects to estimate someone's Alzheimer's risk, but they have mostly been built from studies of people of European ancestry and work poorly elsewhere. This study built scores from European, African, Admixed American and East Asian data, then compared single-population, multi-population and combined models. The combined cross-ancestry model predicted best in non-European groups, and its results lined up with poorer thinking scores and with heavier amyloid and tau in the brain.

Cerebral amyloid angiopathy is amyloid in the walls of brain blood vessels rather than in brain tissue, and it raises the risk of bleeding, which matters for the new anti-amyloid drugs. Researchers examined 1,938 donated brains from people followed through studies of ageing. Moderate or severe vessel amyloid was present in 38 percent, and the odds were more than three times higher in people carrying an APOE e4 copy, rising further with age.

Blood tests for Alzheimer's are now widely used, but how much of a person's reading is inherited rather than acquired has been unclear. This Finnish study measured amyloid, tau, neurofilament and GFAP in the blood of 696 twins aged 65 to 85, none of whom had dementia. Between 39 and 66 percent of the variation in these markers was explained by genetics, and the two tau markers were also linked to thinking scores.

BACE1 is the enzyme that makes the first cut in the protein that becomes amyloid, and drugs blocking it throughout the body have failed in trials. This study tried a narrower approach in mice: a harmless virus delivering a small RNA molecule that turns BACE1 down only where it is overactive, in one part of the hippocampus. A single injection lowered amyloid and improved memory in the mice. Results in mice often do not carry over to people.

Damage to the brain's small blood vessels is common in Alzheimer's, but nobody knew whether it follows amyloid and tau or comes first. Working with donated brain tissue from people carrying the PSEN1 E280A mutation, and with mice carrying the same change, this study found the vessel changes were more severe in the inherited form. The mice showed twisted small vessels and matching protein changes without ever developing plaques or tangles, pointing to direct damage from the mutation.

Researchers grew small clusters of brain tissue, called organoids, from the stem cells of a person carrying the inherited PSEN1 A246E change that causes familial Alzheimer's disease. Recording electrical activity from day 60 onward, they saw the tissue first become overactive and unusually synchronised, then gradually quieten. The amount of amyloid beta and the size of its clumps tracked with that early overactivity. The work suggests amyloid trouble and disturbed circuit activity develop side by side rather than one simply following the other.

Doctors in Japan describe two sisters with inherited Alzheimer's disease caused by a newly identified change in the PSEN1 gene. One sister first showed depression at 39, later developed dementia and involuntary movements, and died at 51. The other developed dementia at 46 without other neurological signs. Their mother also had early onset dementia. The report is a reminder that PSEN1 changes can produce quite different symptoms even within one family, so careful long term follow up matters.

This paper reports the starting measurements and the untreated changes over time from the Alzheimer's Prevention Initiative trial in Colombia, which enrolled people aged 30 to 60 who carry the PSEN1 E280A change and had no memory problems yet. It draws on the world's largest known family with autosomal dominant Alzheimer's disease. The trial drug crenezumab did not slow the disease, but the detailed scan, spinal fluid, blood and thinking measurements described here map how the illness builds long before symptoms.

How strongly APOE4 raises Alzheimer's risk depends on ancestry, and evidence suggests its effect is weaker in American Indian communities. Working in partnership with the Bois Forte Band of Chippewa, researchers assessed tribal Elders over 54 at their own health clinic and urban office, examining white matter microstructure, an early sign of declining brain health, in relation to APOE4. Findings like these matter because personalised care built only on European data may not transfer.

The APOE gene comes in three common versions, and e4 raises dementia risk while e2 is thought to protect. Because carrying two copies of e2 is rare, its effect has been hard to measure. Pooling seven population-based cohort studies, this analysis examines how each APOE genotype relates to dementia overall and within self-reported racial groups, paying particular attention to whether the protective effect of the e2/e2 combination holds across populations.

Researchers looked at early changes in mood and behavior in 83 people who carry the PSEN1 E280A change but have no memory problems, alongside 114 relatives who do not carry it. Carriers scored higher on a behavior checklist, mainly through difficulty controlling impulses, and higher scores went with more amyloid in the brain and with concerns reported by a family member. The finding suggests subtle behavior shifts may be among the earliest visible signs in inherited Alzheimer's disease.

Almost everyone with Down syndrome develops Alzheimer's disease, largely because they carry an extra copy of the APP gene. Different forms of tau protein can be measured in spinal fluid and blood, but how each behaves in Down syndrome compared with ordinary Alzheimer's was uncertain. This study analysed 461 samples from two Spanish cohorts, covering people with Down syndrome, people without it who were cognitively healthy, and patients with sporadic Alzheimer's disease.

This case report describes a 40 year old man who developed sensory nerve damage in his limbs almost ten years before any memory problems began. Genetic testing later found a PSEN1 change causing familial early onset Alzheimer's disease. The authors say nerve damage as the first sign of inherited Alzheimer's has not been reported before, and suggest it may be part of the same underlying process. They recommend thorough nerve testing when someone from an affected family reports unexplained sensory symptoms.

Most genetic work on Alzheimer's disease has been done in European populations, so this study sequenced the genes of 29 patients from eastern India whose diagnosis was confirmed by brain imaging. The team picked out likely disease causing changes and used computer simulations to see how variants in PSEN1, SORL1 and ABCA7 alter the shape and stability of the proteins they make. Broadening genetic research to more populations matters because risk genes and their effects can differ between ancestries.

Adults with Down syndrome develop Alzheimer's brain changes by around the age of 40, because chromosome 21 carries an extra copy of the APP gene. What the separate APOE risk gene adds in this group is unclear. Researchers grew small clusters of brain tissue from the cells of people with Down syndrome and from others, then aged them. The Down syndrome clusters were smaller and built up amyloid in proportion to how much apoE protein they made.

Genes are read in sections that can be assembled in different combinations, and in Alzheimer's some of those combinations go wrong, including one in the tau gene MAPT that drives tau tangles. This preprint identifies a regulator that normally holds that faulty combination in check and is reduced in donated brains from people with Alzheimer's. Antisense drugs designed to restore its effect reduced tau pathology and memory problems in mice.

People with Down syndrome carry an extra copy of chromosome 21, which holds the APP gene, and this gives them a very high lifetime risk of Alzheimer's disease. Comparing 198 adults with Down syndrome against 172 other adults using repeated brain scans and blood tests, researchers found amyloid and tau changes start earlier and follow one another more quickly. Knowing this compressed timetable helps doctors judge when to offer treatment or enrollment in a trial.

People with Down syndrome face a high risk of Alzheimer's, and spotting the earliest decline is hard because of lifelong differences in learning. This study used blood samples from 246 participants in a long-running Down syndrome biomarker consortium, followed over 32 months. A model built from 13 blood markers, plus age, sex and APOE status, identified most of those who went on to develop mild cognitive impairment or dementia up to 16 months beforehand, though it also flagged many who stayed stable.

Alzheimer's arrives at fairly predictable ages in people with Down syndrome, which raises a blunt question: how much do scans and blood tests add over simply knowing someone's age? Using up to 461 participants and 148 different measures, researchers compared age against imaging, blood, thinking, movement and behaviour measures. Age alone separated amyloid build-up, tau build-up and mild cognitive impairment well, and nothing beat it, though it could not tell mild impairment from dementia.

High blood pressure in middle age is one of the few dementia risks a person can act on, while inherited risk cannot be changed. This long-running US community study followed Black and white participants from age 55, sorting them into low, medium and high inherited risk using a polygenic score, and tracked who developed dementia over the following decades. The question it sets out to answer is whether treating midlife hypertension matters as much for people whose inherited risk is high.

The limbic tracts, the wiring that connects memory regions, deteriorate in ageing and in Alzheimer's, but what drives that has been unclear. Combining brain scans and genetics from 2,614 older adults across seven studies, researchers showed the condition of this wiring is substantially inherited, and found genetic signals near several genes, including one active in the cells that make myelin. Activity of three of them tracked with thinking scores and Alzheimer's changes in donated brain tissue.

Gene-based treatments, which change how a gene is read rather than treating its consequences, are moving from rare childhood conditions into Alzheimer's, with more than 200 trials now across neurological disease. Getting them into the brain raises safety questions that are still being worked out. This review sets out the approaches being tried in Alzheimer's, including virus-delivered gene therapy and antisense drugs, reviews the safety records of existing trials, and argues the published safety data is too patchy to compare.

This study describes 1,010 people with Alzheimer's seen at a Tunisian hospital neurology department over 21 years, alongside their APOE genotypes. Average age at onset was 68.9 years, about two thirds reported a family history of cognitive disorder, and 30 percent reported parents who were related. Forty-seven percent carried an APOE e4 copy. Detailed pictures from populations that are rarely studied matter, because most of what is known about this gene comes from a narrow set of cohorts.

Blood tests for Alzheimer's are being adopted quickly, and this study asked whether the same result means the same thing for everyone. It followed 2,467 women aged 65 and over from a hormone therapy trial for an average of 18 years. Lower amyloid ratios and higher tau, GFAP and neurofilament all predicted later cognitive impairment or dementia, with GFAP the strongest. The tau and neurofilament links were stronger in women carrying an APOE e4 copy.

Alzheimer's that begins before 65 follows a different pattern of brain shrinkage from the more common later-onset form, and it was unclear whether spinal fluid markers track that damage. In 80 people with early-onset disease, researchers compared eight spinal fluid markers against thinning in the regions this form attacks. Neurofilament light, a general marker of nerve damage, best matched the amount of shrinkage, and combining the two explained thinking difficulties better than either alone.

People with Down syndrome develop Alzheimer's far earlier than the general population, because chromosome 21 carries the APP gene in triplicate. This review pulls together studies published from 2020 onwards on the genetics behind that. It reports Alzheimer's in more than 60 percent of people with Down syndrome over 65, an average age at diagnosis of 53, and names other genes involved alongside APP. It also sets out why diagnosis is hard alongside a lifelong intellectual disability.

Carrying APOE e4 is linked to a smaller hippocampus, but it was unresolved whether that reflects a brain that was always slightly different or a faster ongoing loss. This review combined 18 studies covering 4,311 people, then tested the pattern again over time in two separate groups. Asking whether one or two copies of the variant makes a difference, and whether the effect depends on amyloid being present, helps say what an e4 result actually predicts.

Down syndrome is described here as a genetically determined form of Alzheimer's disease, because the extra copy of chromosome 21 carries the APP gene. This review pulls together studies that measured proteins in brain tissue, spinal fluid and blood, alongside gene activity data, to map the biological pathways linking the extra chromosome to nerve cell loss. Understanding those pathways matters both for people with Down syndrome and for the wider effort to find treatments for Alzheimer's disease generally.

Rather than studying people diagnosed in clinic, this study looked at the genes of 12,509 people whose brains were examined after death, so the pathology was known for certain. It is the largest such analysis so far. APOE was linked to Alzheimer's and related pathologies but not to blood vessel damage, and twelve regions were tied to particular lesions, seven of them new. Several known Alzheimer's and Parkinson's variants were also linked to Lewy body pathology.

Genome studies have linked more than 75 genetic variants to Alzheimer's and dementia, raising hopes that a combined "polygenic risk score" could flag people at higher risk. But most scores were built mainly from people of European ancestry. This study tested several scoring methods in more than 6,000 African American, Chinese, Hispanic, and White participants and found performance varied by approach and ancestry. The work is an important step toward fair, accurate genetic risk prediction that works across diverse populations.

APOE is the strongest common gene affecting late-onset Alzheimer's, and carrying two copies of its ε4 version raises risk most. Earlier reports suggested the effect was unusually large in Japanese people (over 20-fold). This meta-analysis reappraised the data and found the risk from two ε4 copies is about 12 to 15 times higher than the common ε3 form, similar to what is seen in people of European descent. Getting these numbers right matters for accurate genetic counseling and for fairly comparing Alzheimer's risk across populations.

Researchers in China built a new mouse model carrying the human PSEN1 V97L change, which is common in Chinese families with inherited Alzheimer's disease. Unlike older models that flood the animal with extra protein, this one places the human change in its natural position in the genome. By four months the mice already showed inflammation from activated microglia, before any amyloid had built up. Memory problems, loss of nerve branches and myelin damage followed by eight months, pointing to inflammation as an early event.

Genetic studies keep pointing at immune genes in Alzheimer's, but not at which immune cells matter. This study combined gene activity measured in single immune cells from a large donor cohort with Alzheimer's genetic association data. It identified 24 genes whose effect on risk was specific to one cell type, such as monocytes, CD8 T cells or B cells, several of them involved in immune presentation. Narrowing a risk signal to a particular cell is how genetic findings start becoming drug targets.

APOE4 is the strongest common genetic risk factor for Alzheimer's disease, and it works partly through a protein called ABCA1 that helps "fatten up" APOE so it can clear debris from the brain. Drugs that switch on ABCA1 (LXR agonists) help in animal models but have caused fatty-liver side effects in people. This study screened many LXR-activating compounds to find ones that boost the beneficial brain pathway without the liver problem, an early step toward APOE-targeted Alzheimer's therapies for people at genetic risk.

APOE4 is the strongest common genetic risk factor for Alzheimer's disease. Working in mice that carry human APOE4, researchers reduced a microglial gene called Lilrb4a, either by deleting it or by using an antisense drug of the kind already used in people. Both approaches cut amyloid plaque build up in the cortex and reduced amyloid in blood vessel walls, without changing how much amyloid was produced. The microglia appeared to switch into a state better at clearing amyloid away.

Blood markers are becoming a practical way to test for Alzheimer's, so it helps to know how much family background shapes them. Researchers measured amyloid, tau, neurofilament and GFAP in the Midwestern Amish, a community with unusually well documented family trees. Inherited factors explained between 11 and 37 percent of the variation in these markers, with similar results among people who were cognitively healthy and among those carrying no APOE e4 copy.

APOE is the strongest common genetic influence on Alzheimer's risk, but the gene is also switched up or down by chemical tags on the DNA, and standard methods cannot tell which copy of the gene carries which tag. Using long-read sequencing on 332 donated brain samples from people of European, African and African admixed ancestry, this study read each copy separately. It found 18 previously unreported tagged sites tied to the e2, e4 and rs769455 variants.

New Alzheimer's drugs in Australia require APOE genotype testing, raising the question of how to share such results safely. This pilot tested a video-based protocol for disclosing APOE status to 15 cognitively healthy adults (with a family history of dementia) over several online sessions including mood and readiness checks. All completed it with no adverse events; anxiety actually fell after disclosure, and any rise in low mood stayed minor. The study suggests remote, structured genetic disclosure can be feasible and well tolerated, helping widen access to counseling.

This preprint, which has not yet been through peer review, maps genetic risk genes for Alzheimer's disease, Lewy body dementia and frontotemporal dementia onto a large atlas of where genes are switched on across organs, brain regions and cell types. All three diseases converged on nerve cells, while Alzheimer's risk genes were also concentrated in immune and liver related gene groups. The approach offers a way of asking not just which genes raise risk but where they act.

Certain variants of the TREM2 gene (R47H and R62H) raise Alzheimer's risk by changing how the brain's immune cells (microglia) respond to amyloid, while a protective variant in a related gene, CD33, blunts that risk. Studying human postmortem brain, this UK team showed the two genes interact: the protective CD33 form normalized amyloid differences in TREM2-variant carriers. The variants also shifted microglial gene activity, with R47H dampening protective responses. Untangling how these risk genes work together clarifies why they raise risk and where treatments might intervene.

Genes can be read in several different ways to make slightly different versions of a protein, a process called splicing. This study introduces a more sensitive way of measuring those versions and applies it to Alzheimer's genes across large public datasets. It establishes which forms of APP, the gene that makes amyloid precursor protein, are the main ones, and finds one form that appears mainly in immune cells. Fine detail like this can shape which version a future drug should target.

Amyloid starts building up in the brain decades before memory problems appear, so knowing who will accumulate it, and when, could guide early treatment. Researchers built two genetic scores, one for Alzheimer's risk and one for resilience, and tested them in 2,175 people with brain scans. Higher risk scores predicted both a greater chance of accumulating amyloid and reaching the threshold younger, while higher resilience scores predicted a later crossing. Both effects were separate from APOE e4.

Alzheimer's shrinks specific brain regions, yet earlier work found no overall genetic link between the disease and brain shape, which is puzzling. Using UK Biobank data from 272,513 people alongside genetic studies of 89 brain measures, this analysis looked region by region across the genome rather than genome-wide. That finer approach is designed to reveal overlaps that stay hidden when opposite-direction effects cancel each other out, and to map which shared stretches connect brain structure to late-onset disease.

This review asks whether faulty gene splicing, the editing step that decides which version of a protein a cell makes, is a cause of Alzheimer's disease or a consequence of it. The authors examine how splicing goes wrong in key genes including APP, MAPT and PSEN1 and PSEN2, and how aging, inflammation and cellular stress disturb the machinery that does the editing. They argue the evidence points both ways, and set out what research would settle the question.

Researchers turned human stem cells into the type of nerve cell that is lost early in Alzheimer's disease, comparing cells carrying two copies of the APOE4 risk gene against otherwise identical cells carrying APOE3. The APOE4 cells matured faster at first but were slower to form proper connections between neurons, and they responded differently to an inflammatory signal. Because the cells were identical apart from that one gene, the differences can be attributed to APOE4 itself.

Some of a person's Alzheimer's risk is inherited, and researchers are still mapping which gene variants contribute. This case-control study compared 95 Alzheimer's patients with 97 healthy people, testing several common variations in the SNCA gene (which makes the protein alpha-synuclein) using statistics and machine learning. A few variants were more frequent in patients, hinting they may nudge up disease risk. Findings like these help build the genetic risk picture of Alzheimer's, though they need confirmation in larger and more diverse groups.

When Alzheimer's begins before age 65, doctors often look for a genetic cause. This report describes a 59-year-old woman with biomarker-confirmed early-onset Alzheimer's whose standard genetic tests (APP, APOE, PSEN1) were negative, but who carried a variant in CHMP2B, a gene involved in the cell's waste-recycling system and usually linked to frontotemporal dementia. The authors suggest this variant may act as a "modifier" influencing her disease. Cases like this widen understanding of the genes that can shape early-onset Alzheimer's.

Most searches for Alzheimer's risk genes look at single-letter DNA changes, but the genome also contains short repeated sequences that are harder to study. Using data from about 330,000 people, this study systematically tested these "short tandem repeats" and found 15 regions linked to Alzheimer's risk, including some not clearly seen before. Mapping these overlooked kinds of genetic variation deepens understanding of the inherited component of Alzheimer's and points to new biological mechanisms behind the disease.

Does the number of APOE ε4 gene copies affect how fast mild cognitive impairment progresses to Alzheimer's dementia? Using 1,115 participants from the ADNI study, researchers tracked time to conversion by ε4 count. Median dementia-free survival was far longer for people with no ε4 copies than for those with one or two, and each additional copy raised the conversion risk substantially even after accounting for memory-region size and baseline cognition. The authors frame ε4 dose as a useful marker of progression risk, helpful for prognosis and trial planning.

This is the largest genetic study of Alzheimer's disease and related dementias to date, combining data from about 128,000 patients and 850,000 people without dementia. It confirms 91 regions of the genome linked to risk, 16 of them new. A score combining these regions, leaving out APOE, was tied mainly to Alzheimer's changes rather than other dementias, and people in the top tenth of scores had roughly twice the chance of extensive tangle and plaque pathology at death.

A person's other genes shape how Alzheimer's unfolds, but most mouse models use a single genetic background. Researchers bred Alzheimer's-model mice onto a different genetic strain and showed they develop amyloid in blood-vessel walls, vascular dysfunction, and white-matter damage that more closely mirror human disease, and that crossing in different APOE gene variants altered the severity. The model gives researchers a more realistic, genetically varied tool for studying how inherited factors influence the blood-vessel side of Alzheimer's.

People with autosomal dominant Alzheimer's carry a mutation (in PSEN1, PSEN2, or APP) that makes the disease near-certain, yet the age and way it strikes still vary. To find inherited factors that modify that course, this genome-wide study compared 101 people with these mutations against thousands of controls and identified three genetic regions tied to risk, checking their effects on blood and spinal-fluid markers, brain imaging, and age at onset. Genetic modifiers like these help explain why the same mutation plays out differently and point toward targets for therapy.

Because the APOE ε4 gene so strongly drives Alzheimer's, finding other genes that counteract its effects could reveal treatments. This large study ran a genome-wide search separately in ε4 carriers and non-carriers (nearly 448,000 people) and combined it with detailed brain cell-type data to pinpoint genes acting through specific cells, with oligodendrocytes especially prominent in carriers. Several of the genes were druggable, and the team flagged existing compounds that might be repurposed depending on a person's ε4 status. It is a step toward genetically tailored Alzheimer's therapies.

The locus coeruleus, a small brainstem hub, is among the first regions affected in Alzheimer's. This study examined the nerve-fiber tract linking it to the entorhinal cortex (a memory area) in people carrying the PSEN1-E280A mutation that causes inherited Alzheimer's. Weaker tract integrity was tied to higher tau buildup and poorer memory in mutation carriers, with tau and amyloid partly explaining the memory link as the disease advanced. The findings mark this tract as an early vulnerability worth tracking, potentially useful for timing treatment in autosomal dominant Alzheimer's.

The Dutch mutation in the APP gene causes an inherited condition in which amyloid builds up in the blood vessels of the brain. Studying mice carrying this change, researchers found that loose, non fibrous clumps of amyloid, rather than classic dense plaques, disturbed the way nerve endings release their chemical signals, and did so without detectable inflammation. The finding supports the view that smaller, soluble forms of amyloid may do more damage to communication between nerve cells than plaques do.

Doctors in China report a 43 year old woman with three years of worsening memory problems, brain scans showing widespread shrinkage, and spinal fluid results typical of Alzheimer's disease. Gene sequencing found a previously undescribed change in PSEN1, the gene most often responsible for autosomal dominant early onset Alzheimer's disease. Reports like this gradually build the catalog of which specific changes cause disease, which is what allows a laboratory to tell a family whether a variant found in testing is meaningful.

Some people who carry a strong familial-Alzheimer's mutation (in the PSEN1 gene) develop the disease later than expected, hinting at protective "modifier" genes. Researchers found that lower activity of a gene called SH3RF3 was linked to delayed Alzheimer's onset in PSEN1 carriers, and in lab studies reducing SH3RF3 calmed the inflammatory responses of microglia (the brain's immune cells). The finding points to a new potential drug target and helps explain why the same inherited mutation can affect family members differently.

The R47H change in the TREM2 gene is one of the strongest genetic risk factors for late-onset Alzheimer's. Using mice carrying this human variant, researchers found it disturbs fat and metabolite signaling not only in the brain but along a liver-blood-brain axis, with the earliest changes appearing in the liver and blood. The results suggest this Alzheimer's-risk gene has body-wide metabolic effects, and that blood-based measures might one day help track its influence.

Nearly everyone with Down syndrome carries an extra copy of the APP gene, giving them a very high genetic risk of Alzheimer's disease. The Trial-Ready Cohort-Down Syndrome (TRC-DS) enrolls healthy adults with Down syndrome, aged 25 to 55, for repeated memory testing, brain imaging, and genetic and biomarker measurements. The goal is to identify the best measures of early Alzheimer's changes so this group can join future prevention trials. It is observational. Families can ask the study team or their care team whether taking part makes sense.

This New York study is looking for the genetic factors behind dementia that begins before age 70, including Alzheimer's disease, mild cognitive impairment and other causes. It aims to enrol across all ethnic groups, which matters because most genetic findings so far come from people of European ancestry and do not always transfer. Both risk of developing the condition and how it progresses are being examined. It is recruiting.

This study tests whether an investigational drug, NIO752, lowers the brain's production of tau, a protein that, in Alzheimer's disease, clumps into tangles inside nerve cells and drives symptoms. It uses a labelling technique (SILK) to measure tau production directly, and includes people with autosomal-dominant Alzheimer's caused by PSEN1, PSEN2 or APP mutations. Participants aged 21 to 80 with mild-to-moderate Alzheimer's may qualify. It is an early-stage study of a tau-lowering approach; talk with your care team about whether a trial like this fits you.

This trial focuses on members of the large Colombian family that carries the PSEN1 E280A gene mutation, which causes autosomal-dominant Alzheimer's disease. It studies whether the amyloid-clearing antibody donanemab, an experimental drug called RG6289, or their combination can remove or prevent amyloid-plaque build-up in the brain, measured by PET imaging over up to 18 months. Mutation carriers aged 25 to 65 are the focus. The study is not yet open for enrollment. Any decisions about genetic testing or treatment should be made with your own specialists.

This observational study in Beijing follows people under 65 who have Alzheimer's disease and a family history of it, while they receive lecanemab at 10 mg per kilogram every two weeks for 18 months. Participants have cognitive assessments, PET and MRI scans, blood and fluid tests, and whole genome sequencing. The aim is to see how inherited factors affect how well the treatment works in early-onset familial disease. It is recruiting.